Assessing the pattern electroretinogram as a proxy measure for dopamine in the context of iron deficiency.

OBJECTIVES: Animal studies have suggested that dietary iron deficiency (ID) negatively affects dopamine (DA) synthesis and re-uptake, which in turn negatively affects memory and cognition. This study was intended to assess whether the pattern electroretinogram (pattern ERG) could be used as an indirect measure of DA in college-age women with and without ID by determining the extent to which features of the ERG were sensitive to iron status and were related to other indirect measures of DA. METHODS: The pattern ERG was measured in 21 iron deficient non-anemic (IDNA) and 21 iron sufficient (IS) women, who also performed a contrast detection and probabilistic selection task, both with concurrent electroencephalography (EEG). Both spontaneous and task-related blink rates were also measured. RESULTS: The implicit times of the A- and B-waves were significantly longer for the IDNA than for the IS women. Both the amplitudes and implicit times of the A- and B-waves were significantly correlated with levels of serum ferritin (sFt). Only the amplitude of the A-wave was correlated with spontaneous blink rate. It was possible to accurately identify a woman's iron status solely on the basis of the implicit time of the B-wave. Finally, the implicit times of the ERG features mediated the relationship between iron levels and accuracy in the probabilistic selection task. CONCLUSIONS: Results suggest the utility of the pattern ERG in testing the hypothesis that iron deficiency affects DA levels in humans and that this may be one of the mechanisms by which iron deficiency negatively affects cognition.

Electrophysiological resting state brain network and episodic memory in healthy aging adults.

Recent studies have emphasized the changes in large-scale brain networks related to healthy aging, with the ultimate purpose to aid in differentiating normal neurocognitive aging from neurodegenerative disorders that also arise with age. Emerging evidence from functional Magnetic Resonance Imaging (fMRI) indicates that connectivity patterns within specific brain networks, especially the Default Mode Network (DMN), distinguish those with Alzheimer's disease from healthy individuals. In addition, disruptive alterations in the large-scale brain systems that support high-level cognition are shown to accompany cognitive decline at the behavioral level, which is commonly observed in the aging populations, even in the absence of disease. Although fMRI is useful for assessing functional changes in brain networks, its high costs and limited accessibility discourage studies that need large populations. In this study, we investigated the aging-effect on large-scale networks of the human brain using high-density electroencephalography and electrophysiological source imaging, which is a less costly and more accessible alternative to fMRI. In particular, our study examined a group of healthy subjects in the age range from middle- to older-aged adults, which is an under-studied range in the literature. Employing a high-resolution computation model, our results revealed age associations in the connectivity pattern of DMN in a consistent manner with previous fMRI findings. Particularly, in combination with a standard battery of cognitive tests, our data showed that in the posterior cingulate / precuneus area of DMN higher brain connectivity was associated with lower performance on an episodic memory task. The findings demonstrate the feasibility of using electrophysiological imaging to characterize large-scale brain networks and suggest that changes in network connectivity are associated with normal aging.

Modeling relationships between iron status, behavior, and brain electrophysiology: evidence from a randomized study involving a biofortified grain in Indian adolescents.

BACKGROUND: Iron deficiency (ID) and iron deficiency anemia (IDA) are highly-prevalent nutrient deficiencies and have been shown to have a range of negative effects on cognition and brain function. Human intervention studies including measures at three levels-blood, brain, and behavior-are rare and our objective was to model the relationships among measures at these three levels in school-going Indian adolescents. METHODS: Male and female adolescents in rural India were screened for ID/IDA. Subjects consumed 2 meals/day for 6 months; half were randomly assigned to consume meals made from a standard grain (pearl millet) and half consumed meals made from an iron biofortified pearl millet (BPM). Prior to and then at the conclusion of the feeding trial, they completed a set of cognitive tests with concurrent electroencephalography (EEG). RESULTS: Overall, serum ferritin (sFt) levels improved over the course of the study. Ten of 21 possible measures of cognition showed improvements from baseline (BL) to endline (EL) that were larger for those consuming BPM than for those consuming the comparison pearl millet (CPM). Critically, the best model for the relationship between change in iron status and change in cognition had change in brain measures as a mediating factor, with both change in serum ferritin as a primary predictor and change in hemoglobin as a moderator. CONCLUSIONS: A dietary intervention involving a biofortified staple grain was shown to be efficacious in improving blood iron biomarkers, behavioral measures of cognition, and EEG measures of brain function. Modeling the relationships among these variables strongly suggests multiple mechanisms by which blood iron level affects brain function and cognition. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, NCT02152150 , 02 June 2014.

Identifying Electronic Nicotine Delivery System Brands and Flavors on Instagram: Natural Language Processing Analysis.

BACKGROUND: Electronic nicotine delivery system (ENDS) brands, such as JUUL, used social media as a key component of their marketing strategy, which led to massive sales growth from 2015 to 2018. During this time, ENDS use rapidly increased among youths and young adults, with flavored products being particularly popular among these groups. OBJECTIVE: The aim of our study is to develop a named entity recognition (NER) model to identify potential emerging vaping brands and flavors from Instagram post text. NER is a natural language processing task for identifying specific types of words (entities) in text based on the characteristics of the entity and surrounding words. METHODS: NER models were trained on a labeled data set of 2272 Instagram posts coded for ENDS brands and flavors. We compared three types of NER models-conditional random fields, a residual convolutional neural network, and a fine-tuned distilled bidirectional encoder representations from transformers (FTDB) network-to identify brands and flavors in Instagram posts with key model outcomes of precision, recall, and F1 scores. We used data from Nielsen scanner sales and Wikipedia to create benchmark dictionaries to determine whether brands from established ENDS brand and flavor lists were mentioned in the Instagram posts in our sample. To prevent overfitting, we performed 5-fold cross-validation and reported the mean and SD of the model validation metrics across the folds. RESULTS: For brands, the residual convolutional neural network exhibited the highest mean precision (0.797, SD 0.084), and the FTDB exhibited the highest mean recall (0.869, SD 0.103). For flavors, the FTDB exhibited both the highest mean precision (0.860, SD 0.055) and recall (0.801, SD 0.091). All NER models outperformed the benchmark brand and flavor dictionary look-ups on mean precision, recall, and F1. Comparing between the benchmark brand lists, the larger Wikipedia list outperformed the Nielsen list in both precision and recall. CONCLUSIONS: Our findings suggest that NER models correctly identified ENDS brands and flavors in Instagram posts at rates competitive with, or better than, others in the published literature. Brands identified during manual annotation showed little overlap with those in Nielsen scanner data, suggesting that NER models may capture emerging brands with limited sales and distribution. NER models address the challenges of manual brand identification and can be used to support future infodemiology and infoveillance studies. Brands identified on social media should be cross-validated with Nielsen and other data sources to differentiate emerging brands that have become established from those with limited sales and distribution.

Obinutuzumab for the First-Line Treatment of Follicular Lymphoma.

BACKGROUND: Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma. METHODS: We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS: Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).

Changes in Iron Status Are Related to Changes in Brain Activity and Behavior in Rwandan Female University Students: Results from a Randomized Controlled Efficacy Trial Involving Iron-Biofortified Beans.

BACKGROUND: Evidence suggests that iron deficiency (ID) affects cognitive performance, as measured in behavior. Although such effects must be mediated by changes in the brain, very few studies have included measures of brain activity to assess this relation. OBJECTIVE: We tested the hypothesis that provision of iron-biofortified beans would result in improvements in measures of iron status, brain dynamics, and behavior. METHODS: A double-blind, randomized, intervention study was conducted in 55 women aged 18-27 y with low iron status (serum ferritin <20 µg/L). Women were randomly assigned to consume iron-biofortified (86.1 ppm iron) or comparison beans (50.1 ppm iron) daily for 18 wk. Iron status was assessed by hemoglobin, ferritin, transferrin receptor, and body iron; cognitive performance with 5 computerized tasks; and brain dynamics by concurrent electroencephalography (EEG). All measures were taken at baseline and endline. RESULTS: The groups did not differ on any measures at baseline. Intention-to-treat analyses revealed significant (all P < 0.05) improvements in hemoglobin (partial effect size attributable to the independent variable, η2 = 0.16), ferritin (η2 = 0.17), and body iron (η2 = 0.10), speed of responding in attentional and mnemonic tasks (η2 = 0.04-0.29), sensitivity and efficiency of memory retrieval (η2 = 0.12-0.55), and measures of EEG amplitude and spectral power (η2 = 0.08 to 0.49). Mediation models provided evidence in support of the hypothesis that changes in iron status produce changes in behavior by way of changes in brain activity. CONCLUSIONS: Behavioral performance and brain activity, as measured by EEG, are sensitive to iron status, and the consumption of iron-biofortified beans for 18 wk resulted in improvements in measures of both, relative to what was obtained with a comparison bean, in a sample of female university students. Furthermore, the results support the conclusion that changes in brain activity resulting from consumption of biofortified beans mediate the relations between changes in iron biomarkers and changes in cognition. Clinical trial registry: ClinicalTrials.gov Reg No. NCT01594359.

Effect of iron deficiency on simultaneous measures of behavior, brain activity, and energy expenditure in the performance of a cognitive task.

OBJECTIVES: Iron deficiency (ID) - the highly prevalent nutritional deficiency - has been shown to have deleterious effects on measures of cognitive performance and brain activity. Many of these results are suggestive of the impact of ID on neurotransmitter regulation and myelination. A third critical potential effect of ID on brain function is at the level of brain energy expenditure; however, to date there has not been any method for indirectly estimating the impact of ID on energy expenditure in humans in the context of cognitive work. METHODS: We report here a study comparing ID and iron sufficient (IS) college students in which simultaneous behavioral, encephelographic (EEG), and metabolic data were collected in a task designed as a cognitive analog to standard physical exertion tasks. RESULTS: We show that increases in cognitive demands produced decrements in behavioral measures of performance, and increases in EEG and metabolic measures of work. Critically, we found that the magnitudes of those changes were directly related to iron levels. DISCUSSION: We find support for the idea that brain activity mediates the relationship between cognitive demands and energy expenditure, with ferritin and hemoglobin moderating those relationships in distinct ways. Finally, we show that levels of energy expenditure can be indirectly estimated by measures of EEG spectral power.

Supplementing a survey with respondent Twitter data to measure e-cigarette information exposure.

Social media data are increasingly used by researchers to gain insights on individuals' behaviors and opinions. Platforms like Twitter provide access to individuals' postings, networks of friends and followers, and the content to which they are exposed. This article presents the methods and results of an exploratory study to supplement survey data with respondents' Twitter postings, networks of Twitter friends and followers, and information to which they were exposed about e-cigarettes. Twitter use is important to consider in e-cigarette research and other topics influenced by online information sharing and exposure. Further, Twitter metadata provide direct measures of user's friends and followers as opposed to survey self-reports. We find that Twitter metadata provide similar information to survey questions on Twitter network size without inducing recall error or other measurement issues. Using sentiment coding and machine learning methods, we find Twitter can elucidate on topics difficult to measure via surveys such as online expressed opinions and network composition. We present and discuss models predicting whether respondents' tweet positively about e-cigarettes using survey and Twitter data, finding the combined data to provide broader measures than either source alone.

Cognitive Performance in Indian School-Going Adolescents Is Positively Affected by Consumption of Iron-Biofortified Pearl Millet: A 6-Month Randomized Controlled Efficacy Trial.

BACKGROUND: Iron deficiency remains the most prevalent micronutrient deficiency globally, but few studies have examined how iron status relates to cognition in adolescents. Iron biofortification of staple food crops is being scaled up, yet it is unknown whether consuming biofortified crops can benefit cognition. Objective: Our objective was to determine the efficacy of iron-biofortified pearl millet in improving attention and memory in Indian school-going adolescents. Methods: A double-blind, randomized, intervention study was conducted in 140 Indian boys and girls, aged 12-16 y, who were assigned to consume iron-biofortified [Fe = 86 parts per million (ppm)] or conventional (Fe = 21-52 ppm) pearl millet. Hemoglobin, ferritin, and transferrin receptor (TfR) were measured and body iron (BI) was calculated at baseline and after 4 and 6 mo. Five measures of cognitive function were obtained at baseline and 6 mo: simple reaction time (SRT), Go/No-Go (GNG) task, Attentional Network Task (ANT), Composite Face Effect (CFE) task, and Cued Recognition Task (CRT). Intention-to-treat analysis was used. Results: Daily iron intake from pearl millet was higher in those consuming biofortified compared with conventional pearl millet (19.6 compared with 4.8 mg/d). Effects on ferritin, TfR, and BI at 4 mo, and on TfR at 6 mo (all P < 0.05), indicated efficacy of biofortified pearl millet over conventional pearl millet in improving iron status. Compared with conventional pearl millet, the consumption of biofortified pearl millet resulted in greater improvement in attention (SRT, GNG, and ANT) and memory (CFE and CRT). Reaction time decreased twice as much from 0 to 6 mo in those consuming biofortified compared with conventional pearl millet on attention tasks (SRT: -123 compared with -63 ms; GNG: -67 compared with -30 ms; ANT double cue: -74 compared with -32 ms; all P < 0.01). Conclusion: Consuming iron-biofortified pearl millet improves iron status and some measures of cognitive performance in Indian adolescents. This trial was registered at http://www.clinicaltrials.gov as NCT02152150.

Converging operations and the role of perceptual and decisional influences on the perception of faces: Neural and behavioral evidence.

Theoretical analyses suggest that the regularities indicative of holistic processing can be obtained by combinations of perceptual and decisional factors. Kuefner and colleagues used electrophysiological results to suggest that the composite face effect is driven solely by perceptual factors. Two limitations of their approach are (a) it did not involve behavioral measures of perceptual sensitivity or bias, and (b) it is unclear how the measures used in that study are consistent with other measures of perceptual and decisional processing. Eight observers completed three tasks involving the stimuli used by Kuefner et al.. The first was a direct replication. The second was a complete identification task, associated with the perceptual and decisional distinctions formalized in general recognition theory. The third was an implementation of the Eriksen fianker task, which allows for a pattern of results that have been interpreted in terms of perceptual and decisional influences. While the empirical distinctions used by Kuefner et al. were not consistent with either the EEG data from the other tasks or the established behavioral measures of perceptual sensitivity and decisional bias, the inferences drawn from the EEG and behavioral data from those tasks were consistent with one another, underscoring the importance of converging operations.

Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.

BACKGROUND: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. METHODS: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. RESULTS: The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. CONCLUSIONS: Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).

Consumption of Iron-Biofortified Beans Positively Affects Cognitive Performance in 18- to 27-Year-Old Rwandan Female College Students in an 18-Week Randomized Controlled Efficacy Trial.

Background: Evidence shows that iron deficiency in adulthood may affect cognitive performance, possibly by disrupting neurotransmitter regulation or brain energy metabolism. Women of reproductive age (WRA) are among those who are most vulnerable to iron deficiency; however, they have been largely ignored in the literature relating iron status to cognition.Objective: Our aim was to determine the efficacy of iron-biofortified beans in improving cognition in WRA compared with control beans.Methods: A double-blind, randomized intervention study was conducted in 150 women aged 18-27 y with low iron status (ferritin <20 µg/L). Women were randomly assigned to consume iron-biofortified beans (86.1 ppm iron) or control beans (50.1 ppm iron) daily for 18 wk. Iron status was assessed based on hemoglobin, ferritin, transferrin receptor, and body iron values and on cognitive performance on 5 computerized tasks at baseline and endline.Results: Groups did not differ on any variables at baseline. Per protocol analyses revealed that consumption of the biofortified beans resulted in a 17% larger improvement in the speed of spatial selective attention; a nearly 7-fold larger improvement in the speed, a 68% greater improvement in the efficiency, and a >2-fold greater improvement in the specificity of memory retrieval; and a >2-fold larger improvement in the speed and a >3-fold larger improvement in the efficiency of memory search-all of which are relative to consumption of the control beans (P < 0.01 for all comparisons).Conclusions: Cognitive performance is sensitive to iron status, and consumption of iron-biofortified beans for 18 wk improved cognitive performance, especially the efficiency of search and the speed of retrieval on memory tasks, in young adult women. This trial was registered at clinicaltrials.gov as NCT01594359.

Consumption of a Double-Fortified Salt Affects Perceptual, Attentional, and Mnemonic Functioning in Women in a Randomized Controlled Trial in India.

Background: Iron deficiency and iron deficiency anemia have been shown to have negative effects on aspects of perception, attention, and memory.Objective: The purpose of this investigation was to assess the extent to which increases in dietary iron consumption are related to improvements in behavioral measures of perceptual, attentional, and mnemonic function.Methods: Women were selected from a randomized, double-blind, controlled food-fortification trial involving ad libitum consumption of either a double-fortified salt (DFS) containing 47 mg potassium iodate/kg and 3.3 mg microencapsulated ferrous fumarate/g (1.1 mg elemental Fe/g) or a control iodized salt. Participants' blood iron status (primary outcomes) and cognitive functioning (secondary outcomes) were assessed at baseline and after 10 mo at endline. The study was performed on a tea plantation in the Darjeeling district of India. Participants (n = 126; 66% iron deficient and 49% anemic at baseline) were otherwise healthy women of reproductive age, 18-55 y.Results: Significant improvements were documented for iron status and for perceptual, attentional, and mnemonic function in the DFS group (percentage of variance accounted for: 16.5%) compared with the control group. In addition, the amount of change in perceptual and cognitive performance was significantly (P < 0.05) related to the amount of change in blood iron markers (mean percentage of variance accounted for: 16.0%) and baseline concentrations of blood iron markers (mean percentage of variance accounted for: 25.0%). Overall, there was evidence that the strongest effects of change in iron status were obtained for perceptual and low-level attentional function.Conclusion: DFS produced measurable and significant improvements in the perceptual, attentional, and mnemonic performance of Indian female tea pickers of reproductive age. This trial was registered at clinicaltrials.gov as NCT01032005.

Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study.

GAUGUIN evaluated the safety and efficacy of obinutuzumab (GA101) monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In phase 1 (dose escalation), 13 patients received obinutuzumab 400 to 1200 mg (days 1 and 8 of cycle 1; day 1 of cycles 2-8). In phase 2, 20 patients received a fixed dose of 1000 mg (days 1, 8, and 15 of cycle 1; day 1 of cycles 2-8). Infusion-related reactions occurred in nearly all patients, but few were grade 3/4. Grade 3/4 neutropenia occurred in 7 patients in phase 1 (but was not dose-related) and in 4 patients in phase 2. Overall end-of-treatment response (all partial responses) was 62% (phase 1) and 15% (phase 2); best overall response was 62% and 30%, respectively. Phase 2 median progression-free survival was 10.7 months and median duration of response was 8.9 months. In summary, obinutuzumab monotherapy is active in patients with heavily pretreated relapsed/refractory CLL.

Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, ß2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia.

Addition of rituximab (R) to fludarabine and cyclophosphamide (FC) has significantly improved patient outcomes in chronic lymphocytic leukemia (CLL). Whether baseline gene expression can identify patients who will benefit from immunochemotherapy over chemotherapy alone has not been determined. We assessed genome-wide expression of 300 pretreatment specimens from a subset of 552 patients in REACH, a study of FC or R-FC in relapsed CLL. An independent test set was derived from 282 pretreatment specimens from CLL8, a study of FC or R-FC in treatment-naïve patients. Genes specific for benefit from R-FC were determined by assessing treatment-gene interactions in Cox proportional hazards models. REACH patients with higher pretreatment protein tyrosine kinase 2 (PTK2) messenger RNA levels derived greater benefit from R-FC, with significant improvements in progression-free survival, independent of known prognostic factors in a multivariate model. Examination of PTK2 gene expression in CLL8 patients yielded similar results. Furthermore, PTK2 inhibition blunted R-dependent cell death in vitro. This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials. These trials were registered at www.clinicaltrials.gov as #NCT00090051 (REACH) and #NCT00281918 (CLL8).

Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma.

Obinutuzumab (GA101) is a type II, glycoengineered anti-CD20 monoclonal antibody for the treatment of hematologic malignancies. Obinutuzumab has mechanisms of action that are distinct from those of rituximab, potentially translating into improved clinical efficacy. We present the pharmacokinetic and clinical data from the phase I/II GAUGUIN and phase I GAUDI studies that were used to identify the obinutuzumab dose and regimen undergoing phase III assessment. In phase I (GAUGUIN and GAUDI), non-Hodgkin lymphoma patients received up to a maximum 9 fixed doses (obinutuzumab 50-2000 mg). In GAUGUIN phase II, patients received obinutuzumab 400/400 mg or 1600/800 mg [first dose day (D)1, D8, cycle (C) 1; second dose D1, C2-C8]. The influence of demographic factors on pharmacokinetics and drug exposure on tumor response and toxicity were analyzed using exploratory graphical analyses. Obinutuzumab serum concentrations with 1600/800 mg were compared with a 1000 mg fixed-dose regimen (D1, D8 and D15, C1; D1, C2-C8) using pharmacokinetic modeling simulations. Factors related to CD20-antigenic mass were more influential on obinutuzumab pharmacokinetics with 400/400 versus 1600/800 mg. Higher serum concentrations were observed with 1600/800 versus 400/400 mg, irrespective of CD20-antigenic mass. Tumor shrinkage was greater with 1600/800 versus 400/400 mg; there was no significant increase in adverse events. Fixed dose 1000 mg with an additional C1 infusion resulted in similar serum concentrations to 1600/800 mg in model-based analyses. The obinutuzumab 1000 mg fixed-dose regimen identified in this exploratory analysis was confirmed in a full covariate analysis of a larger dataset, and is undergoing phase III evaluation. GAUGUIN and GAUDI are registered at www.clinicaltrials.gov (clinicaltrials.gov identifier:00517530 and 00825149, respectively).

Consuming Iron Biofortified Beans Increases Iron Status in Rwandan Women after 128 Days in a Randomized Controlled Feeding Trial.

BACKGROUND: Food-based strategies to reduce nutritional iron deficiency have not been universally successful. Biofortification has the potential to become a sustainable, inexpensive, and effective solution. OBJECTIVE: This randomized controlled trial was conducted to determine the efficacy of iron-biofortified beans (Fe-Beans) to improve iron status in Rwandan women. METHODS: A total of 195 women (aged 18-27 y) with serum ferritin <20 µg/L were randomly assigned to receive either Fe-Beans, with 86 mg Fe/kg, or standard unfortified beans (Control-Beans), with 50 mg Fe/kg, 2 times/d for 128 d in Huye, Rwanda. Iron status was assessed by hemoglobin, serum ferritin, soluble transferrin receptor (sTfR), and body iron (BI); inflammation was assessed by serum C-reactive protein (CRP) and serum α1-acid glycoprotein (AGP). Anthropometric measurements were performed at baseline and at end line. Random weekly serial sampling was used to collect blood during the middle 8 wk of the feeding trial. Mixed-effects regression analysis with repeated measurements was used to evaluate the effect of Fe-Beans compared with Control-Beans on iron biomarkers throughout the course of the study. RESULTS: At baseline, 86% of subjects were iron-deficient (serum ferritin <15 µg/L) and 37% were anemic (hemoglobin <120 g/L). Both groups consumed an average of 336 g wet beans/d. The Fe-Beans group consumed 14.5 ± 1.6 mg Fe/d from biofortified beans, whereas the Control-Beans group consumed 8.6 ± 0.8 mg Fe/d from standard beans (P < 0.05). Repeated-measures analyses showed significant time-by-treatment interactions for hemoglobin, log serum ferritin, and BI (P < 0.05). The Fe-Beans group had significantly greater increases in hemoglobin (3.8 g/L), log serum ferritin (0.1 log µg/L), and BI (0.5 mg/kg) than did controls after 128 d. For every 1 g Fe consumed from beans over the 128 study days, there was a significant 4.2-g/L increase in hemoglobin (P < 0.05). CONCLUSION: The consumption of iron-biofortified beans significantly improved iron status in Rwandan women. This trial was registered at clinicaltrials.gov as NCT01594359.

Does Number of Perceptions or Cross-Modal Auditory Cueing Influence Audiovisual Processing Speed?

What factors contribute to redundant target processing speed besides statistical facilitation? One possibility is that multiple percepts may drive these effects. Another, although not mutually exclusive hypothesis, is that cross-channel cueing from one modality to another may influence response times. We implemented an auditory-visual detection task using the sound-induced flash illusion to examine whether one or both of these possibilities contributes to changes in processing speed; we did so by examining the data of individual participants. Our results indicated shorter response times in several participants when multiple flashes were perceived in the standard sound-induced flash illusion, thereby replicating previous work in the literature. Additionally, we found evidence for faster responses in several participants when carrying out the same analysis in trials in which 1 beep was presented with 2 real flashes. Overall, our analysis indicates that some observers benefit from cross-modal facilitation, whereas others may benefit from a combination of cross-modal facilitation and increased perceptual judgments.