EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma.

Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE: BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

Evaluation of a semi-automated approach for FDG PET image analysis for routine clinical application in patients with multiple myeloma.

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Venetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM. PATIENTS AND METHODS: This phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy. RESULTS: Eight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months. CONCLUSIONS: Given the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.

INTRODUCTION: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. METHODS: A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS: No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.

INTRODUCTION: Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. METHODS: In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. RESULTS: Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. CONCLUSIONS: The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. FUNDING: AbbVie in collaboration with Genentech/Roche.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.

Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 µg/mL, 12.6 ± 5.4 µg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.

Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin.

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate. 2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100  mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study. 3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (Cmax) by 35% and area under the plasma-concentration time curve (AUC0-∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Neupsilin-Inf em um modelo de avaliação neuropsicológica breve para centros de saúde / Neupsilin-Inf in a model of brief neuropsychological assesment for health centers / Neupsilin-Inf en un modelo de evaluación neuropsicológica breve para centros de salud

Este estudo teve como objetivo analisar o uso do NEUPSILIN-Inf num modelo de avaliação neuropsicológica breve em crianças atendidas em um serviço assistencial. As etapas seguidas no modelo de avaliação neuropsicológica breve são: sala de espera, grupo de crianças e avaliação neuropsicológica individual. A análise da aplicabilidade do NEUPSILIN-Inf na detecção de déficits cognitivos foi realizada comparando o desempenho de 171 crianças com possíveis transtornos do neurodesenvolvimento a 358 crianças da amostra de normatização, tendo a média marginal do escore ajustado pela idade. Em todas as tarefas do NEUPSILIN-Inf, o grupo clínico mostrou desempenho inferior. O conjunto de dados do modelo de avaliação pode gerar hipóteses diagnósticas, como deficiência intelectual, possíveis quadros de transtornos da aprendizagem ou específicos de linguagem. Frente à alta escassez de atendimento público para crianças com possíveis transtornos do neurodesenvolvimento, este pode ser um modelo economicamente eficiente para centros de saúde em diversas regiões do Brasil. (AU)

This study aimed to analyze the use of NEUPSILIN-Inf in a model of brief neuropsychological assessment for children attending a helthcare service. The steps followed in the brief neuropsychological assessment model are waiting room, children's group, and individual assessment. The analysis of this model's efficacy in detecting cognitive deficits through NEUPSILIN-Inf was conducted by comparing the performance of 171 children with possible developmental disorders to 358 children from the normative sample of NEUPSILIN-Inf. The clinical group showed lower performance in all NEUPSILIN-Inf 's tasks. The set of data derived from the evaluation model can underlie diagnostic hypotheses, such as intellectual disabilities, learning disorders or specific language impairment. Taking into account the restrictive public care for children with possible developmental disorders, this model can be considered a cost-effective possibility to be accomplished by health centers in different Brazilian regions. (AU)

Este estudio tuvo como objetivo analizar el uso de NEUPSILIN-Inf como un modelo de evaluación neuropsicológica breve para niños, atendidos en un servicio de asistencia pública. Las etapas seguidas para evaluación neuropsicológica breve fueron: sala de espera, grupo de niños, evaluación neuropsicológica individual. El análisis de aplicabilidad NEUPSILIN-Inf para detectar déficits cognitivos, fue realizado comparando el rendimiento de 171 niños con posibles trastornos de neuro-desarrollo y 358 niños de la muestra de normalización, obteniendo la media marginal del resultado, ajustado por la edad. En todas las tareas del NEUPSILIN-Inf, el grupo clínico tuvo un rendimiento inferior. El conjunto de datos del modelo de evaluación puede generar hipótesis diagnósticas, como deficiencia intelectual, posibles trastornos de aprendizaje o específicos de lenguaje. Ante la escasez de atendimiento público para niños con posibles trastornos de neurodesarrollo, este modelo puede ser eficiente desde el punto de vista económico en centros de salud en varias regiones de Brasil. (AU)

Haloperidol increases false recognition memory of thematically related pictures in healthy volunteers.

Dopamine can modulate long-term episodic memory. Its potential role on the generation of false memories, however, is less well known. In a randomized, double-blind, placebo-controlled experiment, 24 young healthy volunteers ingested a 4-mg oral dose of haloperidol, a dopamine D2 -receptor antagonist, or placebo, before taking part in a recognition memory task. Haloperidol was active during both study and test phases of the experiment. Participants in the haloperidol group produced more false recognition responses than those in the placebo group, despite similar levels of correct recognition. These findings show that dopamine blockade in healthy volunteers can specifically increase false recognition memory.

Effects of Sulpiride on True and False Memories of Thematically Related Pictures and Associated Words in Healthy Volunteers.

Episodic memory, working memory, emotional memory, and attention are subject to dopaminergic modulation. However, the potential role of dopamine on the generation of false memories is unknown. This study defined the role of the dopamine D2 receptor on true and false recognition memories. Twenty-four young, healthy volunteers ingested a single dose of placebo or 400 mg oral sulpiride, a dopamine D2-receptor antagonist, just before starting the recognition memory task in a randomized, double-blind, and placebo-controlled trial. The sulpiride group presented more false recognitions during visual and verbal processing than the placebo group, although both groups had the same indices of true memory. These findings demonstrate that dopamine D2 receptors blockade in healthy volunteers can specifically increase the rate of false recognitions. The findings fit well the two-process view of causes of false memories, the activation/monitoring failures model.

Versões Alternativas do Subteste Memória Lógica da WMS-R: análise de desempenho de uma amostra saudável da cidade de São Paulo / Alternative Versions of the Logical Memory Subtest of the WMS-R: performance analyses of a healthy sample from the city of São Paulo

O teste Memória Lógica da Wechsler Memory Scale - Revised (WMS-R) é amplamente utilizado na prática clínica como instrumento de avaliação da memória verbal. O objetivo deste estudo foi analisar as propriedades psicométricas iniciais de versões alternativas das histórias traduzidas e livremente adaptadas da WMS-R empregadas no Brasil: três histórias equiparáveis à história Ana Soares e três à de Roberto Mota. A amostra foi constituída de 655 universitários, com idades entre 18 e 35 anos. Foi solicitada a recordação livre imediata e tardia (após 30 min) de cada história, original e alternativas. A análise de equivalência entre a recordação imediata e tardia das histórias alternativas e originais mostrou que cinco histórias foram memorizadas de forma equiparável às histórias originais se aplicadas individualmente. A recordação de três pares dessas histórias alternativas também foi equivalente à recordação do par original. Uma análise utilizando a Teoria de Resposta ao Item apontou os itens com melhor índice discriminativo. Assim, propõe-se histórias alternativas às do WMS-R que poderão ser usadas em estudos de normatização.

The Logical Memory test of the Wechsler Memory Scale - Revised (WMS-R) is widely used in clinical practice as a tool for verbal memory assessment. The aim of this study was to examine the initial psychometric properties of alternative versions of the stories translated and freely adapted from WMS -R used in Brazil: three stories comparable to Ana Soares' and three to Roberto Mota's stories. The sample consisted of 655 adults aged between 18 and 35 years. Immediate and delayed free recall of each original and alternative story was requested. The analysis of equivalence between the recall of alternative and original stories showed that five stories proved equivalent to the original stories, if applied individually. Recall of three pairs of these alternative stories was also equivalent to that of the original pair. An analysis using Item Response Theory (IRT) showed the items with best discriminative index. Therefore, the alternative stories proposed here can be used in normalization studies.

Late positive slow waves as markers of chunking during encoding.

Electrophysiological markers of chunking of words during encoding have mostly been shown in studies that present pairs of related stimuli. In these cases it is difficult to disentangle cognitive processes that reflect distinctiveness (i.e., conspicuous items because they are related), perceived association between related items and unified representations of various items, or chunking. Here, we propose a paradigm that enables the determination of a separate Event-related Potential (ERP) marker of these cognitive processes using sequentially related word triads. Twenty-three young healthy individuals viewed 80 15-word lists composed of unrelated items except for the three words in the middle serial positions (triads), which could be either unrelated (control list), related perceptually, phonetically or semantically. ERP amplitudes were measured at encoding of each one of the words in the triads. We analyzed two latency intervals (350-400 and 400-800 ms) at midline locations. Behaviorally, we observed a progressive facilitation in the immediate free recall of the words in the triads depending on the relations between their items (control < perceptual < phonetic < semantic), but only semantically related items were recalled as chunks. P300-like deflections were observed for perceptually deviant stimuli. A reduction of amplitude of a component akin to the N400 was found for words that were phonetically and semantically associated with prior items and therefore were not associated to chunking. Positive slow wave (PSW) amplitudes increased as successive phonetically and semantically related items were presented, but they were observed earlier and were more prominent at Fz for semantic associates. PSWs at Fz and Cz also correlated with recall of semantic word chunks. This confirms prior claims that PSWs at Fz are potential markers of chunking which, in the proposed paradigm, were modulated differently from the detection of deviant stimuli and of relations between stimuli.

Contrasting group analysis of Brazilian students with dyslexia and good readers using the computerized reading and writing assessment battery "BALE".

The analysis of cognitive processes underpinning reading and writing skills may help to distinguish different reading ability profiles. The present study used a Brazilian reading and writing battery to compare performance of students with dyslexia with two individually matched control groups: one contrasting on reading competence but not age and the other group contrasting on age but not reading competence. Participants were 28 individuals with dyslexia (19 boys) with a mean age of 9.82 (SD ± 1.44) drawn from public and private schools. These were matched to: (1) an age control group (AC) of 26 good readers with a mean age of 9.77 (SD ± 1.44) matched by age, sex, years of schooling, and type of school; (2) reading control group (RC) of 28 younger controls with a mean age of 7.82 (SD ± 1.06) matched by sex, type of school, and reading level. All groups were tested on four tasks from the Brazilian Reading and Writing Assessment battery ("BALE"): Written Sentence Comprehension Test (WSCT); Spoken Sentence Comprehension Test (OSCT); Picture-Print Writing Test (PPWT 1.1-Writing); and the Reading Competence Test (RCT). These tasks evaluate reading and listening comprehension for sentences, spelling, and reading isolated words and pseudowords (non-words). The dyslexia group scored lower and took longer to complete tasks than the AC group. Compared with the RC group, there were no differences in total scores on reading or oral comprehension tasks. However, dyslexics presented slower reading speeds, longer completion times, and lower scores on spelling tasks, even compared with younger controls. Analysis of types of errors on word and pseudoword reading items showed students with dyslexia scoring lower for pseudoword reading than the other two groups. These findings suggest that the dyslexics overall scores were similar to those of younger readers. However, specific phonological and visual decoding deficits showed that the two groups differ in terms of underpinning reading strategies.

Sensory processing abilities of children with ADHD

OBJECTIVE: To assess and compare the sensory processing abilities of children with Attention Deficit/Hyperactivity Disorder (ADHD) and children without disabilities, and to analyze the relationship between sensory processing difficulties and behavioural symptoms presented by children with ADHD. METHOD : Thirty-seven children with ADHD were compared with thirty-seven controls using a translated and adapted version of the "Sensory Profile" answered by the parents/caregivers. For the ADHD group, Sensory Profile scores were correlated to behavioural symptoms assessed using the Child Behaviour Check List (CBCL) and the Behavioural Teacher Rating Scale (EACI-P). The statistical analyses were conducted using the Mann Whitney test and Pearson correlation coefficients. RESULTS : Children with ADHD showed significant impairments compared to the control group in sensory processing and modulation, as well as in behavioural and emotional responses as observed in 11 out of 14 sections and 6 out of 9 factors. Differences in all Sensory Profile response patterns were also observed between the two groups of children. Sensory Profile scores showed a moderately negative correlation with CBCL and EACI-P scores in the ADHD group. CONCLUSION : These results indicate that children with ADHD may present sensory processing impairments, which may contribute to the inappropriate behavioural and learning responses displayed by children with ADHD. It also suggests the importance of understanding the sensory processing difficulties and its possible contribution to the ADHD symptomatology. .

Sensory processing abilities of children with ADHD.

OBJECTIVE: To assess and compare the sensory processing abilities of children with Attention Deficit/Hyperactivity Disorder (ADHD) and children without disabilities, and to analyze the relationship between sensory processing difficulties and behavioural symptoms presented by children with ADHD. METHOD: Thirty-seven children with ADHD were compared with thirty-seven controls using a translated and adapted version of the "Sensory Profile" answered by the parents/caregivers. For the ADHD group, Sensory Profile scores were correlated to behavioural symptoms assessed using the Child Behaviour Check List (CBCL) and the Behavioural Teacher Rating Scale (EACI-P). The statistical analyses were conducted using the Mann Whitney test and Pearson correlation coefficients. RESULTS: Children with ADHD showed significant impairments compared to the control group in sensory processing and modulation, as well as in behavioural and emotional responses as observed in 11 out of 14 sections and 6 out of 9 factors. Differences in all Sensory Profile response patterns were also observed between the two groups of children. Sensory Profile scores showed a moderately negative correlation with CBCL and EACI-P scores in the ADHD group. CONCLUSION: These results indicate that children with ADHD may present sensory processing impairments, which may contribute to the inappropriate behavioural and learning responses displayed by children with ADHD. It also suggests the importance of understanding the sensory processing difficulties and its possible contribution to the ADHD symptomatology.

Executive functioning and reading achievement in school: a study of Brazilian children assessed by their teachers as "poor readers".

This study examined executive functioning and reading achievement in 106 6- to 8-year-old Brazilian children from a range of social backgrounds of whom approximately half lived below the poverty line. A particular focus was to explore the executive function profile of children whose classroom reading performance was judged below standard by their teachers and who were matched to controls on chronological age, sex, school type (private or public), domicile (Salvador/BA or São Paulo/SP) and socioeconomic status. Children completed a battery of 12 executive function tasks that were conceptual tapping cognitive flexibility, working memory, inhibition and selective attention. Each executive function domain was assessed by several tasks. Principal component analysis extracted four factors that were labeled "Working Memory/Cognitive Flexibility," "Interference Suppression," "Selective Attention," and "Response Inhibition." Individual differences in executive functioning components made differential contributions to early reading achievement. The Working Memory/Cognitive Flexibility factor emerged as the best predictor of reading. Group comparisons on computed factor scores showed that struggling readers displayed limitations in Working Memory/Cognitive Flexibility, but not in other executive function components, compared to more skilled readers. These results validate the account that working memory capacity provides a crucial building block for the development of early literacy skills and extends it to a population of early readers of Portuguese from Brazil. The study suggests that deficits in working memory/cognitive flexibility might represent one contributing factor to reading difficulties in early readers. This might have important implications for how educators might intervene with children at risk of academic under achievement.