Efficacy and safety of imeglimin add-on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): A randomized, double-blind, placebo-controlled phase 3 trial with a 36-week open-label extension period.

AIMS: To evaluate the efficacy and safety of imeglimin for up to 52 weeks as combination therapy with insulin in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: This double-blind, randomized, parallel-group phase 3 trial was performed at 35 sites in Japan. Eligible patients were individuals aged ≥20 years with type 2 diabetes and inadequate glycaemic control with insulin. Patients were randomly assigned (1:1) to either imeglimin (1000 mg twice daily) or matched placebo, in combination with insulin, for 16 weeks. In a subsequent 36-week, open-label extension period, all patients received imeglimin 1000 mg twice daily. The primary endpoint was change in mean glycated haemoglobin (HbA1c) from baseline to week 16. RESULTS: In all, 108 and 107 patients were randomly assigned to treatment with imeglimin 1000 mg twice daily or placebo, respectively. Compared with placebo, the adjusted mean difference in change from baseline HbA1c at Week 16 was -0.60% (95% confidence interval [CI] -0.80 to -0.40; P < 0.0001). This decrease was sustained up to 52 weeks with a mean decrease of -0.64% (95% CI -0.82 to -0.46) versus baseline. The incidence of patients experiencing adverse events and serious adverse events was similar in the two treatment groups. The number of patients experiencing hypoglycaemia was similar in the two treatment groups. In patients receiving imeglimin, all hypoglycaemic events were mild in severity; no episodes required assistance. CONCLUSIONS: Imeglimin significantly improved HbA1c in Japanese patients with insufficiently controlled type 2 diabetes by insulin and had a similar safety profile to placebo. The efficacy of imeglimin on top of insulin was sustained for 52 weeks. Imeglimin represents a potential new treatment option for this population as add-on to insulin therapy.

Varieties of Cognitive Profiles in Poor Readers: Evidence for a VAS-Impaired Subtype.

A wide share of secondary school children does not reach the expected competence level in reading. These children could benefit from more efficient intervention responses, providing a better understanding of their cognitive weaknesses/deficits. Our aim was to explore the cognitive heterogeneity of a population of poor readers identified from a large sample of 948 sixth-grade children. We first assessed the contribution of phoneme awareness (PA), rapid automatized naming (RAN), and visual attention span (VAS) to reading performance in a subset of 281 children including poor and average readers/spellers. We show that all three skills are unique and significant predictors of reading fluency. We then restricted the analysis to participants with normal Raven's score (IQ) and oral language skills to focus on 110 children with more specific reading difficulties. A unique VAS deficit was found in 18% of these poor readers while 20% and 15.5% showed a unique PA or RAN deficit. Children with multiple or no deficit were further identified. The overall findings provide evidence for a variety of cognitive profiles in poor readers. They suggest that, in addition to PA interventions, training programs targeting VAS might be useful for the nontrivial share of poor readers who exhibit a VAS deficit.

A deficit in post-graphemic writing processes: Evidence for a graphomotor buffer.

Post-graphemic writing processes transform abstract letter representations into representations of writing movements. We describe an individual with an acquired post-graphemic writing deficit. NGN is normal in spelling words aloud, but impaired in writing words to dictation, with most errors involving letter substitutions (e.g., RUMOR written as BUMOR). NGN's deficit affects graphic motor plans, which specify the writing strokes for producing letters. Analyses of writing speed, fluency, and stroke patterns suggest that NGN's errors result from incomplete motor-plan activation. NGN's error rate is high for the first letter in a word, and declines across subsequent positions. On the basis of this serial position effect and other results, we propose that post-graphemic writing mechanisms include a graphomotor buffer, a writing-specific working memory that holds activated graphic motor plans bound to specific serial positions. We suggest that NGN's graphomotor buffer is damaged such that early serial positions are affected most severely. Finally, we present results speaking to the roles and capabilities of the graphomotor buffer, and the structure of graphic motor plans.

Knowledge about writing influences reading: Dynamic visual information about letter production facilitates letter identification.

How are reading and writing related? In this study, we address the relationship between letter identification and letter production, uncovering a link in which production information can be used to identify letters presented dynamically. By testing an individual with a deficit in letter identification, we identified a benefit which would be masked by ceiling effects in unimpaired readers. In Experiment 1 we found that letter stimuli defined by the direction of dot motion (tiny dots within letter move leftward, background dots move rightward) provided no advantage over static letters. In Experiment 2, we tested dynamic stimuli in which the letter shapes emerged over time: drawn as they would be written, drawn in reverse, or with the letter shape filled in randomly. Improved identification was observed only for letters drawn as they are typically written. These results demonstrate that information about letter production can be integrated into letter identification, and point to bi-directional connections between stored letter production information (used for writing) and abstract letter identity representations (used in both reading and writing). The links from stored production information to abstract letter identities allow the former to activate the latter. We also consider the implications of our results for remediation of acquired letter identification deficits, including letter-drawing treatments and the underlying cause of their efficacy.

Cognitive processes in spatial mapping: Evidence from a developmental spatial deficit.

We report a case study of an adolescent girl (N.K.Y.) with a developmental deficit affecting spatial processing. In a simple spatial mapping task, N.K.Y. shows a striking dissociation: She succeeds in one variant of the experiment in which the stimuli are objects, but struggles in a structurally identical task with people as stimuli. We present evidence that this dissociation stems from a tendency to automatically adopt the spatial perspective of other people, but not objects-a phenomenon also observed in neurotypical individuals. When adopting another person's perspective, N.K.Y. imagines herself in the other's position, representing the other's left and right as if it were her own. N.K.Y.'s deficit in relating left-right information to her own body then disrupts her performance. Our results shed light on the nature of N.K.Y.'s deficit as well as the cognitive operations involved in spatial perspective taking.

The phonological and visual basis of developmental dyslexia in Brazilian Portuguese reading children.

Evidence from opaque languages suggests that visual attention processing abilities in addition to phonological skills may act as cognitive underpinnings of developmental dyslexia. We explored the role of these two cognitive abilities on reading fluency in Brazilian Portuguese, a more transparent orthography than French or English. Sixty-six children with developmental dyslexia and normal Brazilian Portuguese children participated. They were administered three tasks of phonological skills (phoneme identification, phoneme, and syllable blending) and three visual tasks (a letter global report task and two non-verbal tasks of visual closure and visual constancy). Results show that Brazilian Portuguese children with developmental dyslexia are impaired not only in phonological processing but further in visual processing. The phonological and visual processing abilities significantly and independently contribute to reading fluency in the whole population. Last, different cognitively homogeneous subtypes can be identified in the Brazilian Portuguese population of children with developmental dyslexia. Two subsets of children with developmental dyslexia were identified as having a single cognitive disorder, phonological or visual; another group exhibited a double deficit and a few children showed no visual or phonological disorder. Thus the current findings extend previous data from more opaque orthographies as French and English, in showing the importance of investigating visual processing skills in addition to phonological skills in children with developmental dyslexia whatever their language orthography transparency.

Role of the superior parietal lobules in letter-identity processing within strings: FMRI evidence from skilled and dyslexic readers.

Traditionally, the ventral occipito-temporal (vOT) area, but not the superior parietal lobules (SPLs), is thought as belonging to the neural system of visual word recognition. However, some dyslexic children who exhibit a visual attention span disorder - i.e. poor multi-element parallel processing - further show reduced SPLs activation when engaged in visual multi-element categorization tasks. We investigated whether these parietal regions further contribute to letter-identity processing within strings. Adult skilled readers and dyslexic participants with a visual attention span disorder were administered a letter-string comparison task under fMRI. Dyslexic adults were less accurate than skilled readers to detect letter identity substitutions within strings. In skilled readers, letter identity differs related to enhanced activation of the left vOT. However, specific neural responses were further found in the superior and inferior parietal regions, including the SPLs bilaterally. Two brain regions that are specifically related to substituted letter detection, the left SPL and the left vOT, were less activated in dyslexic participants. These findings suggest that the left SPL, like the left vOT, may contribute to letter string processing.

Effect of orthographic processes on letter identity and letter-position encoding in dyslexic children.

The ability to identify letters and encode their position is a crucial step of the word recognition process. However and despite their word identification problem, the ability of dyslexic children to encode letter identity and letter-position within strings was not systematically investigated. This study aimed at filling this gap and further explored how letter identity and letter-position encoding is modulated by letter context in developmental dyslexia. For this purpose, a letter-string comparison task was administered to French dyslexic children and two chronological age (CA) and reading age (RA)-matched control groups. Children had to judge whether two successively and briefly presented four-letter strings were identical or different. Letter-position and letter identity were manipulated through the transposition (e.g., RTGM vs. RMGT) or substitution of two letters (e.g., TSHF vs. TGHD). Non-words, pseudo-words, and words were used as stimuli to investigate sub-lexical and lexical effects on letter encoding. Dyslexic children showed both substitution and transposition detection problems relative to CA-controls. A substitution advantage over transpositions was only found for words in dyslexic children whereas it extended to pseudo-words in RA-controls and to all type of items in CA-controls. Letters were better identified in the dyslexic group when belonging to orthographically familiar strings. Letter-position encoding was very impaired in dyslexic children who did not show any word context effect in contrast to CA-controls. Overall, the current findings point to a strong letter identity and letter-position encoding disorder in developmental dyslexia.

A visual processing but no phonological disorder in a child with mixed dyslexia.

The case study of Martial, a French 9-year-old boy, who exhibits severe mixed dyslexia and surface dysgraphia is reported. Despite very poor pseudo-word reading, Martial has preserved phonological processing skills as his good oral language, good phoneme awareness and good verbal short-term memory show. He exhibited a strong length effect when reading briefly presented words but no sign of mini-neglect. His letter-string processing abilities were assessed through tasks of whole and partial report. In whole report, Martial could only name a few letters from briefly displayed 5-consonant strings. He showed an initial-position advantage and a sharper than expected left-to-right gradient of performance. He performed better when asked to report a single cued letter within the string but then showed an atypical right-side advantage. The same rightward attentional bias was observed in whole report when top-down control was prevented. Otherwise, Martial showed preserved single letter identification skills and good processing of 5-letter strings when letters were sequentially displayed one at a time. His poor letter-string processing thus reflects a parallel visual processing disorder that is compatible with either a visual attention (VA) span or a visual short-term memory disorder. Martial was further engaged in a complex reaching movement task involving VA and simultaneous processing. He performed motor sequences not as a whole but as a succession of independent motor units, suggesting that his attention was not allocated in parallel to the two to-be-reached targets prior to movement execution. Against a more basic motor disorder however, he showed good performance in a task of cyclical pointing movements. The overall findings suggest that Martial suffers from a visual simultaneous processing disorder that disturbs letter identification in strings. Instead of being restricted to letter-string processing, this VA disorder might extend to non-verbal task.