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A variety of studies have demonstrated gains in cognitive ability following cognitive training interventions. However, other studies have not shown such gains, and questions remain regarding the efficacy of specific cognitive training interventions. Cognitive training research often involves programs made up of just one or a few exercises, targeting limited and specific cognitive endpoints. In addition, cognitive training studies typically involve small samples that may be insufficient for reliable measurement of change. Other studies have utilized training periods that were too short to generate reliable gains in cognitive performance. The present study evaluated an online cognitive training program comprised of 49 exercises targeting a variety of cognitive capacities. The cognitive training program was compared to an active control condition in which participants completed crossword puzzles. All participants were recruited, trained, and tested online (N = 4,715 fully evaluable participants). Participants in both groups were instructed to complete one approximately 15-minute session at least 5 days per week for 10 weeks. Participants randomly assigned to the treatment group improved significantly more on the primary outcome measure, an aggregate measure of neuropsychological performance, than did the active control group (Cohen's d effect size = 0.255; 95% confidence interval = [0.198, 0.312]). Treatment participants showed greater improvements than controls on speed of processing, short-term memory, working memory, problem solving, and fluid reasoning assessments. Participants in the treatment group also showed greater improvements on self-reported measures of cognitive functioning, particularly on those items related to concentration compared to the control group (Cohen's d = 0.249; 95% confidence interval = [0.191, 0.306]). Taken together, these results indicate that a varied training program composed of a number of tasks targeted to different cognitive functions can show transfer to a wide range of untrained measures of cognitive performance. ClinicalTrials.gov NCT-02367898.

Making new breakthroughs in understanding the processes underlying human cognition may depend on the availability of very large datasets that have not historically existed in psychology and neuroscience. Lumosity is a web-based cognitive training platform that has grown to include over 600 million cognitive training task results from over 35 million individuals, comprising the largest existing dataset of human cognitive performance. As part of the Human Cognition Project, Lumosity's collaborative research program to understand the human mind, Lumos Labs researchers and external research collaborators have begun to explore this dataset in order uncover novel insights about the correlates of cognitive performance. This paper presents two preliminary demonstrations of some of the kinds of questions that can be examined with the dataset. The first example focuses on replicating known findings relating lifestyle factors to baseline cognitive performance in a demographically diverse, healthy population at a much larger scale than has previously been available. The second example examines a question that would likely be very difficult to study in laboratory-based and existing online experimental research approaches at a large scale: specifically, how learning ability for different types of cognitive tasks changes with age. We hope that these examples will provoke the imagination of researchers who are interested in collaborating to answer fundamental questions about human cognitive performance.

How do humans learn contingencies between events? Both pathway-strengthening and inference-based process models have been proposed to explain contingency learning. We propose that each of these processes is used in different conditions. Participants viewed displays that contained single or paired objects and learned which displays were usually followed by the appearance of a dot. Some participants predicted whether the dot would appear before seeing the outcome, whereas other participants were required to respond quickly if the dot appeared shortly after the display. In the prediction task, instructions guiding participants to infer which objects caused the dot to appear were necessary in order for contingencies associated with one object to influence participants' predictions about the object with which it had been paired. In the response task, contingencies associated with one object affected responses to its pair mate irrespective of whether or not participants were given causal instructions. Our results challenge single-mechanism accounts of contingency learning and suggest that the mechanisms underlying performance in the two tasks are distinct.

Mitchell et al. describe many fascinating studies, and in the process, propose what they consider to be a unified framework for human learning in which effortful, controlled learning results in propositional knowledge. However, it is unclear how any of their findings privilege a propositional account, and we remain concerned that embedding all knowledge in propositional representations obscures the tight interdependence between learning from experiences and the use of the results of learning as a basis for action.

Background A variety of studies have demonstrated gains in cognitive ability following cognitive training interventions. However, other studies have not shown such gains, and questions remain regarding the efficacy of specific cognitive training interventions. Cognitive training research often involves programs made up of just one or a few exercises, targeting limited and specific cognitive endpoints. In addition, cognitive training studies typically involve small samples that may be insufficient for reliable measurement of change. Other studies have utilized training periods that were too short to generate reliable gains in cognitive performance. Methods The present study evaluated an online cognitive training program comprised of 49 exercises targeting a variety of cognitive capacities. The cognitive training program was compared to an active control condition in which participants completed crossword puzzles. All participants were recruited, trained, and tested online (N = 4,715 fully evaluable participants). Participants in both groups were instructed to complete one approximately 15-minute session at least 5 days per week for 10 weeks. Results Participants randomly assigned to the treatment group improved significantly more on the primary outcome measure, an aggregate measure of neuropsychological performance, than did the active control group (Cohen's d effect size = 0.255; 95% confidence interval = [0.198, 0.312]). Treatment participants showed greater improvements than controls on speed of processing, short-term memory, working memory, problem solving, and fluid reasoning assessments. Participants in the treatment group also showed greater improvements on self-reported measures of cognitive functioning, particularly on those items related to concentration compared to the control group (Cohen's d = 0.249; 95% confidence interval = [0.191, 0.306]). Conclusion Taken together, these results indicate that a varied training program composed of a number of tasks targeted to different cognitive functions can show transfer to a wide range of untrained measures of cognitive performance. Trial Registration ClinicalTrials.gov NCT-02367898

Simultaneous acquisition of multiple languages to a native level of fluency is common in many areas of the world. This ability must be represented in any cognitive mechanisms used for language. Potential explanations of the evolution of language must also account for the bilingual case. Surprisingly, this fact has not been widely considered in the literature on language origins and evolution. We consider any array of potential accounts for this phenomenon, including arguments by selectionists on the basis for language variation. We find scant evidence for specific selection of the multilingual ability prior to language origins. Thus it seems more parsimonious that bilingualism \"came for free\" along with whatever mechanisms did evolve. Sequential learning mechanisms may be able to accomplish multilingual acquisition without specific adaptations. In support of this perspective, we present a simple recurrent network model that is capable of learning two idealized grammars simultaneously. These results are compared with recent studies of bilingual processing using eyetracking and fMRJ showing vast overlap in the areas in the brain used in processing two different languages.

Among men with high-risk, nonmetastatic, castration-resistant prostate cancer, the addition of enzalutamide to androgen-deprivation therapy improved overall survival by nearly a year as compared with ADT alone: median survival was 67 months with enzalutamide plus ADT and 56 months with ADT alone.

In a randomized trial involving 542 patients with relapsed urothelial cancer, treatment with pembrolizumab resulted in overall survival of more than 10 months, as compared with 7 months with chemotherapy. Urothelial cancer is highly lethal in the metastatic state. 1 Platinum-based combination chemotherapy remains the standard first-line treatment for metastatic disease. Carboplatin-based combinations are associated with a median overall survival of 9 months, 2 and cisplatin-based combinations with a median overall survival of 12 to 15 months. 3 However, after platinum-based chemotherapy, there is no internationally accepted standard of care. Single-agent paclitaxel and docetaxel are commonly used worldwide, 4 , 5 and in Europe, vinflunine has been approved on the basis of an overall survival advantage of 2 months over best supportive care. 6 , 7 Because the median overall survival with second-line therapy is only 6 . . .

In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment. Biomarker analysis of the phase 3 JAVELIN Bladder 100 trial leads to the development of a multi-parameter model comprising tumor and immune features that might identify patients with advanced urothelial cancer who will benefit from avelumab maintenance therapy.

Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2–4a or ypN+ tumours following neoadjuvant chemotherapy or pT3–4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2–29·8). Median disease-free survival was 19·4 months (95% CI 15·9–24·8) with atezolizumab and 16·6 months (11·2–24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. F Hoffmann-La Roche/Genentech.