Perceptual abstraction and attention

This is a report on the preliminary achievements of WP4 of the IM-CleVeR project on abstraction for cumulative learning, in particular directed to: (1) producing algorithms to develop abstraction features under top-down action influence; (2) algorithms for supporting detection of change in motion pictures; (3) developing attention and vergence control on the basis of locally computed rewards; (4) searching abstract representations suitable for the LCAS framework; (5) developing predictors based on information theory to support novelty detection. The report is organized around these 5 tasks that are part of WP4. We provide a synthetic description of the work done for each task by the partners

Novelty detection and learning drives

This document presents Deliverable 5.1 of the IM-CLeVeR (Intrinsically Motivated Cumulative Learning Versatile Robots) EU FP7 project. It represents one of two deliverables from Workpackage 5 (Novelty Detection and Drives for Autonomous Learning)

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Comparison of Military and Civilian Methods for Determining Potentially Preventable Deaths: A Systematic Review.

IMPORTANCE: Military and civilian trauma experts initiated a collaborative effort to develop an integrated learning trauma system to reduce preventable morbidity and mortality. Because the Department of Defense does not currently have recommended guidelines and standard operating procedures to perform military preventable death reviews in a consistent manner, these performance improvement processes must be developed. OBJECTIVES: To compare military and civilian preventable death determination methods to understand the existing best practices for evaluating preventable death. EVIDENCE REVIEW: This systematic review followed the PRISMA reporting guidelines. English-language articles were searched from inception to February 15, 2017, using the following databases: MEDLINE (Ovid), Evidence-Based Medicine Reviews (Ovid), PubMed, CINAHL, and Google Scholar. Articles were initially screened for eligibility and excluded based on predetermined criteria. Articles reviewing only prehospital deaths, only inhospital deaths, or both were eligible for inclusion. Information on study characteristics was independently abstracted by 2 investigators. Reported are methodological factors affecting the reliability of preventable death studies and the preventable death rate, defined as the number of potentially preventable deaths divided by the total number of deaths within a specific patient population. FINDINGS: Fifty studies (8 military and 42 civilian) met the inclusion criteria. In total, 1598 of 6500 military deaths reviewed and 3346 of 19 108 civilian deaths reviewed were classified as potentially preventable. Among military studies, the preventable death rate ranged from 3.1% to 51.4%. Among civilian studies, the preventable death rate ranged from 2.5% to 85.3%. The high level of methodological heterogeneity regarding factors, such as preventable death definitions, review process, and determination criteria, hinders a meaningful quantitative comparison of preventable death rates. CONCLUSIONS AND RELEVANCE: The reliability of military and civilian preventable death studies is hindered by inconsistent definitions, incompatible criteria, and the overall heterogeneity in study methods. The complexity, inconsistency, and unpredictability of combat require unique considerations to perform a methodologically sound combat-related preventable death review. As the Department of Defense begins the process of developing recommended guidelines and standard operating procedures for performing military preventable death reviews, consideration must be given to the factors known to increase the risk of bias and poor reliability

Retinoblastoma cells are inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase

5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an analog of AMP, is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. We studied the effects of AICAR on the growth of retinoblastoma cell lines (Y79, WERI, and RB143). AICAR inhibited Rb cell growth, induced apoptosis and S-phase cell cycle arrest, and led to activation of AMPK. These effects were abolished by treatment with dypiridamole, an inhibitor that blocks entrance of AICAR into cells. Treatment with the adenosine kinase inhibitor 5-iodotubericidin to inhibit the conversion of AICAR to ZMP (the direct activator of AMPK) reversed most of the growth-inhibiting effects of AICAR, indicating that some of the antiproliferative effects of AICAR are mediated through AMPK activation. In addition, AICAR treatment was associated with inhibition of the mammalian target of rapamycin pathway, decreased phosphorylation of ribosomal protein-S6 and 4E-BP1, down-regulation of cyclins A and E, and decreased expression of p21. Our results indicate that AICAR-induced activation of AMPK inhibits retinoblastoma cell growth. This is one of the first descriptions of a nonchemotherapeutic drug with low toxicity that may be effective in treating Rb patients.—Theodoropoulou, S., Kolovou, P. E., Morizane, Y., Kayama, M., Nicolaou, F., Miller, J. W., Gragoudas, E., Ksander, B. R., Vavvas, D. G. Retinoblastoma cells are inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase

Corrigendum to “Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study” [Eur Urol 83 (2023) 15–26, (S0302283822025544), (10.1016/j.eururo.2022.08.005)]

The authors regret that there was an error in the supplementary files – Table 6. The correct values for ‘Severe skin reaction’ are shown below, and also updated online accordingly. [Table presented] The authors would like to apologise for any inconvenience caused