Replay across Experiments: A Natural Extension of Off-Policy RL

Replaying data is a principal mechanism underlying the stability and data efficiency of off-policy reinforcement learning (RL). We present an effective yet simple framework to extend the use of replays across multiple experiments, minimally adapting the RL workflow for sizeable improvements in controller performance and research iteration times. At its core, Replay Across Experiments (RaE) involves reusing experience from previous experiments to improve exploration and bootstrap learning while reducing required changes to a minimum in comparison to prior work. We empirically show benefits across a number of RL algorithms and challenging control domains spanning both locomotion and manipulation, including hard exploration tasks from egocentric vision. Through comprehensive ablations, we demonstrate robustness to the quality and amount of data available and various hyperparameter choices. Finally, we discuss how our approach can be applied more broadly across research life cycles and can increase resilience by reloading data across random seeds or hyperparameter variations

Complex structural rearrangements are present in high-grade dysplastic Barrett\u27s oesophagus samples

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett’s oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals. Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples. Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples. Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC

Complex structural rearrangements are present in high-grade dysplastic Barrett’s oesophagus samples

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Background Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett’s oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals. Methods In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples. Results We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples. Conclusions The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Lymphocytic esophagitis: an Australian (Queensland) case series of a newly recognized mimic of eosinophilic esophagitis

Background and Aim: Lymphocytic esophagitis (LoE) is a recently described upper gastrointestinal tract "disorder" diagnosis of which hinges on histology and is characterized by the excessive infiltration of lymphocytes in the peripapillary fields of the esophageal epithelium, with clinical manifestations similar to those of eosinophilic esophagitis (EoE). In this article, we aim to describe for the first time the clinico-pathological characteristics of a large cohort of Australian (Queensland) cases of LoE. Methods: Histological data that fulfilled the criteria (predominant lymphocytic infiltration in the peripapillary fields, none or minimal neutrophils or eosinophils, and no infection) were collected between January 2014 and May 2016 from a number of major Queensland Public Hospital anatomical pathology laboratories. Patient presentations were subsequently examined to compile clinical and endoscopic correlates. Results: A total of 62 cases of LoE were identified. The median age was 55 years, with 59.6% of subjects being male. Major clinical manifestations included dysphagia (32), epigastric or abdominal pain (8), gastro-esophageal reflux (8), association with Crohn's disease (8), and vomiting or diarrhea (6). Endoscopy was normal in 47% of cases; 47% had appearances similar to those of EoE. There were three cases with associated mild monilial esophagitis (6%). Conclusion: LoE is a relatively recently recognized condition of the esophagus with variable clinical and endoscopic findings. Diagnosis is based on characteristic histological features. Further investigation is needed to ascertain the etiopathology and natural history of the condition and to establish a safe and effective treatment regimen

Khat-associated hepatitis

We report a case of khat-associated hepatitis in a 32-year-old Somali man living in Australia. This is the first case of hepatoxicity related to khat ingestion reported in Australia

Is Alpha-B Crystallin an Independent Marker for Prognosis in Lung Cancer?

Background: Alpha B-crystallin (CRYAB) is an oncogene that increases tumour survival by promoting angiogenesis and preventing apoptosis. CRYAB is an independent prognostic marker in epithelial tumours including head and neck squamous cell carcinoma and breast cancer where it is predictive of nodal status and associated with poor outcome. We explored the role of CRYAB in non-small-cell lung cancer (NSCLC). Methods: Immunohistochemical analysis was performed on 50 samples. Following staining with anti-alpha-B crystallin antibody, a blinded pathologist scored samples for nuclear (N) and cytoplasmic (C) staining intensity. Analysis was performed using Cox's proportional hazards model. Results: There were 32 adenocarcinomas and 18 squamous cell carcinomas. The median tumour size was T2, grade 2 moderately differentiated, and 10 patients had nodal spread. Recurrence was seen in 22 patients (46%). Mortality was 48%, with median time to mortality 871 days. N staining was detected in eight samples (16%), and C staining in 20 (40%), with both N and C staining positive in five (10%). Staining for CRYAB predicted neither recurrence (N stain p= 0.78, C stain p= 0.38) nor mortality (N stain p= 0.86, C stain p= 0.66). Conclusion: CRYAB did not predict outcomes in patients treated for NSCLC. Larger studies are required to validate this finding