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This paper describes a heat pump investigation for GreenSCIES (GS), a fifth Generation district heating and cooling (5DHC) network in Islington, London. The paper describes the GreenSCIES concept integrating Mobility, Power and Heat into a Smart Local Energy System (SLES). At the heart of the system is an ultra-low temperature ambient loop network, which permits bi-directional flow within the pipes to allow energy exchange between heating and cooling customers at different times and in different locations, depending on where demand is at any given time. An existing data centre provides the primary source of waste heat for the scheme. Heat pumps in distributed energy centres are utilised to amplify the temperature of the ambient loop to deliver heat in connected buildings. The energy centres integrate heat pumps with building-mounted solar photovoltaic (PV) systems and electric vehicle (EV) charging points. The paper provides an overview of the integrated SLES concept, focussing on the heat pump selection and the short and long-term thermal storage options designed for the scheme. The results show that even the smaller constructible ‘New River’ scheme will save 5,000 tons of CO2e annually. This will tend to 100% as the grid decarbonise further. Therefore, the GS SLES concept applied to urban areas could deliver significant carbon emission savings in the UK and elsewhere. Practical application: Project GreenSCIES, is a detailed design study to develop a Smart, Local Energy System (SLES) for a large community in the London Borough of Islington. Our consortium have developed an innovative SLES concept, centred around a fifth generation district heating and cooling network. The GS ambient loop systems have negligible losses and much greater efficiencies than traditional district heat networks. As recognised by the UK Government’s Heat and Buildings Strategy, ambient loop systems should be considered where large-scale neighbourhood regeneration occurs. The proposed SLES concept applied to wider urban areas could deliver significant carbon emission savings in the UK.

In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n= 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.

Integrated smartly controlled energy networks have the potential to deliver significant reductions in carbon emissions, improve air quality and reduce energy costs for end-users across the world. This paper introduces a novel methodology for the development of integrated thermal, power and mobility 5th generation (5G) smart energy networks. The proposed 5G concept builds on state of the art by connecting flexible electricity demands such as heat pumps, and electric vehicles to intermittent, renewable and secondary energy sources and storage using artificial intelligence to facilitate optimal control and to maximise revenue and carbon savings. The proposed innovative method is being applied in central London through the development of two independent 5G smart energy schemes. The proposed schemes will incorporate a range of different renewables and secondary energy sources, for example, waste heat from local data centres and the London Underground that will supply a large proportion of the energy demand of the overall district network capacity. Both networks will operate at close to ambient temperature, approximately 15–25 °C as a so-called ‘ambient loop’ system, with individual heat pumps for each end-user or building connected to the network. The system also integrates thermal and electrical storage to create additional flexibility for the network and smart control for demand-side management. A smart management system flexibly controls individual assets such as heat pumps and electric vehicles in response to price signals reflecting the intermittency of renewable energy sources on the electricity grid. The ambient district thermal loop will distribute low carbon energy to a range of end users. Results presented in this paper provide an understanding of capital costs associated with integrated smart energy systems and the relative performance of individual technologies in a complex system using a techno-economic modelling approach. Overall, this paper demonstrates that the implementation of the 5G concept results in lower energy costs to consumers while at the same time transforming a large existing urban area to a near zero-carbon energy system in terms of heating, cooling, electricity and transport.

Clinical detection of sequence and structural variants in known cancer genes points to viable treatment options for a minority of children with cancer.1 To increase the number of children who benefit from genomic profiling, gene expression information must be considered alongside mutations.2,3 Although high expression has been used to nominate drug targets for pediatric cancers,4,5 its utility has not been evaluated in a systematic way.6 We describe a child with a rare sarcoma that was profiled with whole-genome and RNA sequencing (RNA-Seq) techniques. Although the tumor did not harbor DNA mutations targetable by available therapies, incorporation of gene expression information derived from RNA-Seq analysis led to a therapy that produced a significant clinical response. We use this case to describe a framework for inclusion of gene expression into the clinical genomic evaluation of pediatric tumors.

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Myotonic dystrophy type 2 (DM2) is a multisystem degenerative disorder with distinctive clinical and electrophysiological features. Recently, genetic confirmation has become available with the identification of the molecular defect, an expansion of a CCTG repeat located in intron 1 of the zinc finger protein 9 (ZNF9) gene. We present two first-degree relatives with an athletic clinical phenotype, pathological evidence of subsarcolemmal vacuolation, and molecular genetic confirmation of DM2. When found in the proper clinical context, athleticism and pathological subsarcolemmal vacuoles should not dissuade the clinician from the possible diagnosis of DM2.

Some investigators have suggested that medulloblastomas can be distinguished from other cerebellar neoplasms by demonstrating "restricted diffusion" on the Apparent Diffusion Coefficient (ADC) map obtained from diffusion-weighted imaging (DWI) sequences on magnetic resonance imaging. Previous authors have postulated that this observed restricted diffusion is a reflection of very high cell density. There has been a tendency to assert that pediatric medulloblastoma uniformly demonstrates restricted diffusion on DWI. However, our clinical observation has been that there are pediatric medulloblastomas that exhibit normal or even increased diffusion on DWI. The current study was undertaken primarily to determine whether restricted diffusion is uniformly present in pediatric medulloblastoma and secondly to look for pathological features that might distinguish medulloblastomas with and without restricted diffusion.The DWI characteristics of pathologically confirmed medulloblastomas diagnosed at our institution were retrospectively reviewed. The ADC was obtained in two non-overlapping, solid, non-hemorrhagic, non-necrotic regions of tumor and averaged. An ADC below 1 × 10(-3) mm(2)/s was considered to represent restricted diffusion. A detailed pathologic review of each tumor was conducted.Ten cases of medulloblastoma were reviewed, of which two demonstrated average ADCs above 1 × 10(-3) mm(2)/s (1.223 and 1.169 × 10(-3) mm(2)/s, respectively), indicating no restricted diffusion. Pathologic review revealed that both of these non-restricting cases displayed a lack of reticulin deposition by light microscopy.DWI does not appear to be an entirely reliable means of distinguishing medulloblastomas from other cerebellar neoplasms. Histologically, restricted diffusion in medulloblastomas may be related to reticulin deposition.

Nine subjects with late onset unipolar depression were studied, before and after treatment, using I-123 iodoamphetamine SPECT. In all nine subjects clinical improvement was associated with a significant increase (p