• Clinical trial protocol: PRednisolone in early diffuse cutaneous Systemic Sclerosis (PRedSS)

      Herrick, Ariane L; orcid: 0000-0003-4941-7926; email: ariane.herrick@manchester.ac.uk; Griffiths-Jones, Deborah J; Ryder, W David; Mason, Justin C; Denton, Christopher P; orcid: 0000-0003-3975-8938 (SAGE Publications, 2020-09-17)
      Background:: Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function. Methods:: PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness. Results:: Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited. Conclusion:: PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis.
    • Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

      Lenassi, Eva; Clayton-Smith, Jill; Douzgou, Sofia; Ramsden, Simon C.; Ingram, Stuart; Hall, Georgina; Hardcastle, Claire L.; Fletcher, Tracy A.; Taylor, Rachel L.; Ellingford, Jamie M.; et al. (Nature Publishing Group US, 2019-12-18)
      Abstract: Purpose: A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Methods: Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. Results: The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Conclusion: Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.
    • Clinical, humanistic, and economic burden of severe haemophilia B in adults receiving factor IX prophylaxis: findings from the CHESS II real-world burden of illness study in Europe

      Burke, Tom; Asghar, Sohaib; orcid: 0000-0001-8276-0131; O’Hara, Jamie; Chuang, Margaret; Sawyer, Eileen K.; Li, Nanxin; email: n.li@uniqure.com (BioMed Central, 2021-12-20)
      Abstract: Background: Real-world studies of the burden of severe haemophilia B in the context of recent therapeutic advances such as extended half-life (EHL) factor IX (FIX) products are limited. We analysed data from the recent CHESS II study to better understand the clinical, humanistic, and economic burden of severe haemophilia B in Europe. Data from male adults with severe haemophilia B receiving prophylaxis were analysed from the retrospective cross-sectional CHESS II study conducted in Germany, France, Italy, Spain and the United Kingdom. Inhibitors were exclusionary. Patients and physicians completed questionnaires on bleeding, joint status, quality of life, and haemophilia-related direct and indirect costs (2019–2020). All outcomes were summarised using descriptive statistics. Results: A total of 75 CHESS II patients were eligible and included; 40 patients (53%) provided self-reported outcomes. Mean age was 36.2 years. Approximately half the patients were receiving EHL versus standard half-life (SHL) prophylaxis (44% vs 56%). Most patients reported mild or moderate chronic pain (76%) and had ≥ 2 bleeding events per year (70%), with a mean annualised bleed rate of 2.4. Mean annual total haemophilia-related direct medical cost per patient was €235,723, driven by FIX costs (€232,328 overall, n = 40; €186,528 for SHL, €290,620 for EHL). Mean annual indirect costs (€8,973) were driven by early retirement or work stoppage due to haemophilia. Mean quality of life (EQ-5D) score was 0.67. Conclusions: These data document a substantial, persistent real-world burden of severe haemophilia B in Europe. Unmet needs persist for these patients, their caregivers, and society.
    • Clinical, humanistic, and economic burden of severe hemophilia B in the United States: Results from the CHESS US and CHESS US+ population surveys

      Burke, Tom; Asghar, Sohaib; orcid: 0000-0001-8276-0131; O’Hara, Jamie; Sawyer, Eileen K.; Li, Nanxin; email: n.li@uniqure.com (BioMed Central, 2021-03-20)
      Abstract: Background: Hemophilia B is a rare congenital bleeding disorder that has a significant negative impact on patients’ functionality and health-related quality of life. The standard of care for severe hemophilia B in the United States is prophylactic factor IX replacement therapy, which incurs substantial costs for this lifelong condition. Accurate estimates of the burden of hemophilia B are important for population health management and policy decisions, but have only recently accounted for current management strategies. The ‘Cost of Severe Hemophilia across the US: a Socioeconomic Survey’ (CHESS US) is a cross-sectional database of medical record abstractions and physician-reported information, completed by hematologists and care providers. CHESS US+ is a complementary database of completed questionnaires from patients with hemophilia. Together, CHESS US and CHESS US+ provide contemporary, comprehensive information on the burden of severe hemophilia from the provider and patient perspectives. We used the CHESS US and CHESS US+ data to analyze the clinical, humanistic, and economic burden of hemophilia B for patients treated with factor IX prophylaxis between 2017 and 2019 in the US. Results: We conducted analysis to assess clinical burden and direct medical costs from 44 patient records in CHESS US, and of direct non-medical costs, indirect costs, and humanistic burden (using the EQ-5D-5L) from 57 patients in CHESS US+. The mean annual bleed rate was 1.73 (standard deviation, 1.39); approximately 9% of patients experienced a bleed-related hospitalization during the 12-month study period. Nearly all patients (85%) reported chronic pain, and the mean EQ-5D-5L utility value was 0.76 (0.24). The mean annual direct medical cost was $614,886, driven by factor IX treatment (mean annual cost, $611,971). Subgroup analyses showed mean annual costs of $397,491 and $788,491 for standard and extended half-life factor IX treatment, respectively. The mean annual non-medical direct costs and indirect costs of hemophilia B were $2,371 and $6,931. Conclusions: This analysis of patient records and patient-reported outcomes from CHESS US and CHESS US+ provides updated information on the considerable clinical, humanistic, and economic burden of hemophilia B in the US. Substantial unmet needs remain to improve patient care with sustainable population health strategies.
    • Clinical, humanistic, and economic burden of severe hemophilia B in the United States: Results from the CHESS US and CHESS US+ population surveys.

      Burke, Tom; Asghar, Sohaib; orcid: 0000-0001-8276-0131; O'Hara, Jamie; Sawyer, Eileen K; Li, Nanxin; email: n.li@uniqure.com (2021-03-20)
      Hemophilia B is a rare congenital bleeding disorder that has a significant negative impact on patients' functionality and health-related quality of life. The standard of care for severe hemophilia B in the United States is prophylactic factor IX replacement therapy, which incurs substantial costs for this lifelong condition. Accurate estimates of the burden of hemophilia B are important for population health management and policy decisions, but have only recently accounted for current management strategies. The 'Cost of Severe Hemophilia across the US: a Socioeconomic Survey' (CHESS US) is a cross-sectional database of medical record abstractions and physician-reported information, completed by hematologists and care providers. CHESS US+ is a complementary database of completed questionnaires from patients with hemophilia. Together, CHESS US and CHESS US+ provide contemporary, comprehensive information on the burden of severe hemophilia from the provider and patient perspectives. We used the CHESS US and CHESS US+ data to analyze the clinical, humanistic, and economic burden of hemophilia B for patients treated with factor IX prophylaxis between 2017 and 2019 in the US. We conducted analysis to assess clinical burden and direct medical costs from 44 patient records in CHESS US, and of direct non-medical costs, indirect costs, and humanistic burden (using the EQ-5D-5L) from 57 patients in CHESS US+. The mean annual bleed rate was 1.73 (standard deviation, 1.39); approximately 9% of patients experienced a bleed-related hospitalization during the 12-month study period. Nearly all patients (85%) reported chronic pain, and the mean EQ-5D-5L utility value was 0.76 (0.24). The mean annual direct medical cost was $614,886, driven by factor IX treatment (mean annual cost, $611,971). Subgroup analyses showed mean annual costs of $397,491 and $788,491 for standard and extended half-life factor IX treatment, respectively. The mean annual non-medical direct costs and indirect costs of hemophilia B were $2,371 and $6,931. This analysis of patient records and patient-reported outcomes from CHESS US and CHESS US+ provides updated information on the considerable clinical, humanistic, and economic burden of hemophilia B in the US. Substantial unmet needs remain to improve patient care with sustainable population health strategies.
    • Clobazam add-on therapy for drug-resistant epilepsy

      Bresnahan, Rebecca; Martin-McGill, Kirsty J; Williamson, John; Michael, Benedict D; Marson, Anthony G (Wiley, 2019-10-22)
    • Clobazam add-on therapy for drug-resistant epilepsy

      Bresnahan, Rebecca; Martin-McGill, Kirsty J; Williamson, John; Michael, Benedict D; Marson, Anthony G (Wiley, 2019-10-22)
    • Clobazam add-on therapy for drug-resistant epilepsy

      Bresnahan, Rebecca; Martin-McGill, Kirsty J; Williamson, John; Michael, Benedict D; Marson, Anthony G (Wiley, 2019-10-22)
    • Closing the gap: data-based decisions in food, nutrition and health systems: proceedings of the Fifth International Summit on Medical and Public Health Nutrition Education and Research.

      Laur, Celia; orcid: 0000-0003-4555-1407; Johnsen, Jørgen Torgerstuen; orcid: 0000-0001-8041-9968; Bradfield, James; orcid: 0000-0002-1010-2372; Eden, Timothy; Mitra, Sucheta; Ray, Sumantra (2020-09-23)
      Like many of the biological sciences, nutrition has rapidly become a science which relies heavily on data collection, analysis and presentation. Knowledge gaps exist where data does not, and so the fifth annual International Summit on Medical and Public Health Nutrition Education and Research was held to address the theme of 'Closing the Gap: Data-based Decisions in Food, Nutrition and Health Systems'. Homerton College, University of Cambridge, Cambridge in July 2019. Data-driven decision making is more likely to lead to positive change in areas such as malnutrition, food insecurity and food production. These decisions must be informed by multiple stakeholders from various backgrounds in multisectorial collaboration. Case examples presented at the Summit contribute to the International Knowledge Application Network in Nutrition 2025, which aims to help identify and close gaps in nutrition and healthcare. Formation of international networks are required to advance nutrition research, identify gaps and generate high-quality data. These data can be used to adequately train healthcare professionals resulting in positive impact on clinical and public health. Strengthening collaboration between existing networks will be essential in sharing data for better health outcomes. [Abstract copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

      West, Ryan J. H.; orcid: 0000-0001-9873-2258; email: r.j.west@sheffield.ac.uk; Sharpe, Joanne L.; Voelzmann, André; Munro, Anna L.; Hahn, Ines; Baines, Richard A.; Pickering-Brown, Stuart; email: SPB@Manchester.ac.uk (BioMed Central, 2020-09-07)
      Abstract: A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD.
    • Co-producing smart cities: A Quadruple Helix approach to assessment

      Paskaleva, Krassimira; orcid: 0000-0003-2798-3302; email: k.paskaleva@manchester.ac.uk; Evans, James; Watson, Kelly (SAGE Publications, 2021-05-31)
      Cities are increasingly expected to bring urban stakeholders together to deploy smart solutions that address urban challenges and deliver long-term positive impacts. Yet, existing theory and practice struggle to explain how such impacts can be achieved, measured or evidenced. This paper makes two major contributions. Firstly, the paper shows how the Quadruple Helix (QH) innovation approach can be used as the basis for co-producing smart city projects in order to better capture their impacts. In doing so we present a synthesis of current smart city and QH literatures to argue that assessment criteria and indicators must be co-produced with the full set of smart city stakeholders to ensure relevance to context and needs. Secondly, we present an example of a co-produced monitoring and assessment framework and methodology, developed to capture and measure the impacts of smart and sustainable city solutions with the stakeholder teams involved in the European Union Triangulum smart city programme. The paper draws on experiences working with 27 smart city demonstration projects involving public, private and third-sector organisations and communities across Manchester (United Kingdom), Eindhoven (The Netherlands) and Stavanger (Norway). We show how involving QH stakeholders in co-producing impact assessment improves the ability of projects to deliver and measure impacts that matter to cities and citizens. We conclude with a series of lessons and recommendations intended to be of use to the range of organisations and communities currently involved in smart city initiatives across Europe and the world.
    • Coalitions and Public Action in the Reshaping of Corporate Responsibility: The Case of the Retail Banking Industry

      de la Cuesta-González, Marta; Froud, Julie; orcid: 0000-0002-8330-2615; email: julie.froud@manchester.ac.uk; Tischer, Daniel (Springer Netherlands, 2020-05-25)
      Abstract: This paper addresses the question of whether and how public action via civil society and/or government can meaningfully shape industry-wide corporate responsibility (ICR) behaviour. We explore how, in principle, ICR can come about and what conditions might be effective in promoting more ethical behaviour. We propose a framework to understand attempts to develop more responsible behaviour at an industry level through processes of negotiation and coalition building. We suggest that any attempt to meaningfully influence ICR would require stakeholders to possess both power and legitimacy; moreover, magnitude and urgency of the issue at stake may affect the ability to influence ICR. The framework is applied to the retail banking industry, focusing on post-crisis experiences in two countries—Spain and the UK—where there has been considerable pressure on the retail banking industry by civil society and/or government to change behaviours, especially to abandon unethical practices. We illustrate in this paper how corporate responsibility at the sector level in retail banking is the product of context-specific processes of negotiation between civil society and public authorities, on behalf of customers and other stakeholders, drawing on legal and other institutions to influence industry behaviour.
    • Cognitive and Electrophysiological Correlates of Working Memory Impairments in Neurofibromatosis Type 1.

      Pobric, Gorana; Taylor, Jason R; Ramalingam, Hemavathy M; Pye, Emily; Robinson, Louise; Vassallo, Grace; Jung, JeYoung; Bhandary, Misty; Szumanska-Ryt, Karolina; Theodosiou, Louise; et al. (2021-05-08)
      Neurofibromatosis 1 (NF1) is a single gene disorder associated with working Memory (WM) impairments. The aim of this study was to investigate P300 event-related potential (ERP) associated with WM in NF1. Sixteen adolescents with NF1 were compared with controls on measures of WM and EEG was recorded during a WM nback task. The NF1 group showed poorer performance on measures of WM as compared to the control group. No group differences were observed in P300 amplitude at Pz, but P300 latency was shorter in the NF1 group. Topographic analyses of P300 amplitude showed group differences indicating neural processing differences in the NF1 group relative to controls, which possibly contribute to the cognitive deficits seen in this population.
    • Cohomology of profinite groups of bounded rank

      Symonds, Peter; email: Peter.Symonds@manchester.ac.uk (2021-10-11)
      Abstract: We generalise to profinite groups some of our previous results on the cohomology of pro‐ p groups of bounded sectional p ‐rank.
    • Collaborative management of the Grand Ethiopian Renaissance Dam increases economic benefits and resilience

      Basheer, Mohammed; orcid: 0000-0001-9468-2249; Nechifor, Victor; orcid: 0000-0001-8034-4070; Calzadilla, Alvaro; orcid: 0000-0001-8424-8473; Siddig, Khalid; orcid: 0000-0003-1339-4507; Etichia, Mikiyas; Whittington, Dale; Hulme, David; Harou, Julien J.; email: julien.harou@manchester.ac.uk (Nature Publishing Group UK, 2021-09-23)
      Abstract: The landscape of water infrastructure in the Nile Basin is changing with the construction of the Grand Ethiopian Renaissance Dam. Although this dam could improve electricity supply in Ethiopia and its neighbors, there is a lack of consensus between Ethiopia, Sudan, and Egypt on the dam operation. We introduce a new modeling framework that simulates the Nile River System and Egypt’s macroeconomy, with dynamic feedbacks between the river system and the macroeconomy. Because the two systems “coevolve” throughout multi-year simulations, we term this a “coevolutionary” modeling framework. The framework is used to demonstrate that a coordinated operating strategy could allow the Grand Ethiopian Renaissance Dam to help meet water demands in Egypt during periods of water scarcity and increase hydropower generation and storage in Ethiopia during high flows. Here we show the hydrological and macroeconomic performance of this coordinated strategy compared to a strategy that resembles a recent draft proposal for the operation of the dam discussed in Washington DC.
    • Collaborative management of the Grand Ethiopian Renaissance Dam increases economic benefits and resilience.

      Basheer, Mohammed; orcid: 0000-0001-9468-2249; Nechifor, Victor; orcid: 0000-0001-8034-4070; Calzadilla, Alvaro; orcid: 0000-0001-8424-8473; Siddig, Khalid; orcid: 0000-0003-1339-4507; Etichia, Mikiyas; Whittington, Dale; Hulme, David; Harou, Julien J; email: julien.harou@manchester.ac.uk (2021-09-23)
      The landscape of water infrastructure in the Nile Basin is changing with the construction of the Grand Ethiopian Renaissance Dam. Although this dam could improve electricity supply in Ethiopia and its neighbors, there is a lack of consensus between Ethiopia, Sudan, and Egypt on the dam operation. We introduce a new modeling framework that simulates the Nile River System and Egypt's macroeconomy, with dynamic feedbacks between the river system and the macroeconomy. Because the two systems "coevolve" throughout multi-year simulations, we term this a "coevolutionary" modeling framework. The framework is used to demonstrate that a coordinated operating strategy could allow the Grand Ethiopian Renaissance Dam to help meet water demands in Egypt during periods of water scarcity and increase hydropower generation and storage in Ethiopia during high flows. Here we show the hydrological and macroeconomic performance of this coordinated strategy compared to a strategy that resembles a recent draft proposal for the operation of the dam discussed in Washington DC.
    • Combined bezafibrate, medroxyprogesterone acetate and valproic acid treatment inhibits osteosarcoma cell growth without adversely affecting normal mesenchymal stem cells

      Sheard, Jonathan J.; Southam, Andrew D.; MacKay, Hannah L.; Ellington, Max A.; Snow, Martyn D.; Khanim, Farhat L.; Bunce, Christopher M.; Johnson, William E.; orcid: 0000-0002-7247-9087 (Portland Press Ltd., 2021-01-05)
      Abstract Drug repurposing is a cost-effective means of targeting new therapies for cancer. We have examined the effects of the repurposed drugs, bezafibrate, medroxyprogesterone acetate and valproic acid on human osteosarcoma cells, i.e., SAOS2 and MG63 compared with their normal cell counterparts, i.e. mesenchymal stem/stromal cells (MSCs). Cell growth, viability and migration were measured by biochemical assay and live cell imaging, whilst levels of lipid-synthesising enzymes were measured by immunoblotting cell extracts. These drug treatments inhibited the growth and survival of SAOS2 and MG63 cells most effectively when used in combination (termed V-BAP). In contrast, V-BAP treated MSCs remained viable with only moderately reduced cell proliferation. V-BAP treatment also inhibited migratory cell phenotypes. MG63 and SAOS2 cells expressed much greater levels of fatty acid synthase and stearoyl CoA desaturase 1 than MSCs, but these elevated enzyme levels significantly decreased in the V-BAP treated osteosarcoma cells prior to cell death. Hence, we have identified a repurposed drug combination that selectively inhibits the growth and survival of human osteosarcoma cells in association with altered lipid metabolism without adversely affecting their non-transformed cell counterparts.
    • Combined Pulsed RF GD-OES and HAXPES for Quantified Depth Profiling through Coatings

      Bouttemy, Muriel; orcid: 0000-0001-5907-2576; email: muriel.bouttemy@uvsq.fr; Béchu, Solène; email: solene.bechu@uvsq.fr; Spencer, Ben F.; email: ben.spencer@manchester.ac.uk; Dally, Pia; email: pia.dally@ipvf.fr; Chapon, Patrick; email: patrick.chapon@horiba.com; Etcheberry, Arnaud; email: arnaud.etcheberry@uvsq.fr (MDPI, 2021-06-11)
      Chemical characterization at buried interfaces is a real challenge, as the physico-chemical processes operating at the interface govern the properties of many systems and devices. We have developed a methodology based on the combined use of pulsed RF GD-OES (pulsed Radio Frequency Glow Discharge Optical Emission Spectrometry) and XPS (X-ray Photoelectron Spectroscopy) to facilitate the access to deeply buried locations (taking advantage of the high profiling rate of the GD-OES) and perform an accurate chemical diagnosis using XPS directly inside the GD crater. The reliability of the chemical information is, however, influenced by a perturbed layer present at the surface of the crater, hindering traditional XPS examination due to a relatively short sampling depth. Sampling below the perturbed layer may, however, can be achieved using a higher energy excitation source with an increased sampling depth, and is enabled here by a new laboratory-based HAXPES (Hard X-ray PhotoElectron Spectroscopy) (Ga-Kα, 9.25 keV). This new approach combining HAXPES with pulsed RF GD-OES requires benchmarking and is here demonstrated and evaluated on InP. The perturbed depth is estimated and the consistency of the chemical information measured is demonstrated, offering a new route for advanced chemical depth profiling through coatings and heterostructures.
    • Combining single and double parton scatterings in a parton shower

      Cabouat, Baptiste; email: baptiste.cabouat@manchester.ac.uk; Gaunt, Jonathan R. (Springer Berlin Heidelberg, 2020-10-01)
      Abstract: Double parton scattering (DPS) processes in which there is a perturbative “1 → 2” splitting in both protons overlap with loop corrections to single parton scattering (SPS). Any fundamental theoretical treatment of DPS needs to address this double-counting issue. In this paper, we augment our Monte-Carlo simulation of DPS, dShower, to be able to generate kinematic distributions corresponding to the combination SPS+DPS without double counting. To achieve this, we formulate a fully-differential version of the subtraction scheme introduced in Diehl et al. (JHEP 06 (2017) 083). A shower is attached to the subtraction term, and this is combined with the dShower DPS shower along with the usual SPS shower. We perform a proof-of-concept study of this new algorithm in the context of Z0Z0 production. Once the subtraction term is included, we verify that the results do not depend strongly on the artificial “DPS-SPS demarcation” scale ν. As part of the development of the new algorithm, we improve the kinematics of the 1 → 2 splitting in the DPS shower (and subtraction term), allowing the daughter partons to have a relative transverse momentum. Several reasonable choices for the transverse profile in the 1 → 2 splitting are studied. We find that many kinematic distributions are not strongly affected by the choice, although we do observe some differences in the region where the transverse momenta of both bosons are small.