What Next After Metformin in Type 2 Diabetes? Selecting the Right Drug for the Right Patient

This is the final version. Available on open access from Springer via the DOI in this recordIntroduction: Metformin is the recommended initial treatment in type 2 diabetes mellitus (T2DM), but when this does not give adequate glucose control the choice of which second-line drug to use is uncertain as none have been found to have a better overall glycaemic response. In this real-world study dipeptidyl peptidase 4 inhibitors (DPP4i), sulphonylureas (SU), thiazolidinediones (TZD) and sodium glucose co-transporter 2 inhibitors (SGLT2i) were compared for their effectiveness in lowering glycated haemoglobin (HbA1c) levels for a particular individual based on their clinical characteristics. Methods: A retrospective analysis was undertaken of electronic health records of people with T2DM prescribed metformin alongside a DPP4i, SU, TZD or SGLT2i at second-line. Regression modelling was used to model the changes in HbA1c from baseline at month 6 and month 12 for the individual therapies, adjusting for demographic and clinical characteristics. Results: There were 7170 people included in the study. Treatment at second-line with SUs, DPP4i, TZDs and SGLT2i resulted in similar percentages of people achieving the recommended HbA1c target of < 7.5% (58 mmol/mol) at both 6 and 12 months. For those receiving SGLT2i and SUs, the greatest improvement in HbA1c was observed in relatively younger and older people, respectively. Trends were detected between other baseline characteristics and HbA1c improvement by drug class, but they were not statistically significant. Non-adherence rates were low for all drug classes. People with a higher medication possession ratio (≥ 80%) also had greater improvements in HbA1c at 12 months. Conclusion: This study identified patients’ phenotypic characteristics that may have the potential to influence individual treatment response. Accounting for these characteristics in clinical treatment decisions may facilitate individualised prescribing by being able to select the right drug for the right patient.Takeda UK Ltd

Counter-propagating radiative shock experiments on the Orion laser and the formation of radiative precursors

We present results from new experiments to study the dynamics of radiative shocks, reverse shocks and radiative precursors. Laser ablation of a solid piston by the Orion high-power laser at AWE Aldermaston UK was used to drive radiative shocks into a gas cell initially pressurised between $0.1$ and $1.0 \ bar with different noble gases. Shocks propagated at {80 \pm 10 \ km/s} and experienced strong radiative cooling resulting in post-shock compressions of { \times 25 \pm 2}. A combination of X-ray backlighting, optical self-emission streak imaging and interferometry (multi-frame and streak imaging) were used to simultaneously study both the shock front and the radiative precursor. These experiments present a new configuration to produce counter-propagating radiative shocks, allowing for the study of reverse shocks and providing a unique platform for numerical validation. In addition, the radiative shocks were able to expand freely into a large gas volume without being confined by the walls of the gas cell. This allows for 3-D effects of the shocks to be studied which, in principle, could lead to a more direct comparison to astrophysical phenomena. By maintaining a constant mass density between different gas fills the shocks evolved with similar hydrodynamics but the radiative precursor was found to extend significantly further in higher atomic number gases (\sim$$4$ times further in xenon than neon). Finally, 1-D and 2-D radiative-hydrodynamic simulations are presented showing good agreement with the experimental data.Comment: HEDLA 2016 conference proceeding

Marginalization of end-use technologies in energy innovation for climate protection

Mitigating climate change requires directed innovation efforts to develop and deploy energy technologies. Innovation activities are directed towards the outcome of climate protection by public institutions, policies and resources that in turn shape market behaviour. We analyse diverse indicators of activity throughout the innovation system to assess these efforts. We find efficient end-use technologies contribute large potential emission reductions and provide higher social returns on investment than energy-supply technologies. Yet public institutions, policies and financial resources pervasively privilege energy-supply technologies. Directed innovation efforts are strikingly misaligned with the needs of an emissions-constrained world. Significantly greater effort is needed to develop the full potential of efficient end-use technologies

Developing Objective Metrics for Unit Staffing (DOMUS) study

OBJECTIVE: Safe midwifery staffing levels on delivery suites is a priority area for any maternity service. Escalation policies are tools that provide an operational response to emergency pressures. The aim of this study was to assess the feasibility of using a scoring system to contemporaneously assess the required staffing level based on demand and use this to determine delivery suite escalation level and utilise the information generated regarding clinical activity (Demand) and staffing levels (Capacity) to generate unit-specific calculation for the actual number of midwifery staff required. SETTING: A maternity unit of a university-affiliated tertiary referral hospital. DESIGN: Over a 12-month period, specifically designed scoring sheets were completed by delivery suite shift co-ordinators four times a day (04:00, 10:00, 16:00 and 22:00). Based on the dependency score (Demand) and the number of midwifery staff available (Capacity), an escalation level was determined for each shift. The 80th centile of the demand was used to determine optimal capacity. RESULTS: A total of 1160 scoring sheets were completed. Average staff number throughout the year on any shift was 7 (range 3–11). Average dependency score was 7 (range 1–14). The 80th centile for demand was calculated to be 11. CONCLUSIONS: This study stresses the importance and usefulness of a simple tool that can be used to determine the level of escalation on delivery suite based on an objective scoring system and can also be used to determine the appropriate staffing on delivery suite

Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial

BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is non-inferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: haemoglobin efficacy and cardiovascular safety. METHODS: We report the trial design, key demographic, clinical, and laboratory findings, and baseline therapies of 2964 patients randomised in the open-label (sponsor-blinded) active-controlled, parallel-group, randomised ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large cardiovascular outcome trials (CVOTs) and in the most relevant registries. RESULTS: The median age of patients was 58 years, 43% were female; 67% were white and 16% were black. The median haemoglobin at baseline was 10.4 g/dL. Among randomised patients, 89% were receiving haemodialysis and 11% peritoneal dialysis. Among key co-morbidities, 42% reported a history of diabetes mellitus, and 45% a history of cardiovascular disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron use was noted in 64% and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. CONCLUSION: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anaemia with CKD G5D

Gross solids from combined sewers in dry weather and storms, elucidating production, storage and social factors

Variation in rates of sanitary hygiene products, toilet tissue and faeces occurring in sewers are presented for dry and wet weather from three steep upstream urban catchments with different economic, age and ethnic profiles. Results show, for example, that total daily solids per capita from the low income and ageing populations are almost twice that from high income or ethnic populations. Relative differences are verified through independent questionnaires. The relationship between solids stored in sewers prior to storms, antecedent dry weather period and the proportion of roof to total catchment area is quantified. A full solids' flush occurs when storm flows exceed three times the peak dry weather flow. The data presented will assist urban drainage designers in managing pollution caused by the discharge of sewage solids

The ASCEND-ND trial: Study design and participant characteristics

BACKGROUND: Anaemia is common in chronic kidney disease (CKD), and assessment of the risks and benefits of new therapies is important. METHODS: The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL, or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open- label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28 to 52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. RESULTS: Overall, 3872 patients were randomised from 39 countries (median age 67 years, 56% female; 56% White, 27% Asian, and 10% Black). Median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and eGFR was 18 mL/min/1.73 m2. Among randomised patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin- angiotensin system blockers, 55% were taking statin and 49% oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. CONCLUSION: ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients A Randomized Clinical Trial

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients. Design, Setting, and Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa. Main Outcomes and Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability. Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. Conclusions and Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population. Trial Registration: ClinicalTrials.gov Identifier: NCT03029208

The challenge of policy coordination for sustainable sociotechnical transitions: the case of the zero-carbon homes agenda in England

Emerging in recent research on sociotechnical transitions towards a low-carbon economy is the question of the extent to which such transitions require centralised, intentional coordination by government. Drawing from Hayek's conceptualisation of coordination, I evaluate the effectiveness of policy for low-carbon and zero-carbon homes in England. A detailed analysis is presented of how policy makers address complex choices and trade-offs as well as significant uncertainty. Particular attention is given to those policy decisions which are widely agreed by stakeholders to cause distortive effects. The focus here on the impacts of policy definition and delivery in terms of multiple evaluative criteria can complement and enrich the more process-orientated cross-sector and multilevel analyses that predominate in existing research on policy coordination. Furthermore, the coordination problems identified yield further insights into the actual and potential effectiveness of policy processes in shaping complex sociotechnical transitions

Comparing nuclear power trajectories in Germany and the UK: from ‘regimes' to ‘democracies’ in sociotechnical transitions and Discontinuities

This paper focuses on arguably the single most striking contrast in contemporary major energy politics in Europe (and even the developed world as a whole): the starkly differing civil nuclear policies of Germany and the UK. Germany is seeking entirely to phase out nuclear power by 2022. Yet the UK advocates a ‘nuclear renaissance’, promoting the most ambitious new nuclear construction programme in Western Europe.Here,this paper poses a simple yet quite fundamental question: what are the particular divergent conditions most strongly implicated in the contrasting developments in these two countries. With nuclear playing such an iconic role in historical discussions over technological continuity and transformation, answering this may assist in wider understandings of sociotechnical incumbency and discontinuity in the burgeoning field of‘sustainability transitions’. To this end, an ‘abductive’ approach is taken: deploying nine potentially relevant criteria for understanding the different directions pursued in Germany and the UK. Together constituted by 30 parameters spanning literatures related to socio-technical regimes in general as well as nuclear technology in particular, the criteria are divided into those that are ‘internal’ and ‘external’ to the ‘focal regime configuration’ of nuclear power and associated ‘challenger technologies’ like renewables. It is ‘internal’ criteria that are emphasised in conventional sociotechnical regime theory, with ‘external’ criteria relatively less well explored. Asking under each criterion whether attempted discontinuation of nuclear power would be more likely in Germany or the UK, a clear picture emerges. ‘Internal’ criteria suggest attempted nuclear discontinuation should be more likely in the UK than in Germany– the reverse of what is occurring. ‘External’ criteria are more aligned with observed dynamics –especially those relating to military nuclear commitments and broader ‘qualities of democracy’. Despite many differences of framing concerning exactly what constitutes ‘democracy’, a rich political science literature on this point is unanimous in characterising Germany more positively than the UK. Although based only on a single case,a potentially important question is nonetheless raised as to whether sociotechnical regime theory might usefully give greater attention to the general importance of various aspects of democracy in constituting conditions for significant technological discontinuities and transformations. If so, the policy implications are significant. A number of important areas are identified for future research, including the roles of diverse understandings and specific aspects of democracy and the particular relevance of military nuclear commitments– whose under-discussion in civil nuclear policy literatures raises its own questions of democratic accountability