Estimability and efficiency in nearly orthogonal 2[m1] x 3[m2] deletion designs

This article considers single replicate factorial experiments in incomplete blocks. A single replicate 2^m1 x 3^m2 deletion design in 3 incomplete blocks is obtained from a single replicate 3^m, where m = m_1 + m_2, preliminary design by deleting all runs (or treatment combinations) with the first m_1 factors at the level two. A systematic method for determining the unbiasedly estimable (u.e.) and not unbiasedly estimable (n.u.e.) factorial effects is provided. It is shown that for m_2 > 0 all factorial effects of the type F( α_1 · · · α_m_1 , α_(m_1 +1) · · · α_m), where α_i; = 0, l for i = 1, · · ·, m_1, α_i; = 0, 1, 2 for i = m_(1+1), · · ·, m, with (α_1 · · · α_m) != (0 · · · 0), and (α_m,+l · · · _m) != α(l · · · 1) for a= 1, 2, are u.e. and the remaining factorial effects are n.u.e. It is noted that (2^m_1 - 1) factorial effects of 2^m_1 factorial experiments and (3^m_2) factorial effects of 3^m, factorial experiments, which are embedded in 2^m_1 x 3^m, factorial experiments, are u. e. The 2 x 3m-l deletion designs were considered in the work of Voss (1986). Defining factorial effects of a 2^m_1 x 3^m, factorial experiment in a form different than in Voss (1986), we develop a simple representation of u.e. and n. u. e. factorial effects. In this representation, there are (2^(m_1 + 1) + 1) n. u. e. factorial effects of the type F( α_1 · · · α_m_1, α· · · α). This number is smaller than the corresponding number of n. u. e. factorial effects in the representation of Voss (1986). The relative efficiency expressions, and their bounds, in the estimation of factorial effects of 2^m_1 x 3^m_2 deletion designs are also given

Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes:A joint modelling approach

This is the author accepted manuscript. The final version is available from Dove Medical Press via the DOI in this record.Data statement: No additional data are available from the authors although the individual participant data from the ADOPT trial used in this study are available from GlaxoSmithKline on application via www.clinicalstudydatarequest.comObjective: Precision medicine drug therapy seeks to maximise efficacy and minimise harm for individual patients. This will be difficult if drug response and side-effects are positively associated, meaning patients likely to respond best are at increased risk of side-effects. We applied joint longitudinal-survival models to evaluate associations between drug response (longitudinal outcome) and risk of side-effects (survival outcome) for patients initiating type 2 diabetes therapy. Study Design and Setting: Participants were randomised to metformin, sulfonylurea or thiazolidinedione therapy in the ADOPT drug-efficacy trial (n=4,351). Joint models were parameterised for: 1) current HbA1c response (change from baseline in HbA1c); 2) cumulative HbA1c response (total HbA1c change). Results: With metformin, greater HbA1c response did not increase risk of gastrointestinal events (Hazard ratio (HR) per 1% absolute greater current response 0.82 (95% confidence interval 0.67,1.01); HR per 1% higher cumulative response 0.90 (0.81,1.00)). With sulfonylureas, greater current response was associated with increased risk of hypoglycaemia (HR 1.41 (1.04,1.91)). With thiazolidinediones, greater response was associated with increased risk of oedema (current HR 1.45 (1.05,2.01); cumulative 1.22 (1.07,1.38)) but not fracture. Conclusion: Joint modelling provides a useful framework to evaluate the association between response to a drug and risk of developing side-effects. There may be great potential for widespread application of joint modelling to evaluate the risks and benefits of both new and established medications.This work was supported by the Medical Research Council (UK) (Grant MR/N00633X/1). ATH is a NIHR Senior Investigator and a Wellcome Trust Senior Investigator. ERP is a Wellcome Trust New Investigator (102820/Z/13/Z). AGJ is supported by an NIHR Clinician Scientist award. ATH and BMS are supported by the NIHR Exeter Clinical Research Facility. WEH received additional support from IQVIA and the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR CLAHRC South West Peninsula)

Leak detection and calibration using transients and genetic algorithms

Leak detection and calibration of pipe internal roughnesses in a water network are significant issues for water authorities around the world. Computer simulation of water distribution systems to determine the location and size of leaks is emerging as an important tool. A major uncertainty in developing computer models is the condition of the interior of the pipes in the network, especially if they are old. An innovative technique for leak detection and calibration called the inverse transient technique has been recently developed. This paper uses the genetic algorithm (GA) technique in conjunction with the inverse transient method to detect leaks and friction factors in water distribution systems. A continuous variable representation has been developed for the GA coding scheme in this paper. Two new GA operators for crossover and mutation are also introduced. The inverse transient method using the GA technique is effective at finding leakage locations and magnitudes while simultaneously finding the friction factors for different transient data record lengths.John P. Vítkovský, Angus R.Simpson and Martin F. Lamber

Gearing up impact assessment as a vehicle for achieving the UN sustainable development goals

This article reflects on the potential for impact assessment (IA) to be a major vehicle for implementing the UN Sustainable Development Goals (SDGs). While it is acknowledged that the SDGs are intended to deliver broader outcomes than IA currently does, we nevertheless argue there is significant convergence between IA and the SDGs, which we explore utilising the key dimensions of sustainability assessment: comprehensiveness, strategicness and integratedness. We conclude that ‘geared up’ IA might be used as a major vehicle to facilitate achievement of the SDGs. However, IA must become more comprehensive and integrated, such that the full suite of SDGs and their relationships, including trade-offs, can be dealt with in a transparent and inclusive way. © 2019, © 2019 IAIA

Aerosol-Assisted Chemical Vapor Deposited Thin Films for Space Photovoltaics

Copper indium disulfide thin films were deposited via aerosol-assisted chemical vapor deposition using single source precursors. Processing and post-processing parameters were varied in order to modify morphology, stoichiometry, crystallography, electrical properties, and optical properties in order to optimize device-quality material. Growth at atmospheric pressure in a horizontal hot-wall reactor at 395 C yielded best device films. Placing the susceptor closer to the evaporation zone and flowing a more precursor-rich carrier gas through the reactor yielded shinier, smoother, denser-looking films. Growth of (112)-oriented films yielded more Cu-rich films with fewer secondary phases than growth of (204)/(220)-oriented films. Post-deposition sulfur-vapor annealing enhanced stoichiometry and crystallinity of the films. Photoluminescence studies revealed four major emission bands (1.45, 1.43, 1.37, and 1.32 eV) and a broad band associated with deep defects. The highest device efficiency for an aerosol-assisted chemical vapor deposited cell was 1.03 percent

Pipeline break detection using pressure transient monitoring

Sudden pipe breaks occur in water transmission pipelines and distribution mains. The consequences of these breaks can be very expensive because of the service interruption, the cost of repair, and damage to surrounding property and infrastructure. The costs associated with the pipeline breaks can be reduced by minimizing the break detection and location time. This paper presents a new continuous monitoring approach for detecting and locating breaks in pipelines. A sudden pipe break creates a negative pressure wave that travels in both directions away from the break point and is reflected at the pipeline boundaries. Using the pressure data measured at one location along the pipeline, the timing of the initial and reflected transient waves induced by the break determines the location of the break. The magnitude of the transient wave provides an estimate of the break size. The continuous monitoring technique uses a modified two-sided cumulative sum (CUSUM) algorithm to detect abrupt break-induced changes in the pressure data. The adaptive tuning of CUSUM parameters is implemented to detect breaks of differing sizes and opening times. The continuous monitoring technique is verified by using results from both laboratory and field experiments and shows potential for detecting and locating sudden breaks in real pipelines.Dalius Misiunas, John Vítkovský, Gustaf Olsson, Angus Simpson, M.ASCE, and Martin Lambert

Costimulatory molecule-deficient dendritic cell progenitors (MHC class II⁺, CD80(dim), CD86^-) prolong cardiac allograft survival in nonimmunosuppressed recipients

We have shown previously that granulocyte-macrophage colony-stimulating factor-stimulated mouse bone marrow-derived MHC class II+ dendritic cell (DC) progenitors that are deficient in cell surface expression of the costimulatory molecules B7-1 (CD8O) and B7-2 (CD86) can induce alloantigen- specific T-cell anergy in vitro. To test the in vivo relevance of these findings, 2 x 106 B10 (H2(b)) mouse bone marrow-derived DC progenitors (NLDC 145+, MHC class II+, B7-1(dim), B7-2(-/dim)) that induced T-cell hyporesponsiveness in vitro were injected systemically into normal C3H (H2(k)) recipients. Seven days later, the mice received heterotopic heart transplants from B10 donors. No immunosuppressive treatment was given. Median graft survival time was prolonged significantly from 9.5 to 22 days. Median graft survival time was also increased, although to a lesser extent (16.5 days), in mice that received third-party (BALB/c; H2(d)) DC progenitors. Ex vivo analysis of host T-cell responses to donor and third-party alloantigens 7 days after the injection of DC progenitors (the time of heart transplant) revealed minimal anti-donor mixed leukocyte reaction and cytotoxic T lymphocyte reactivity. These responses were reduced substantially compared with those of spleen cells from animals pretreated with 'mature' granulocyte- macrophage colony-stimulating factor + interleukin-4-stimulated DC (MHC class II(bright), B7-1+, B7-2(bright)), many of which rejected their heart grafts in an accelerated fashion. Among the injected donor MHC class II+ DC progenitors that migrated to recipient secondary lymphoid tissue were cells that appeared to have up-regulated cell surface B7-1 and B7-2 molecule expression. This observation may explain, at least in part, the temporary or unstable nature of the hyporesponsiveness induced by the DC progenitors in nonimmunosuppressed recipients

Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors:a retrospective analysis of primary care data, 2010-2017

This is the author accepted manuscript. The final version is available on open access from Wiley via the DOI in this recordAim: Prescribing in type 2 diabetes has changed markedly in recent years, with increasing use of newer, more expensive glucose-lowering drugs. We aimed to describe population-level time trends in both prescribing patterns and short-term patient outcomes (HbA1c, weight, blood pressure, hypoglycemia and treatment discontinuation) after initiating new therapy. Materials and methods: We studied 81,532 UK patients with type 2 diabetes initiating a first to fourth line drug in primary care between 2010-2017 inclusive (Clinical Practice Research Datalink). Trends in new prescriptions and subsequent six and twelve-month adjusted changes in glycemic response (reduction in HbA1c), weight, blood pressure, and rates of hypoglycemia and treatment discontinuation were examined. Results: DPP4-inhibitor use second-line near doubled (41% of new prescriptions in 2017 vs. 22% 2010), replacing sulfonylureas as the most common second-line drug (29% 2017 vs. 53% 2010). SGLT2-inhibitors, introduced in 2013, comprised 17% of new first-fourth line prescriptions by 2017. First-line use of metformin remained stable (91% of new prescriptions in 2017 vs. 91% 2010). Over the study period there was little change in average glycemic response and treatment discontinuation. There was a modest reduction in weight second and third-line (second line 2017 vs. 2010: -1.5 kg (95%CI -1.9;-1.1), p<0.001), and a slight reduction in systolic blood pressure first to third-line (2017 vs. 2010 difference range -1.7 to -2.1 mmHg, all p<0.001). Hypoglycemia rates decreased second-line (incidence rate ratio 0.94 per-year (95%CI 0.88;1.00, p=0.04)), mirroring the decline in use of sulfonylureas. 4 Conclusions: Recent changes in prescribing of therapy in type 2 diabetes have not led to a change in glycemic response and have resulted in modest improvements in other population-level short-term patient outcomes.Medical Research Council (MRC)National Institute for Health Research (NIHR)Wellcome Trus

Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes:the TriMaster study

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData availability: To minimize the risk of patient re-identification, de-identified individual patient-level clinical data are available under restricted access. Requests for access to anonymized individual participant data and study documents should be made to the corresponding author and will be reviewed by the Peninsula Research Bank Steering Committee. Access to data through the Peninsula Research Bank will be granted for requests with scientifically valid questions by academic teams with the necessary skills appropriate for the research. Data that can be shared will be released with the relevant transfer agreement.Code availability: Requests for access to code should be made to the corresponding author and will be reviewed by the Peninsula Research Bank Steering Committee. Access to code through the Peninsula Research Bank will be granted for requests with scientifically valid questions by academic teams with the necessary skills appropriate for the research. Code will be released by the lead statistician.Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. In this study, we tested two hypotheses: (1) individuals with body mass index (BMI) > 30 kg/m2, compared to BMI ≤ 30 kg/m2, have greater glucose lowering with thiazolidinediones than with DPP4 inhibitors, and (2) individuals with estimated glomerular filtration rate (eGFR) 60-90 ml/min/1.73 m2, compared to eGFR >90 ml/min/1.73 m2, have greater glucose lowering with DPP4 inhibitors than with SGLT2 inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. In total, 525 people with type 2 diabetes participated in this UK-based randomized, double-blind, three-way crossover trial of 16 weeks of treatment with each of sitagliptin 100 mg once daily, canagliflozin 100 mg once daily and pioglitazone 30 mg once daily added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs: pioglitazone 59.6 mmol/mol, sitagliptin 60.0 mmol/mol and canagliflozin 60.6 mmol/mol (P = 0.2). Participants with BMI > 30 kg/m2, compared to BMI ≤ 30 kg/m2, had a 2.88 mmol/mol (95% confidence interval (CI): 0.98, 4.79) lower HbA1c on pioglitazone than on sitagliptin (n = 356, P = 0.003). Participants with eGFR 60-90 ml/min/1.73 m2, compared to eGFR >90 ml/min/1.73 m2, had a 2.90 mmol/mol (95% CI: 1.19, 4.61) lower HbA1c on sitagliptin than on canagliflozin (n = 342, P = 0.001). There were 2,201 adverse events reported, and 447/525 (85%) randomized participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple, routinely available clinical measures to identify the drug class most likely to deliver the greatest glycemic reduction for a given patient. (ClinicalTrials.gov registration: NCT02653209 ; ISRCTN registration: 12039221 .).Medical Research Council (MRC)National Institute for Health and Care Research (NIHR