Optimisation of a Multi-Functional Piezoelectric Component for a Climbing Robot.

Force sensors on climbing robots give important information to the robot control system, however, off-the-shelf sensors can be both heavy and bulky. We investigate the optimisation of a lightweight integrated force sensor made of piezoelectric material for the multi-limbed climbing robot MAGNETO. We focus on three design objectives for this piezoelectric component. The first is to develop a lightweight component with minimal compliance that can be embedded in the foot of the climbing robot. The second objective is to ensure that the component has sensing capability to replace the off-the-shelf force sensor. Finally, the component should be robust for a range of climbing configurations. To this end, we focus on a compliance minimisation problem with constrained voltage and volume fraction. We present structurally optimised designs that satisfy the three main design criteria and improve upon baseline results from a reference component. Our computational study demonstrates that the optimisation of embedded robotic components with piezoelectric sensing is worthy of future investigation.

Stochastic analysis of capillary condensation in disordered mesopores.

Most mesoporous materials of practical interest are inherently disordered, which has a significant impact on the condensation and evaporation of vapours in their pores. Traditionally, the effect of disorder is theoretically analyzed in a perturbative approach whereby slight elements of disorder (constriction, corrugation) are added to geometrically ideal pores. We propose an alternative approach, which consists of using a stochastic geometrical model to describe both the porous material and the condensate within the pores. This is done through a multiphase generalisation of the standard Gaussian random field model of disordered materials. The model parameters characterising the condensate provide a low-dimensional approximation of its configuration space, and we use a Derjaguin-Broekhoff-de Boer approximation to calculate the free-energy landscape. Our analysis notably questions the existence of vapour-like metastable states in realistically disordered mesoporous materials. Beyond capillary condensation, our general methodology is applicable to a broad array of confined phenomena.

Seizure induced by sudden cessation of pregabalin in a patient with chronic kidney disease.

A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a diarrhoeal illness. She was found to have acute on chronic renal impairment with an estimated glomerular filtration rate (eGFR) of 10 mL/min, and her usual 150 mg/day of pregabalin was abruptly ceased. Although renal recovery to her baseline of eGFR 15 mL/min was achieved within 3 days, her pregabalin was not restarted. She suffered a tonic-clonic seizure 4 days later, thought to be due to pregabalin withdrawal as there were no other likely causes identified. She suffered no further seizures on recommencement of pregabalin at a renally adjusted dose of 75 mg/day.

Physically Realizable Three-Dimensional Bone Prosthesis Design With Interpolated Microstructures.

We present a new approach to designing three-dimensional, physically realizable porous femoral implants with spatially varying microstructures and effective material properties. We optimize over a simplified design domain to reduce shear stress at the bone-prosthetic interface with a constraint on the bone resorption measured using strain energy. This combination of objective and constraint aims to reduce implant failure and allows a detailed study of the implant designs obtained with a range of microstructure sets and parameters. The microstructure sets are either specified directly or constructed using shape interpolation between a finite number of microstructures optimized for multifunctional characteristics. We demonstrate that designs using varying microstructures outperform designs with a homogeneous microstructure for this femoral implant problem. Further, the choice of microstructure set has an impact on the objective values achieved and on the optimized implant designs. A proof-of-concept metal prototype fabricated via selective laser melting (SLM) demonstrates the manufacturability of designs obtained with our approach.

Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.

BACKGROUND: Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. RESULTS: Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10-8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10-4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. CONCLUSIONS: Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.

Contact inhibition of locomotion and mechanical cross-talk between cell-cell and cell-substrate adhesion determine the pattern of junctional tension in epithelial cell aggregates.

We used a computational approach to analyze the biomechanics of epithelial cell aggregates-islands, stripes, or entire monolayers-that combines both vertex and contact-inhibition-of-locomotion models to include cell-cell and cell-substrate adhesion. Examination of the distribution of cell protrusions (adhesion to the substrate) in the model predicted high-order profiles of cell organization that agree with those previously seen experimentally. Cells acquired an asymmetric distribution of basal protrusions, traction forces, and apical aspect ratios that decreased when moving from the edge to the island center. Our in silico analysis also showed that tension on cell-cell junctions and apical stress is not homogeneous across the island. Instead, these parameters are higher at the island center and scale up with island size, which we confirmed experimentally using laser ablation assays and immunofluorescence. Without formally being a three-dimensional model, our approach has the minimal elements necessary to reproduce the distribution of cellular forces and mechanical cross-talk, as well as the distribution of principal stress in cells within epithelial cell aggregates. By making experimentally testable predictions, our approach can aid in mechanical analysis of epithelial tissues, especially when local changes in cell-cell and/or cell-substrate adhesion drive collective cell behavior.

Modelling wound closure in an epithelial cell sheet using the cellular Potts model.

We use a two-dimensional cellular Potts model to represent the behavior of an epithelial cell layer and describe its dynamics in response to a microscopic wound. Using an energy function to describe properties of the cells, we found that the interaction between contractile tension along cell-cell junctions and cell-cell adhesion plays an important role not only in determining the dynamics and morphology of cells in the monolayer, but also in influencing whether or not a wound in the monolayer will close. Our results suggest that, depending on the balance between cell-cell adhesion and junctional tension, mechanics of the monolayer can either correspond to a hard or a soft regime that determines cell morphology and polygonal organization in the monolayer. Moreover, the presence of a wound in a hard regime, where junctional tension is significant, can lead to two results: (1) wound closure or (2) an initial increase and expansion of the wound area towards an equilibrium value. Theoretical approximations and simulations allowed us to determine the thresholds in the values of cell-cell adhesion and initial wound size that allow the system to lead to wound closure. Overall, our results suggest that around the site of injury, changes in the balance between contraction and adhesion determine whether or not non-monotonous wound closure occurs.

The morbidity and mortality linked to melancholia: two cohorts compared, 1875-1924 and 1995-2005.

For over a century, melancholia has been linked to increased rates of morbidity and mortality. Data from two epidemiologically complete cohorts of patients presenting to mental health services in North Wales (1874-1924 and 1995-2005) have been used to look at links between diagnoses of melancholia in the first period and severe hospitalized depressive disorders today and other illnesses, and to calculate mortality rates. This is a study of the hospitalized illness rather than the natural illness, and the relationship between illness and hospitalization remains poorly understood. These data confirm that melancholia is associated with a substantial increase in the standardized mortality rate both formerly and today, stemming from a higher rate of deaths from tuberculosis in the historical sample and from suicide in the contemporary sample. The data do not link melancholia to cancer or cardiac disease. The comparison between outcomes for melancholia historically and severe mood disorder today argue favourably for the effectiveness of asylum care.

Mortality in schizophrenia and related psychoses: data from two cohorts, 1875-1924 and 1994-2010.

OBJECTIVE: To investigate death rates in schizophrenia and related psychoses. DESIGN: Data from two epidemiologically complete cohorts of patients presenting for the first time to mental health services in North Wales for whom there are at least 1, and up to 10-year follow-up data have been used to calculate survival rates and standardised death rates for schizophrenia and related psychoses. SETTING: The North Wales Asylum Denbigh (archived patient case notes) and the North West Wales District General Hospital psychiatric unit. POPULATION: Cohort 1: The North Wales Asylum Denbigh (archived patient case notes). Of 3168 patients admitted to the North Wales Asylum Denbigh 1875-1924, 1074 had a schizophrenic or related psychosis. Cohort 2: Patients admitted between 1994 and 2010 to the North West Wales District General Hospital psychiatric unit, of whom 355 had first admissions for schizophrenia or related psychoses. RESULTS: We found a 10-year survival probability of 75% in the historical cohort and a 90% survival probability in the contemporary cohort with a fourfold increase in standardised death rates in schizophrenia and related psychoses in both historical and contemporary periods. Suicide is the commonest cause of death in schizophrenia in the contemporary period (SMR 35), while tuberculosis was the commonest cause historically (SMR 9). In the contemporary data, deaths from cardiovascular causes arise in the elderly and deaths from suicide in the young. CONCLUSIONS: Contemporary death rates in schizophrenia and related psychoses are high but there are particular hazards and windows of risk that enable interventions. The data point to possible interventions in the incident year of treatment that could give patients with schizophrenia a normal life expectancy.

The incidence of admissions for schizophrenia and related psychoses in two cohorts: 1875-1924 and 1994-2010.

Objective To investigate changes in incidence of admissions for schizophrenia and related non-affective psychoses in North Wales. Design Data from two epidemiologically complete cohorts of patients presenting for the first time to mental health services in North Wales between 1875-1924 and 1994-2010 are used in this study to map the incidence of hospital admissions for schizophrenia and non-affective psychoses. Setting The North Wales Asylum Denbigh (archived patient case notes) and the North West Wales District General Hospital psychiatric unit. Population 3168 patients admitted to the North Wales Asylum Denbigh between 1875 and 1924 and 355 patients admitted to the District General Hospital psychiatric unit between 1994 and 2010. Results There was an increasing admission incidence for schizophrenia between 1875 and 1900, a higher admission rate in the 1990s for men, followed by a drop in rates of admission for both genders since 2006. Admission incidences switch from parity between the sexes in the historical period to a doubling of the admission rates for men compared with women in the modern period. This admission pattern differs from the admission patterns for affective psychoses or organic disorders. Conclusion There have been changes in the incidence of admissions for schizophrenia in North Wales.

The incidence and prevalence of admissions for melancholia in two cohorts (1875-1924 and 1995-2005).

BACKGROUND AND METHOD: There have been recent proposals to have melancholia reinstated in classification systems as a disorder distinct from major depressive disorder. Data from two epidemiologically complete cohorts of patients presenting to mental health services in North Wales between 1875-1924 and 1995-2005 have been used to map the features of melancholia. RESULTS: The data point to a decline in the contemporary incidence of hospital admissions for depressive psychosis, and greater heterogeneity among hospitalized severe non-psychotic depressions today. They indicate that historically untreated episodes of "melancholia" had a sudden onset, an average duration of less than 6 months and a lesser likelihood of relapse than severe depressive disorders have today. LIMITATIONS: This is a study of the hospitalized illness rather than the natural illness and the relationship between illness and being hospitalized remains at present poorly understood. CONCLUSIONS: These are the first data on the comparative incidence and natural history of melancholia in historical and contemporary samples. They point to the distinctiveness of the condition and support arguments for its separation from other mood disorders.

Electrostatic approximation of source-to-target mean first-passage times on networks.

We show that the distance dependence of the source-to-target mean-first-passage time (MFPT) on a finite network with M links is approximately given by 2M times the target-to-shell resistance. For networks on which a random walker is transient the long-range MFPT is well approximated by the site-dependent resistance from the target to infinity. The result extends a recent scaling result for the MFPT to site-inhomogeneous lattices where the MFPT depends on the location of the source and targets and can be highly source-target asymmetric.

Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.

OBJECTIVE: Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 µmol/L; n = 59), IDeg(B) (900 µmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments. CONCLUSIONS: In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.

Impact of implementation of evidence-based strategies to reduce door-to-balloon time in patients presenting with STEMI: continuous data analysis and feedback using a statistical process control plot.

BACKGROUND: Strategies to reduce DTB (door-to-balloon) time have been previously described. However, there is no well-established data-monitoring system that can be used for prompt feedback. The aims of this study were to use statistical process control (SPC) methodology to measure current processes, to provide real-time feedback on the impact of a change in service delivery and to identify individual outliers for specific investigation. METHODS: A prospective study was conducted in a tertiary centre in North England. Data were collected for 841 consecutive STEMI patients from the local district undergoing PPCI. The impact on median DTB time after changes in protocols were prospectively determined. RESULTS: Median DTB times fell significantly as a result of changes in protocol. The upper control limit (UCL) decreased from 209 to 86 min and narrower control limits indicated improved performance. The main outliers included patients presenting to the Accident and Emergency department and patients who developed STEMI while being treated in non-cardiology wards for other reasons (18.3% of the study population). CONCLUSIONS: SPC provides a statistically robust mechanism for assessing the effect of process redesign interventions, and in this context provides a clear visual representation of DTB times for individual patients. Identification of significant outliers allows investigation of any variation with a special cause. It allows a unit to identify when a system of service delivery, albeit stable, is inadequate and needs redesign and can monitor the impact of changes in protocol.

Diffusion on asymmetric fractal networks.

We derive a renormalization method to calculate the spectral dimension d of deterministic self-similar networks with arbitrary base units and branching constants. The generality of the method allows the affect of a multitude of microstructural details to be quantitatively investigated. In addition to providing models for physical networks, the results allow precise tests of theories of diffusive transport. For example, the properties of a class of nonrecurrent trees (d > 2) with asymmetric elements and branching violate the Alexander-Orbach scaling law.

Generalization of the fractal Einstein law relating conduction and diffusion on networks.

We settle a long-standing controversy about the exactness of the fractal Einstein and Alexander-Orbach laws by showing that the properties of a class of fractal trees violate both laws. A new formula is derived which unifies the two classical results by showing that if one holds, then so must the other, and resolves a puzzling discrepancy in the properties of Eden trees and diffusion-limited aggregates. We also conjecture that the result holds for networks which have no fractal dimension. The failure of the classical laws is attributed to anisotropic exploration of the network by a random walker. The occurrence of this newly revealed behavior means that the conventional laws must be checked if they, or numerous results which depend on them, are to be applied accurately.

Funnel plots for comparing performance of PCI performing hospitals and cardiologists: demonstration of utility using the New York hospital mortality data.

BACKGROUND: The New York State Department of Health collects and reports outcome data on the hospitals and cardiologists who perform percutaneous coronary intervention (PCI) to allow them to examine their quality of care. Results are provided in tabular form. However funnel plots are the display method of choice for comparison of institutions and operators, using the principles of statistical process control (SPC). We aimed to demonstrate that funnel plots, which aid a meaningful interpretation of the results, can be derived from the New York PCI dataset. METHODS: The risk-adjusted mortality rates for 48 hospitals and cardiologists performing PCI were used for this analysis. Funnel plots (with control limits at 3 and 2 sigma) of all hospitals and operators performing PCI procedures were generated. Separate plots for emergency and nonemergency PCI procedures were derived. RESULTS: 149,888 patients underwent PCI procedures between January 1, 2002 and December 31, 2004. The 3-year risk-adjusted mortality rates for all PCI patients ranged from 0.00 to 1.37%. The funnel plots show risk-adjusted mortality rates against the denominator for that percentage (number of cases), displayed as a scatter plot and compared with the binomial funnel plot calculated around the mean for all cases reported. The risk-adjusted mortality rates of all hospitals were within 3 sigma (99.8%) upper control limits. The risk-adjusted mortality rates for three hospitals were above or on the upper warning limit (2 sigma control limit, equating to the 95% confidence interval) and three hospitals had risk-adjusted mortality rates below the 2 and 3 sigma control limits. CONCLUSION: The SPC funnel plot is an easy-to-interpret, risk-adjusted means of identifying units whose performance, in terms of mortality, diverges significantly from the population mean. Funnel plots may be applied to a complex dataset and allow a visual comparison of data derived from multiple healthcare units. Variation is readily identified permitting hospitals and cardiologists to appraise their practices so that effective quality improvement may take place.

Structure development of resorcinol-formaldehyde gels: microphase separation or colloid aggregation.

Time-resolved small-angle x-ray scattering (SAXS) is used to follow the formation of resorcinol-formaldehyde (RF) gels. An existing morphological model based on Gaussian random fields, and validated on RF aerogels, is generalized to analyze the data. The generalization is done in two different ways, one being relevant to colloid aggregation and the other to microphase separation. The SAXS data do not enable discrimination between the two mechanisms of gel formation, which shows that aggregation and microphase separation can generate very similar morphologies at the length scales explored by SAXS. Furthermore, physical arguments suggest that, in the case of RF gels, aggregation and microphase separation can be regarded as two idealizations of the same complex physical process.

Cumulative funnel plots for the early detection of interoperator variation: retrospective database analysis of observed versus predicted results of percutaneous coronary intervention.

OBJECTIVE: To use funnel plots and cumulative funnel plots to compare in-hospital outcome data for operators undertaking percutaneous coronary interventions with predicted results derived from a validated risk score to allow for early detection of variation in performance. DESIGN: Analysis of prospectively collected data. SETTING: Tertiary centre NHS hospital in the north east of England. PARTICIPANTS: Five cardiologists carrying out percutaneous coronary interventions between January 2003 and December 2006. MAIN OUTCOME MEASURES: In-hospital major adverse cardiovascular and cerebrovascular events (in-hospital death, Q wave myocardial infarction, emergency coronary artery bypass graft surgery, and cerebrovascular accident) analysed against the logistic north west quality improvement programme predicted risk, for each operator. Results are displayed as funnel plots summarising overall performance for each operator and cumulative funnel plots for an individual operator's performance on a case series basis. RESULTS: The funnel plots for 5198 patients undergoing percutaneous coronary interventions showed an average observed rate for major adverse cardiovascular and cerebrovascular events of 1.96% overall. This was below the predicted risk of 2.06% by the logistic north west quality improvement programme risk score. Rates of in-hospital major adverse cardiovascular and cerebrovascular events for all operators were within the 3sigma upper control limit of 2.75% and 2sigma upper warning limit of 2.49%. CONCLUSION: The overall in-hospital major adverse cardiovascular and cerebrovascular events rates were under the predicted event rate. In-hospital rates after percutaneous coronary intervention procedure can be monitored successfully using funnel and cumulative funnel plots with 3sigma control limits to display and publish each operator's outcomes. The upper warning limit (2sigma control limit) could be used for internal monitoring. The main advantage of these charts is their transparency, as they show observed and predicted events separately. By this approach individual operators can monitor their own performance, using the predicted risk for their patients but in a way that is compatible with benchmarking to colleagues, encapsulated by the funnel plot. This methodology is applicable regardless of variations in individual operator case volume and case mix.