Is the SMART risk prediction model ready for real-world implementation? A validation study in a routine care setting of approximately 380 000 individuals

AIMS: Reliably quantifying event rates in secondary prevention could aid clinical decision-making, including quantifying potential risk reductions of novel, and sometimes expensive, add-on therapies. We aimed to assess whether the SMART risk prediction model performs well in a real-world setting. METHODS AND RESULTS: We conducted a historical open cohort study using UK primary care data from the Clinical Practice Research Datalink (2000-2017) diagnosed with coronary, cerebrovascular, peripheral, and/or aortic atherosclerotic cardiovascular disease (ASCVD). Analyses were undertaken separately for cohorts with established (≥6 months) vs. newly diagnosed ASCVD. The outcome was first post-cohort entry occurrence of myocardial infarction, stroke, or cardiovascular death. Among the cohort with established ASCVD [n = 244 578, 62.1% male, median age 67.3 years, interquartile range (IQR) 59.2-74.0], the calibration and discrimination achieved by the SMART model was not dissimilar to performance at internal validation [Harrell's c-statistic = 0.639, 95% confidence interval (CI) 0.636-0.642, compared with 0.675, 0.642-0.708]. Decision curve analysis indicated that the model outperformed treat all and treat none strategies in the clinically relevant 20-60% predicted risk range. Consistent findings were observed in sensitivity analyses, including complete case analysis (n = 182 482; c = 0.624, 95% CI 0.620-0.627). Among the cohort with newly diagnosed ASCVD (n = 136 445; 61.0% male; median age 66.0 years, IQR 57.7-73.2), model performance was weaker with more exaggerated risk under-prediction and a c-statistic of 0.559, 95% CI 0.556-0.562. CONCLUSIONS: The performance of the SMART model in this validation cohort demonstrates its potential utility in routine healthcare settings in guiding both population and individual-level decision-making for secondary prevention patients

Graphs Identified by Logics with Counting

We classify graphs and, more generally, finite relational structures that are identified by C2, that is, two-variable first-order logic with counting. Using this classification, we show that it can be decided in almost linear time whether a structure is identified by C2. Our classification implies that for every graph identified by this logic, all vertex-colored versions of it are also identified. A similar statement is true for finite relational structures. We provide constructions that solve the inversion problem for finite structures in linear time. This problem has previously been shown to be polynomial time solvable by Martin Otto. For graphs, we conclude that every C2-equivalence class contains a graph whose orbits are exactly the classes of the C2-partition of its vertex set and which has a single automorphism witnessing this fact. For general k, we show that such statements are not true by providing examples of graphs of size linear in k which are identified by C3 but for which the orbit partition is strictly finer than the Ck-partition. We also provide identified graphs which have vertex-colored versions that are not identified by Ck.Comment: 33 pages, 8 Figure

Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child (Review).

Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy. Objectives To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence. Search methods We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies. Selection criteria Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. Data collection and analysis Three authors (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible. Main results Twenty‐two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of ‐5.58 (95% confidence interval (CI) ‐10.83 to ‐0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD ‐7.22, 95% CI ‐12.76 to ‐ 1.67, P = 0.01). Further analysis using a random‐effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD ‐0.03, 95% CI ‐3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI ‐2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD ‐8.72, 95% ‐14.31 to ‐3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD ‐8.94, 95% CI ‐11.96 to ‐5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD ‐8.17, 95% CI ‐12.80 to ‐3.55, P = 0.0005). In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI ‐0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD ‐1.62, 95% CI ‐5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI ‐2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD ‐3.30, 95% CI ‐7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD ‐10.80, 95% CI ‐14.42 to ‐7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta‐analysis were reported narratively, the majority of which supported the findings of the meta‐analyses. Authors' conclusions The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre‐conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk

Associations between active travel and adiposity in rural India and Bangladesh: a cross-sectional study.

BACKGROUND: Data on use and health benefits of active travel in rural low- and middle- income country settings are sparse. We aimed to examine correlates of active travel, and its association with adiposity, in rural India and Bangladesh. METHODS: Cross sectional study of 2,122 adults (≥18 years) sampled in 2011-13 from two rural sites in India (Goa and Chennai) and one in Bangladesh (Matlab). Logistic regression was used to examine whether ≥150 min/week of active travel was associated with socio-demographic indices, smoking, oil/butter consumption, and additional physical activity. Adjusting for these same factors, associations between active travel and BMI, waist circumference and waist-to-hip ratio were examined using linear and logistic regression. RESULTS: Forty-six percent of the sample achieved recommended levels of physical activity (≥150 min/week) through active travel alone (range: 33.1 % in Matlab to 54.8 % in Goa). This was more frequent among smokers (adjusted odds ratio 1.36, 95 % confidence interval 1.07-1.72; p = 0.011) and those that spent ≥150 min/week in work-based physical activity (OR 1.71, 1.35-2.16; p < 0.001), but less frequent among females than males (OR 0.25, 0.20-0.31; p < 0.001). In fully adjusted analyses, ≥150 min/week of active travel was associated with lower BMI (adjusted coefficient -0.39 kg/m(2), -0.77 to -0.02; p = 0.037) and a lower likelihood of high waist circumference (OR 0.77, 0.63-0.96; p = 0.018) and high waist-to-hip ratio (OR 0.72, 0.58-0.89; p = 0.002). CONCLUSIONS: Use of active travel for ≥150 min/week was associated with being male, smoking, and higher levels of work-based physical activity. It was associated with lower BMI, and lower risk of a high waist circumference or high waist-to-hip ratio. Promotion of active travel is an important component of strategies to address the growing prevalence of overweight in rural low- and middle- income country settings

The galaxy-mass correlation function measured from weak lensing in the Sloan Digital Sky Survey

We present galaxy-galaxy lensing measurements over scales 0.025 to 10 h(-1) Mpc in the Sloan Digital Sky Survey (SDSS). Using a flux-limited sample of 127,001 lens galaxies with spectroscopic redshifts and mean luminosity [L] similar to L-* and 9,020,388 source galaxies with photometric redshifts, we invert the lensing signal to obtain the galaxy-mass correlation function xi(gm). We find xi(gm) is consistent with a power law, xi(gm) (r = r(0))(-gamma), with best-fit parameters gamma = 1.79 +/- 0.06 and r(0) (5.4 +/- 0.7) (0.27/Omega(m))(1/gamma) h(-1) Mpc. At fixed separation, the ratio xi(gg)/xi(gm) = b/r, where b is the bias and r is the correlation coefficient. Comparing with the galaxy autocorrelation function for a similarly selected sample of SDSS galaxies, we find that b/r is approximately scale-independent over scales 0.2 - 6.7 h(-1) Mpc, with mean [b/r] = (1.3 +/- 0.2) (Omega(m)/0.27). We also find no scale dependence in b/r for a volume-limited sample of luminous galaxies (-23.0 < M-r < -21.5). The mean b/r for this sample is [b/r](Vlim) = (2.0 +/- 0.7) (Omega(m)/0.27). We split the lens galaxy sample into subsets based on luminosity, color, spectral type, and velocity dispersion and see clear trends of the lensing signal with each of these parameters. The amplitude and logarithmic slope of xi(gm) increase with galaxy luminosity. For high luminosities (L similar to 5 L-*), xi(gm) deviates significantly from a power law. These trends with luminosity also appear in the subsample of red galaxies, which are more strongly clustered than blue galaxies

Is cannabis use a contributory cause of psychosis?

Objective: To assess whether cannabis use in adolescence and young adulthood is a contributory cause of schizophreniform psychosis in that it may precipitate psychosis in vulnerable individuals. Method: We reviewed longitudinal studies of adolescents and young adults that examined the relations between self-reported cannabis use and the risk of diagnosis with a psychosis or of reporting psychotic symptoms. We also reviewed studies that controlled for potential confounders, such as other forms of drug use and personal characteristics that predict an increased risk of psychosis. We assessed evidence for the biological plausibility of a contributory causal relation. Results: Evidence from 6 longitudinal studies in 5 countries shows that regular cannabis use predicts an increased risk of a schizophrenia diagnosis or of reporting symptoms of psychosis. These relations persisted after controlling for confounding variables, such as personal characteristics and other drug use. The relation did not seem to be a result of cannabis use to self-medicate symptoms of psychosis. A contributory causal relation is biologically plausible because psychotic disorders involve disturbances in the dopamine neurotransmitter systems with which the cannabinoid system interacts, as demonstrated by animal studies and one human provocation study. Conclusion: It is most plausible that cannabis use precipitates schizophrenia in individuals who are vulnerable because of a personal or family history of schizophrenia

Transmit Power Minimization for MIMO Systems of Exponential Average BER with Fixed Outage Probability

This document is the Accepted Manuscript version of the following article: Dian-Wu Yue, and Yichuang Sun, ‘Transmit Power Minimization for MIMO Systems of Exponential Average BER with Fixed Outage Probability’, Wireless Personal Communications, Vol. 90 (4): 1951-1970, first available online on 20 June 2016. Under embargo. Embargo end date: 20 June 2017. The final publication is available at Springer via https://link.springer.com/article/10.1007%2Fs11277-016-3432-4This paper is concerned with a wireless multiple-antenna system operating in multiple-input multiple-output (MIMO) fading channels with channel state information being known at both transmitter and receiver. By spatiotemporal subchannel selection and power control, it aims to minimize the average transmit power (ATP) of the MIMO system while achieving an exponential type of average bit error rate (BER) for each data stream. Under the constraints on each subchannel that individual outage probability and average BER are given, based on a traditional upper bound and a dynamic upper bound of Q function, two closed-form ATP expressions are derived, respectively, which can result in two different power allocation schemes. Numerical results are provided to validate the theoretical analysis, and show that the power allocation scheme with the dynamic upper bound can achieve more power savings than the one with the traditional upper bound.Peer reviewe

Effects of hydroxyapatite and PDGF concentrations on osteoblast growth in a nanohydroxyapatite-polylactic acid composite for guided tissue regeneration

The technique of guided tissue regeneration (GTR) has evolved over recent years in an attempt to achieve periodontal tissue regeneration by the use of a barrier membrane. However, there are significant limitations in the currently available membranes and overall outcomes may be limited. A degradable composite material was investigated as a potential GTR membrane material. Polylactic acid (PLA) and nanohydroxyapatite (nHA) composite was analysed, its bioactive potential and suitability as a carrier system for growth factors were assessed. The effect of nHA concentrations and the addition of platelet derived growth factor (PDGF) on osteoblast proliferation and differentiation was investigated. The bioactivity was dependent on the nHA concentration in the films, with more apatite deposited on films containing higher nHA content. Osteoblasts proliferated well on samples containing low nHA content and differentiated on films with higher nHA content. The composite films were able to deliver PDGF and cell proliferation increased on samples that were pre absorbed with the growth factor. nHA–PLA composite films are able to deliver active PDGF. In addition the bioactivity and cell differentiation was higher on films containing more nHA. The use of a nHA–PLA composite material containing a high concentration of nHA may be a useful material for GTR membrane as it will not only act as a barrier, but may also be able to enhance bone regeneration by delivery of biologically active molecules

Vulnerability assessment and feasibility analysis of seismic strengthening of school buildings

The majority of structures in seismic-prone areas worldwide are structures that have been designed either without seismic design considerations, or using codes of practice that are seriously inadequate in the light of current seismic design principles. In Cyprus, after a series of earthquakes that occurred between 1995 and 1999, it was decided to carry out an unprecedented internationally seismic retrofitting of all school buildings, taking into account the sensitivity of the society towards these structures. In this paper representative school buildings are analysed in both their pristine condition and after applying retrofitting schemes typical of those implemented in the aforementioned large-scale strengthening programme. Non-linear analysis is conducted on calibrated analytical models of the selected buildings and fragility curves are derived for typical reinforced concrete and unreinforced masonry structures. These curves are then used to carry out a feasibility study, including both benefit-cost and life-cycle analysis, and evaluate the effectiveness of the strengthening programme