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Evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) initiation in patients stabilized on oral antipsychotics other than aripiprazole. Previous pivotal Phase III trials have evaluated initiating ARI-OM in patients stabilized on oral aripiprazole1.
Eligible patients were treated with oral atypical antipsychotics other than aripiprazole with a history of oral aripiprazole tolerability. The study included a screening phase (30 days) and a treatment phase (28 days). Patients were stabilized per investigator's judgment for ≥14 days on risperidone, olanzapine, quetiapine, or ziprasidone, before administration of ARI-OM (400 mg). Current oral antipsychotic was co-administered with ARI-OM for 2 weeks to determine safety and tolerability of a single ARI-OM dose following treatment initiation. Safety assessments were adverse events (AEs); extrapyramidal symptoms (EPSs) using standard objective rating scales; Columbia-Suicide Severity Rating Scale; clinical laboratory measures; and weight changes.
60 patients initiated ARI-OM, while continuing treatment for ≤2 weeks with oral risperidone (n=24), quetiapine (n=28), ziprasidone (n=5) or olanzapine (n=3). Treatment-emergent (TE) AEs (≥5%) were fatigue, injection-site pain, and restlessness (risperidone); insomnia, dystonia, injection-site pain, and toothache (quetiapine); and muscle spasm, tooth abscess, and toothache (ziprasidone). Prior olanzapine did not cause any AEs. Incidence of TE-EPSs were similar in all groups (< 5%). There were no unusual changes in objective EPS rating scales, suicidality, weight, laboratory values or fasting metabolic parameters across all groups.
The AE profile of patients receiving ARI-OM concomitant with oral atypical antipsychotics other than aripiprazole was consistent with prior reports1.
Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).
Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.
Glucose intolerance during pregnancy – a major driver of gestational diabetes mellitus (GDM) – has significant short- and long-term health consequences for both the mother and child. As GDM prevalence continues to escalate, there is growing need for preventative strategies. There is limited but suggestive evidence that myo-inositol (MI) and probiotics (PB) could improve glucose tolerance during pregnancy. The present study tested the hypothesis that MI and/or PB supplementation would reduce the risk of glucose intolerance during pregnancy. Female C57BL/6 mice were randomised to receive either no treatment, MI, PB (Lactobacillus rhamnosus and Bifidobacterium lactis) or both (MIPB) for 5 weeks. They were then provided with a high-fat diet for 1 week before mating commenced and throughout mating/gestation, while remaining on their respective treatments. An oral glucose tolerance test occurred at gestational day (GD) 16·5 and tissue collection at GD 18·5. Neither MI nor PB, separately or combined, improved glucose tolerance. However, MI and PB both independently increased adipose tissue expression of Ir, Irs1, Akt2 and Pck1, and PB also increased Pparγ. MI was associated with reduced gestational weight gain, whilst PB was associated with increased maternal fasting glucose, total cholesterol and pancreas weight. These results suggest that MI and PB may improve insulin intracellular signalling in adipose tissue but this did not translate to meaningful differences in glucose tolerance. The absence of fasting hyperglycaemia or insulin resistance suggests this is a very mild model of GDM, which may have affected our ability to assess the impact of these nutrients.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Here we present the synthesis of porous platinum–palladium macrobeams templated from high aspect ratio Magnus’ salt needle derivatives. The combination of [PtCl4]2− and/or [PdCl4]2− with [Pt(NH3)4]2+ ions results in salt needles ranging from 15 to 300 µm in length. Electrochemical reduction of the salt templates results in porous macrobeams with a square cross-section. Porous side wall texture and elemental composition was controlled with initial platinum to palladium salt ratio. Macrobeam free-standing films exhibited a specific capacitance up to 11.73 F/g and a solvent accessible surface area of 26.6 m2/g. These salt-templated porous platinum–palladium macrobeams offer a promising material for fuel cell catalysis.
Small perturbations to a steady uniform granular chute flow can grow as the material moves downslope and develop into a series of surface waves that travel faster than the bulk flow. This roll wave instability has important implications for the mitigation of hazards due to geophysical mass flows, such as snow avalanches, debris flows and landslides, because the resulting waves tend to merge and become much deeper and more destructive than the uniform flow from which they form. Natural flows are usually highly polydisperse and their dynamics is significantly complicated by the particle size segregation that occurs within them. This study investigates the kinematics of such flows theoretically and through small-scale experiments that use a mixture of large and small glass spheres. It is shown that large particles, which segregate to the surface of the flow, are always concentrated near the crests of roll waves. There are different mechanisms for this depending on the relative speed of the waves, compared to the speed of particles at the free surface, as well as on the particle concentration. If all particles at the surface travel more slowly than the waves, the large particles become concentrated as the shock-like wavefronts pass them. This is due to a concertina-like effect in the frame of the moving wave, in which large particles move slowly backwards through the crest, but travel quickly in the troughs between the crests. If, instead, some particles on the surface travel more quickly than the wave and some move slower, then, at low concentrations, large particles can move towards the wave crest from both the forward and rearward sides. This results in isolated regions of large particles that are trapped at the crest of each wave, separated by regions where the flow is thinner and free of large particles. There is also a third regime arising when all surface particles travel faster than the waves, which has large particles present everywhere but with a sharp increase in their concentration towards the wave fronts. In all cases, the significantly enhanced large particle concentration at wave crests means that such flows in nature can be especially destructive and thus particularly hazardous.
Gary P. Baker, Research Associate at the University of East Anglia, and a Researcher at the University of Groningen in the Netherlands.,
Craig L. Lambert, Lecturer in Maritime History at the University of Southampton.,
David Simpkin, Teacher of History at Birkenhead Sixth-Form College.,
J. J. N. Palmer
Given the contribution Andrew Ayton has made to the study of late medieval military history we hope he is not surprised by the production of a Festschrift in his honour. All the editors of this volume were supervised by Andrew for their doctoral studies, and all no doubt thrashed out the general outlines to their theses in one of the infamous ‘Ayton’ meetings that regularly ran into the late evening. Andrew's enthusiasm for his subject was infectious and it is to his credit that many of his former students have gone on to publish contributions on late medieval military and naval history. The papers featured in the present volume highlight the important international impact Andrew's work has had on his students and academic colleagues.
Andrew, a native of Dorset, is in his own words ‘a country dweller at heart’ but has spent much of his working life in the big city. He studied as an undergraduate at the University of Hull in the early 1980s, during which time he undertook several modules taught by Professor John Palmer. John's module on the Hundred Years’ War in particular seems to have kindled Andrew's interest in medieval military history and military communities; it certainly began a fruitful association between two like-minded scholars which was to span some three decades until John's retirement in 2002. Andrew often visited John's home to discuss their latest research and he will be pleased to know he is remembered with some affection by John's children.
After graduating, Andrew spent a brief spell in a ‘real’ job, before returning to Hull to study for his Ph.D. under John Palmer – ‘The Warhorse and Military Service under Edward III’ – and from 1985 to 1987 Andrew was employed, alongside Virginia Davis, on John's Domesday Project. This was a role for which Andrew was particularly well equipped. He had taken John Palmer's special subject on the Domesday Book as an undergraduate, which had provided him with the essential background plus the basic computing skills – in particular related to databases – needed for the research: rare qualifications in the mid-1980s. This period, of course, included the 900th anniversary of Domesday Book, which for Andrew and Virginia entailed a frenetic year, giving lectures and demonstrations around the UK while trying to keep to a research schedule and do some work on their own account.
Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.
Geophysical granular flows, such as avalanches, debris flows, lahars and pyroclastic flows, are always strongly influenced by the basal topography that they flow over. In particular, localised bumps or obstacles can generate rapid changes in the flow thickness and velocity, or shock waves, which dissipate significant amounts of energy. Understanding how a granular material is affected by the underlying topography is therefore crucial for hazard mitigation purposes, for example to improve the design of deflecting or catching dams for snow avalanches. Moreover, the interactions with solid boundaries can also have important applications in industrial processes. In this paper, small-scale experiments are performed to investigate the flow of a granular avalanche over a two-dimensional smooth symmetrical bump. The experiments show that, depending on the initial conditions, two different steady-state regimes can be observed: either the formation of a detached jet downstream of the bump, or a shock upstream of it. The transition between the two cases can be controlled by adding varying amounts of erodible particles in front of the obstacle. A depth-averaged terrain-following avalanche theory that is formulated in curvilinear coordinates is used to model the system. The results show good agreement with the experiments for both regimes. For the case of a shock, time-dependent numerical simulations of the full system show the evolution to the equilibrium state, as well as the deposition of particles upstream of the bump when the inflow ceases. The terrain-following theory is compared to a standard depth-averaged avalanche model in an aligned Cartesian coordinate system. For this very sensitive problem, it is shown that the steady-shock regime is captured significantly better by the terrain-following avalanche model, and that the standard theory is unable to predict the take-off point of the jet. To retain the practical simplicity of using Cartesian coordinates, but have the improved predictive power of the terrain-following model, a coordinate mapping is used to transform the terrain-following equations from curvilinear to Cartesian coordinates. The terrain-following model, in Cartesian coordinates, makes identical predictions to the original curvilinear formulation, but is much simpler to implement.
This paper highlights experimental and theoretical efforts dedicated to developing plasmonic-enhanced electrodes for the photo-electrochemical ethanol oxidation reaction (EOR) at room temperature in alkaline media. However, decoupling the electrocatalytic dark response from the plasmon-enhanced improvement presents a difficult challenge. To understand the plasmonic-enhancement of the photo-electrochemical EOR, multiple Au-Fe2O3 were fabricated and evaluated in parallel with discrete dipole approximation (DDA) modeling. Different Au-Fe2O3 were synthesized with Au nanoparticles located at variable positions within and/or on the Fe2O3 layer(s). The configurations investigated include thin film, embedded, surface and sandwich layered electrodes to facilitate optimal electrode design considerations for plasmonic-enhancement. The design strategies and configurations were guided by DDA simulations to assess absorption, scattering, and near-field enhancements within or near the semiconductor band edge, as well as the solution/electrode interface. For the different Fe2O3 loadings and Au nanoparticle sizes/distributions considered, it is determined that the Au-Fe2O3 surface configurations significantly enhanced the EOR in terms of a large positive current density enhancement, an increased photo-voltage and a lower onset potential relative to the other electrode designs.
Advanced paternal age at childbirth is associated with psychiatric disorders in offspring, including schizophrenia, bipolar disorder and autism. However, few studies have investigated paternal age's relationship with eating disorders in offspring. In a large, population-based cohort, we examined the association between paternal age and offspring eating disorders, and whether that association remains after adjustment for potential confounders (e.g. parental education level) that may be related to late/early selection into fatherhood and to eating disorder incidence.
Data for 2 276 809 individuals born in Sweden 1979–2001 were extracted from Swedish population and healthcare registers. The authors used Cox proportional hazards models to examine the effect of paternal age on the first incidence of healthcare-recorded anorexia nervosa (AN) and all eating disorders (AED) occurring 1987–2009. Models were adjusted for sex, birth order, maternal age at childbirth, and maternal and paternal covariates including country of birth, highest education level, and lifetime psychiatric and criminal history.
Even after adjustment for covariates including maternal age, advanced paternal age was associated with increased risk, and younger paternal age with decreased risk, of AN and AED. For example, the fully adjusted hazard ratio for the 45+ years (v. the 25–29 years) paternal age category was 1.32 [95% confidence interval (CI) 1.14–1.53] for AN and 1.26 (95% CI 1.13–1.40) for AED.
In this large, population-based cohort, paternal age at childbirth was positively associated with eating disorders in offspring, even after adjustment for potential confounders. Future research should further explore potential explanations for the association, including de novo mutations in the paternal germline.
Epidemiological data regarding group A streptococcal (GAS) infections in South East Asia are scarce with no information from Laos. We characterized emm types, emm clusters and the antibiotic resistance profile of 124 GAS isolates recovered in Laos during 2004–2013. Most strains were recovered from skin and invasive infections (76% and 19%, respectively). Thirty-four emm types were identified as belonging to 12 emm clusters and no novel emm types were identified. No significant differences were observed in the distribution of emm types or emm clusters according to age or site of recovery (skin or invasive infections). There was moderate strain diversity in this country but considerable differences in emm-type distribution between Laos, Thailand and Cambodia. Vaccine coverage was high for the J8 vaccine candidate. The theoretical coverage for the 30-valent vaccine candidate needs further investigation. Antibiotic resistance was moderate to erythromycin and chloramphenicol (8% and 7%, respectively) and low to ofloxacin (<1%).
We investigated the prevalence, diversity, and antimicrobial resistance (AMR) profiles of non-typhoidal Salmonella (NTS) and associated risk factors on 341 pig, chicken, and duck farms in Dong Thap province (Mekong Delta, Vietnam). Sampling was stratified by species, district (four categories), and farm size (three categories). Pooled faeces, collected using boot swabs, were tested using ISO 6575: 2002 (Annex D). Isolates were serogrouped; group B isolates were tested by polymerase chain reaction to detect S. Typhimurium and (monophasic) serovar 4,,12:i:- variants. The farm-level adjusted NTS prevalence was 64·7%, 94·3% and 91·3% for chicken, duck and pig farms, respectively. Factors independently associated with NTS were duck farms [odds ratio (OR) 21·2], farm with >50 pigs (OR 11·9), pig farm with 5–50 pigs (OR 4·88) (vs. chickens), and frequent rodent sightings (OR 2·3). Both S. Typhimurium and monophasic S. Typhimurium were more common in duck farms. Isolates had a high prevalence of resistance (77·6%) against tetracycline, moderate resistance (20–30%) against chloramphenicol, sulfamethoxazole-trimethoprim, ampicillin and nalidixic acid, and low resistance (<5%) against ciprofloxacin and third-generation cephalosporins. Multidrug resistance (resistance against ⩾3 classes of antimicrobial) was independently associated with monophasic S. Typhimurium and other group B isolates (excluding S. Typhimurium) and pig farms. The unusually high prevalence of NTS on Mekong Delta farms poses formidable challenges for control.
New low aluminium high niobium TiAl alloys exhibit a nano scale modulated microstructure consisting of lamellae with a tweed substructure. These tweed like appearing lamellae are a modulated arrangement of at least two phases. One constituent of the crystallographic modulation in the lamellae is an orthorhombic phase, which is closely related to both the hexagonal α2-Ti3Al phase and the cubic B2 ordered βo-TiAl phase.
In this study the nature and formation of this orthorhombic phase has been investigated by high-energy X-ray diffraction.
Measurements have shown that the newly formed orthorhombic phase is structurally comparable to the O phase (Ti2AlNb). It forms in the temperature range of 550 °C to 670 °C from the α2 phase by small atomic displacements and chemical reordering. The in situ experiments yielded information about the thermal stability of the orthorhombic phase. After dissolving at temperatures above 700 °C the phase can be re-precipitated by annealing within the temperature range of formation.
Obesity and its related non-communicable diseases (NCDs), such as type 2 diabetes, heart disease and cancer, impose huge burdens on society, particularly the healthcare system. Until recently, public health and policy were primarily focused on secondary prevention and treatment of NCDs. However, epidemiological and experimental evidence indicates that early-life exposures influence the risk of childhood obesity and related diseases later in life, and has now focused attention on the health of both mother and child. During pregnancy and the early neonatal period, individuals respond to their environment by establishing anatomical, physiological and biochemical trajectories that shape their future health. This period of developmental plasticity provides an early window of opportunity to mitigate the environmental insults that may increase an individual’s sensitivity to, or risk of, developing obesity or related diseases later in life. Although much investigation has already occurred in the area of Developmental Origins of Health and Disease research, the science itself is still in its infancy. It remains for researchers to tackle the important outstanding questions and translate their knowledge into workable solutions for the public good. The challenge, however, is to decide which areas to focus on. With these opportunities and challenges in mind, the 2014 Gravida Summit convened to examine how its early-life research program can determine which areas of research into mechanisms, biomarkers and interventions could contribute to the international research strategy to fight childhood obesity and its related diseases.
The effect of prenatal distress on the risk of a small for gestational age (SGA) infant is uncertain. We have addressed the influences of prenatal stress, anxiety and depression on the risk of SGA. We also examined the effects of infant sex and timing of distress during pregnancy on any observed associations.
The study population comprised 5606 healthy nulliparous pregnant women who participated in the international prospective Screening for Obstetric and Pregnancy Endpoints (SCOPE) study. Women completed the Perceived Stress Scale (PSS), the short form of the Spielberger State–Trait Anxiety Inventory (STAI) and the Edinburgh Postnatal Depression Scale (EPDS) at 15 ± 1 and 20 ± 1 weeks' gestation. SGA was defined as birthweight below the 10th customized percentile. Logistic regression was used for data analysis, adjusting for several potential confounders such as maternal age, body mass index (BMI), smoking, socio-economic status and physical exercise.
The risk of SGA was increased in relation to mild [adjusted odds ratio (aOR) 1.35, 95% confidence interval (CI) 1.07–1.71], moderate (aOR 1.26, 95% CI 1.06–1.49), high (aOR 1.45, 95% CI 1.08–1.95) and very high stress scores (aOR 1.56, 95% CI 1.03–2.37); very high anxiety score (aOR 1.45, 95% CI 1.13–1.86); and very high depression score (aOR 1.14, 95% CI 1.05–1.24) at 20 ± 1 weeks' gestation. Sensitivity analyses showed that very high anxiety and very high depression increases the risk of SGA in males but not in females whereas stress increases the risk of SGA in both males and females.
These findings suggest that prenatal stress, anxiety and depression measured at 20 weeks' gestation increase the risk of SGA. The effects of maternal anxiety and depression on SGA were strongest in male infants.
Non-typhoidal Salmonella are an important but poorly characterized cause of paediatric diarrhoea in developing countries. We conducted a hospital-based case-control study in children aged <5 years in Ho Chi Minh City to define the epidemiology and examine risk factors associated with Salmonella diarrhoeal infections. From 1419 diarrhoea cases and 571 controls enrolled between 2009 and 2010, 77 (5·4%) diarrhoea cases were stool culture-positive for non-typhoidal Salmonella. Salmonella patients were more likely to be younger than controls (median age 10 and 12 months, respectively) [odds ratio (OR) 0·97; 95% confidence interval (CI) 0·94–0·99], to report a recent diarrhoeal contact (8·1% cases, 1·8% controls; OR 5·98, 95% CI 1·8–20·4) and to live in a household with >2 children (cases 20·8%, controls 10·2%; OR 2·32, 95% CI 1·2–4·7). Our findings indicate that Salmonella are an important cause of paediatric gastroenteritis in this setting and we suggest that transmission may occur through direct human contact in the home.