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This study directly compares the effectiveness of aripiprazole once-monthly 400 mg (AOM) and paliperidone palmitate once-monthly (PP) on the validated and symptom-focused Heinrichs-Carpenter Quality-of-Life Scale (QLS) in schizophrenia.
A 28-week, randomized, open-label rater-blinded, head-to-head study (NCT01795547) of AOM and PP in adult patients (18-60 years) needing a change from current oral antipsychotic treatment for any reason. The study comprised oral conversion, initiation of AOM or PP treatment according to labels, and treatment continuation with injections every 4 weeks. The primary endpoint assessed non-inferiority and subsequently superiority on change from baseline to week 28 in QLS total score analyzed using a mixed model for repeated measurements.
Of 295 randomized patients, 100/148 (67.6%) of AOM and 83/147 (56.5%) of PP patients completed 28 weeks of treatment. In treated patients, adverse events (AEs) were the most frequent reason for discontinuation; AOM: 16/144 (11.1%), PP: 27/137 (19.7%). The difference in change from baseline to week 28 on QLS total score was statistically significant (4.67 [95%CI: 0.32;9.02], p=0.036), confirming non-inferiority and establishing superiority of AOM compared to PP. The respective changes were 7.47±1.53 for AOM and 2.80±1.62 for PP. AEs occurring at rates ≥5% in either group in the treatment continuation phase were weight increased (AOM: 12/119 [10.1%]; PP: 17/109 [15.6%]), psychotic disorder (AOM: 3/119 [2.5%]; PP: 6/109 [5.5%]) and insomnia (AOM: 3/119 [2.5%]; PP: 6/109 [5.5%]).
Superior improvements on the clinician-rated QLS and lower rates of all-cause discontinuation suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate.
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.
The effect of small noise in a smooth dynamical system is negligible on any finite time interval; in this paper we study situations where the effect persists on intervals increasing to ∞. Such an asymptotic regime occurs when the system starts from an initial condition that is sufficiently close to an unstable fixed point. In this case, under appropriate scaling, the trajectory converges to a solution of the unperturbed system started from a certain random initial condition. In this paper we consider the case of one-dimensional diffusions on the positive half-line; this case often arises as a scaling limit in population dynamics.
Dementia is a leading cause of morbidity and mortality without pharmacologic prevention or cure. Mounting evidence suggests that adherence to a Mediterranean dietary pattern may slow cognitive decline, and is important to characterise in at-risk cohorts. Thus, we determined the reliability and validity of the Mediterranean Diet and Culinary Index (MediCul), a new tool, among community-dwelling individuals with mild cognitive impairment (MCI). A total of sixty-eight participants (66 % female) aged 75·9 (sd 6·6) years, from the Study of Mental and Resistance Training study MCI cohort, completed the fifty-item MediCul at two time points, followed by a 3-d food record (FR). MediCul test–retest reliability was assessed using intra-class correlation coefficients (ICC), Bland–Altman plots and κ agreement within seventeen dietary element categories. Validity was assessed against the FR using the Bland–Altman method and nutrient trends across MediCul score tertiles. The mean MediCul score was 54·6/100·0, with few participants reaching thresholds for key Mediterranean foods. MediCul had very good test–retest reliability (ICC=0·93, 95 % CI 0·884, 0·954, P<0·0001) with fair-to-almost-perfect agreement for classifying elements within the same category. Validity was moderate with no systematic bias between methods of measurement, according to the regression coefficient (y=−2·30+0·17x) (95 % CI −0·027, 0·358; P=0·091). MediCul over-estimated the mean FR score by 6 %, with limits of agreement being under- and over-estimated by 11 and 23 %, respectively. Nutrient trends were significantly associated with increased MediCul scoring, consistent with a Mediterranean pattern. MediCul provides reliable and moderately valid information about Mediterranean diet adherence among older individuals with MCI, with potential application in future studies assessing relationships between diet and cognitive function.
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.
We aimed to describe the natural history of heavy episodic drinking (HED) and associated harms from adolescence to young adulthood in a large Australian population cohort study.
The Australian Temperament Project consists of mothers and babies (4–8 months) recruited from Infant Welfare Centres and followed every 2 to 4 years until age 28 years. Analyses were based on data from 1156 young people (497 male; 659 female) surveyed repeatedly at ages 16, 18, 20, 24 and 28 years. We used dual processes latent class growth analysis to estimate trajectories of HED and associated harms, employing a piecewise approach to model the hypothesized rise and subsequent fall across adolescence and the late twenties, respectively.
We identified four sex-specific trajectories and observed little evidence of maturing-out across the twenties. In males, a normative pattern of increasing HED across the twenties with little related harm was observed (40% of the male sample). Early and late starter groups that peaked in harms at age 20 years with only minor attenuation in binging thereafter were also observed (6.1% and 35%, respectively). In females, a normative pattern of increasing, but moderate, HED with little related harm was observed (44% of the female sample). Early and late starter groups were also identified (18% and 17%, respectively); however, unlike males, the female late starter group showed a pattern of increasing HED and related harms.
Continued patterns of risky alcohol use and related harms are apparent for both males and females across the twenties.
OBJECTIVES/SPECIFIC AIMS: The off-target and organ-specific toxicities observed in cancer immunotherapy present an obstacle to T-cell-based therapeutics. A recent clinical trial underscored the need for improved methods to define TCR specificity after melanoma patients treated with TCR engineered T-cells suffered from fatal cardiovascular toxicity arising from the unpredicted recognition of a muscle-specific peptide. METHODS/STUDY POPULATION: To address this drawback to T-cell-based immunotherapies, we developed a novel protein engineering approach to define the peptide specificity of a given TCR. Here, directed evolution in a yeast display system produced a large scale peptide library, where recognition by the melanoma reactive DMF5 TCR acted as the guiding selective pressure. After this technique identified a panel of putative cross reactive peptides, sequence analysis and computational modeling followed by kinetic binding experiments and structural analysis determined the DMF5 TCR recognizes 2 distinct classes of peptides through chemically distinct mechanisms. RESULTS/ANTICIPATED RESULTS: This information led to the rational, structure-based design of additional cross reactive peptides and introduced a unique approach to screen the human proteome and identify the TCR targets which triggered undesired autoimmunity when this molecule was used in clinical trials. DISCUSSION/SIGNIFICANCE OF IMPACT: The distinct chemical nature of the 2 peptide classes suggest TCRs are more cross reactive than previously thought, presenting an obstacle to cell-based immunotherapy. Defining the peptide specificity of TCRs is of high interest to the immunology community, and will lead to improved approaches to designing engineered TCRs for cell therapy.
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.
The aims of the study were to describe the patterning and persistence of anxiety and depressive symptoms from adolescence to young adulthood and to examine long-term developmental relationships with earlier patterns of internalizing behaviours in childhood.
We used parallel processes latent growth curve modelling to build trajectories of internalizing from adolescence to adulthood, using seven waves of follow-ups (ages 11–27 years) from 1406 participants of the Australian Temperament Project. We then used latent factors to capture the stability of maternal reported child internalizing symptoms across three waves of early childhood follow-ups (ages 5, 7 and 9 years), and examined relationships among these patterns of symptoms across the three developmental periods, adjusting for gender and socio-economic status.
We observed strong continuity in depressive symptoms from adolescence to young adulthood. In contrast, adolescent anxiety was not persistent across the same period, nor was it related to later depressive symptoms. Anxiety was, however, related to non-specific stress in young adulthood, but only moderately so. Although childhood internalizing was related to adolescent and adult profiles, the associations were weak and indirect by adulthood, suggesting that other factors are important in the development of internalizing symptoms.
Once established, adolescent depressive symptoms are not only strongly persistent, but also have the potential to differentiate into anxiety in young adulthood. Relationships with childhood internalizing symptoms are weak, suggesting that early adolescence may be an important period for targeted intervention, but also that further research into the childhood origins of internalizing behaviours is needed.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
In this work we examine a Ti-48Al-2Cr-2Nb alloy obtained with an additive manufacturing technique by Electron Beam Melting (EBM) by conducting monotonic and cyclic loading experiments both on tension and compression samples for investigating the influence of the microstructure in strain accumulation process by fatigue loading. The residual strain maps corresponding to different applied stress levels, number of cycles and microstructures are obtained through the use of high-resolution Digital Image Correlation (DIC). The strain maps were overlaid with the images of the microstructure and detailed analyses were performed to investigate the features of the microstructure where high local strain heterogeneities arise. Such experiments, conducted ex-situ at room temperature, allow to characterize the effect of different microstructures on the strain accumulation process, and to clearly identify the role of the microstructural features of this TiAl intermetallic alloy on the fatigue initiation process.
The terminal lake systems of central Australia are key sites for the reconstruction of late Quaternary paleoenvironments. Paleoshoreline deposits around these lakes reflect repeated lake filling episodes and such landforms have enabled the establishment of a luminescence-based chronology for filling events in previous studies. Here we present a detailed documentation of the morphology and chemistry of soils developed in four well-preserved beach ridges of late Pleistocene and mid-to-late Holocene age at Lake Callabonna to assess changes in dominant pedogenic processes. All soil profiles contain evidence for the incorporation of eolian-derived material, likely via the formation of desert pavements and vesicular horizons, and limited illuviation due to generally shallow wetting fronts. Even though soil properties in the four studied profiles also provide examples of parent material influence or site-specific processes related to the geomorphic setting, there is an overall trend of increasing enrichment of eolian-derived material since at least ~ 33 ka. Compared to the Holocene profiles, the derived average accumulation rates for the late Pleistocene profiles are significantly lower and may suggest that soils record important regional changes in paleoenvironments and dust dynamics related to shifts in the Southern Hemisphere westerlies.
In North America, terrestrial records of biodiversity and climate change that span Marine Oxygen Isotope Stage (MIS) 5 are rare. Where found, they provide insight into how the coupling of the ocean–atmosphere system is manifested in biotic and environmental records and how the biosphere responds to climate change. In 2010–2011, construction at Ziegler Reservoir near Snowmass Village, Colorado (USA) revealed a nearly continuous, lacustrine/wetland sedimentary sequence that preserved evidence of past plant communities between ~140 and 55 ka, including all of MIS 5. At an elevation of 2705 m, the Ziegler Reservoir fossil site also contained thousands of well-preserved bones of late Pleistocene megafauna, including mastodons, mammoths, ground sloths, horses, camels, deer, bison, black bear, coyotes, and bighorn sheep. In addition, the site contained more than 26,000 bones from at least 30 species of small animals including salamanders, otters, muskrats, minks, rabbits, beavers, frogs, lizards, snakes, fish, and birds. The combination of macro- and micro-vertebrates, invertebrates, terrestrial and aquatic plant macrofossils, a detailed pollen record, and a robust, directly dated stratigraphic framework shows that high-elevation ecosystems in the Rocky Mountains of Colorado are climatically sensitive and varied dramatically throughout MIS 5.
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.
Graphene nanoplatelets (GNPs) functionalised with platinum were explored as the active material in a high specific surface area ink. The ink had a transmission at 550nm (T550) = 85% and a charge transfer resistance (Rct) of 6Ω/cm2. Although the Rct is higher than required for laboratory cells having a Jsc of 20mA/cm2 under 1 sun test conditions it is sufficient for industrially produced reverse devices, especially when utilised for indoor applications where light conditions will be lower than 100W/m2. This was demonstrated by reverse illuminated DSC efficiencies with flexible cathodes which were equivalent to cells with sputtered platinum catalysts when subjected to 300W/m2 lighting or less. A modification to the ink, suitable for catalysing a Co2+/3+ electrolyte having an Rct of 2Ω/cm2 and T550= 85% was undertaken. This demonstrates potential for use in high efficiency cobalt mediated DSCs. The work shows that printed graphene catalysts are a versatile low cost replacement to sputtered platinum in reverse illuminated DSCs for dye sensitised solar cells.