To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Patient safety is a complex systems issue. In this study, we used a scoping review of peer-reviewed literature and a case study of provincial and territorial legislation in Canada to explore the influence of mandatory reporting legislation on patient safety outcomes in hospital settings. We drew from a conceptual model that examines the components of mandatory reporting legislation that must be in place as a part of a systems governance approach to patient safety and used this model to frame our results. Our results suggest that mandatory reporting legislation across Canada is generally designed to gather information about – rather than respond to and prevent – patient safety incidents. Overall, we found limited evidence of impact of mandatory reporting legislation on patient safety outcomes. Although legislation is one lever among many to improve patient safety outcomes, there are nonetheless several considerations for patient safety legislation to assist in broader system improvement efforts in Canada and elsewhere. Legislative frameworks may be enhanced by strengthening learning systems, accountability mechanisms and patient safety culture.
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.
Medical residents are an important group for antimicrobial stewardship programs (ASPs) to target with interventions aimed at improving antibiotic prescribing. In this study, we compared antimicrobial prescribing practices of 2 academic medical teams receiving different ASP training approaches along with a hospitalist control group.
Retrospective cohort study comparing guideline-concordant antibiotic prescribing for 3 common infections among a family medicine (FM) resident service, an internal medicine (IM) resident service, and hospitalists.
Community teaching hospital.
Adult patients admitted between July 1, 2016, and June 30, 2017, with a discharge diagnosis of pneumonia, cellulitis, and urinary tract infections were reviewed.
All 3 medical teams received identical baseline ASP education and daily antibiotic prescribing audit with feedback via clinical pharmacists. The FM resident service received an additional layer of targeted ASP intervention that included biweekly stewardship-focused rounds with an ASP physician and clinical pharmacist leadership. Guideline-concordant prescribing was assessed based on the institution’s ASP guidelines.
Of 1,572 patients, 295 (18.8%) were eligible for inclusion (FM, 96; IM, 69; hospitalist, 130). The percentage of patients receiving guideline-concordant antibiotic selection empirically was similar between groups for all diagnoses (FM, 87.5%; IM, 87%; hospitalist, 83.8%; P = .702). No differences were observed in appropriate definitive antibiotic selection among groups (FM, 92.4%; IM, 89.1%; hospitalist, 89.9%; P = .746). The FM resident service was more likely to prescribe a guideline-concordant duration of therapy across all diagnoses (FM, 74%; IM, 56.5%; hospitalist, 44.6%; P < .001).
Adding dedicated stewardship-focused rounds into the graduate medical curriculum demonstrated increased guideline adherence specifically to duration of therapy recommendations.
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.
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.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a disease continuum with common genetic causes and molecular pathology. We recently identified mutations in the T-cell restricted intracellular antigen-1 (TIA1) protein as a cause of ALS +/− FTD. TIA1 is an RNA-binding protein containing a low complexity domain (LCD) that promotes the assembly of membrane-less organelles, such as stress granules (SG). Whole exome sequencing of two family members with fALS/FTD revealed a novel missense mutation in the TIA1 LCD (P362L). Subsequent screening identified five more TIA1 mutations in six additional ALS patients, but none in controls. All mutation carriers presented with weakness, behavioral abnormalities or language impairments and had a final diagnosis of ALS +/− FTD. Autopsy on five TIA1 mutation carriers showed widespread neurodegeneration with TDP-43 pathology. Round eosinophilic inclusions in lower motor neurons were a consistent feature. Cellular assays revealed abnormal SG dynamics in the presence of TIA1 mutations. In summary, missense mutations in the LCD of TIA1 are a newly recognized cause of ALS/FTD with TDP-43 pathology and strengthen the role of RNA metabolism in the pathogenesis in this disease.
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.
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.
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.
The calculation of coupling coefficients for muon telescopes has previously used interpolation from a limited set of asymptotic directions of arrival of primary particles. Furthermore, these calculations have not incorporated curvature of the atmosphere and thus diverge from the true response at zenith angles greater than about 75 degrees. The necessary extensions to calculate coupling coefficients at arbitrary zenith angles are given, including an improved method of incorporating the asymptotic directions of the primary particles. It is shown, using this method, that certain coupling coefficients are highly sensitive to small changes in asymptotic directions for some telescope configurations.
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%).
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.