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Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.
This study evaluated tumour necrosis factor-α, interleukins 10 and 12, and interferon-γ levels, peripheral blood mononuclear cells, and clusters of differentiation 17c and 86 expression in unilateral sudden sensorineural hearing loss.
Twenty-four patients with unilateral sudden sensorineural hearing loss, and 24 individuals with normal hearing and no history of sudden sensorineural hearing loss (who were attending the clinic for other problems), were enrolled. Peripheral blood mononuclear cells, and clusters of differentiation 11c and 86 were isolated and analysed. Plasma and supernatant levels of tumour necrosis factor-α, interferon-γ, and interleukins 10 and 12 were measured.
There were no significant differences with respect to age and gender. Monocyte population, mean tumour necrosis factor-α level and cluster of differentiation 86 expression were significantly increased in the study group compared to the control group. However, interferon-γ and interleukin 12 levels were significantly decreased. The difference in mean interleukin 10 level was not significant.
Increases in tumour necrosis factor-α level and monocyte population might play critical roles in sudden sensorineural hearing loss. This warrants detailed investigation and further studies on the role of dendritic cells in sudden sensorineural hearing loss.
In this study, the combustion instability and emission characteristics of flames of different H2/CH4 compositions were investigated in a partially premixed model gas turbine combustor. A mode shift in the frequency of instability occurred under varying experimental conditions from the first to the seventh mode of longitudinal frequency in the combustor, and a parametric study was conducted to determine the reasons for this shift by using the length of the combustor, a factor that determines the mode frequency of longitudinal instability, as the main parameter. Furthermore, heat load and fuel composition (H2 ratio) were considered as parameters to compare the phenomenon under different conditions. The GRI-3.0 CANTERA code, OH chemiluminescence and the Abel inversion process were applied to analyse the frequency mode shift. NOx emissions, which occurred through the thermal NOx mechanism, increased with increasing heat load and H2 ratio. The instability frequency shifted from the first to the seventh mode as the H2 ratio increased in the H2/CH4 mixture. However, 100% H2 as fuel did not cause combustion instability because it has a higher burning velocity and extinction stretch rate than CH4. Furthermore, the laminar flame speed influenced the frequency mode shift. These phenomena were confirmed by the flame shapes. The Abel inversion process was applied to obtain the cross section of the flames from averaged OH chemiluminescence images. Stable and unstable flames were identified from the radial profile of OH concentration. The combustor length was found to not influence frequency mode shift, whereas the H2 ratio significantly influenced it as well as the flame shape. The results of this experimental study can help in the reliable operation of gas turbine systems in SNG plants.
While studies suggest that nutritional supplementation may reduce aggressive behavior in children, few have examined their effects on specific forms of aggression. This study tests the primary hypothesis that omega-3 (ω-3), both alone and in conjunction with social skills training, will have particular post-treatment efficacy for reducing childhood reactive aggression relative to baseline.
In this randomized, double-blind, stratified, placebo-controlled, factorial trial, a clinical sample of 282 children with externalizing behavior aged 7–16 years was randomized into ω-3 only, social skills only, ω-3 + social skills, and placebo control groups. Treatment duration was 6 months. The primary outcome measure was reactive aggression collected at 0, 3, 6, 9, and 12 months, with antisocial behavior as a secondary outcome.
Children in the ω-3-only group showed a short-term reduction (at 3 and 6 months) in self-report reactive aggression, and also a short-term reduction in overall antisocial behavior. Sensitivity analyses and a robustness check replicated significant interaction effects. Effect sizes (d) were small, ranging from 0.17 to 0.31.
Findings provide some initial support for the efficacy of ω-3 in reducing reactive aggression over and above standard care (medication and parent training), but yield only preliminary and limited support for the efficacy of ω-3 in reducing overall externalizing behavior in children. Future studies could test further whether ω-3 shows promise in reducing more reactive, impulsive forms of aggression.
Introduction: Over 1 million patients with head injuries (HIs) are seen every year at emergency departments (EDs) in North America, with over 90% being minor HIs. Over-utilization of computed tomography (CT) scans in these patients results in unnecessary exposure to radiation and increases health-care resource utilization. Using recommendations from the Choosing Wisely Campaign (CWC) and quality improvement (QI) methodology, we developed a local initiative targeting this issue. Our aim was to reduce the CT scan rate for patients presenting with HIs by 10% over a 6-month period at two academic EDs. This was considered both achievable and meaningful by our stakeholders. Methods: Baseline CT scan rates for patients with HIs were determined through a 10-month retrospective cohort review. We used stakeholder engagement and provider surveys to develop our driver diagram and PDSA cycles, which included: 1) Assessing and improving provider knowledge about the CWC recommendations; 2) Testing, refining and implementing a modified Canadian CT Head Rule checklist in the ED; 3) Developing and giving patients CWC-themed handouts pertaining to HI best practice; 4) Bimonthly reporting of CT scan rates to providers. Our primary outcome measure was the number of CT scans performed for patients with HIs. Process measures included the number of checklists completed and ED length of stay (LOS). Our balance measure was return ED visits within 72 hours. Results: Baseline rate of CT scans prior to our interventions was 47.9%. Our QI initiative resulted in a significant shift in the run chart of the weekly CT scan rates, associated with the second PDSA cycle cluster. We observed a 16% relative decrease in CT scans at 3 months (47.9% to 40.5%, P=0.005) and 10.4% at 8 months (47.9% to 43.1%, P=0.02). Non-sustained trends and shifts were seen in the run chart of median ED LOS for HI patients, but overall before-and-after median times were not significantly different (237min to 225min, P=0.18). 33% of total checklists were completed. 72-hr return visits did not change during the 8-month study period (4.0% to 4.16%, P=0.85). Conclusion: Our local QI initiative was successful in decreasing CT rates for patients presenting with a HI. The decrease in effect at 8 months suggests the need for continued feedback and reminders to ensure long-term sustainability. Other centres could use similar QI methods, as well as the materials we developed, to achieve similar results of improved evidence-based utilization of diagnostic tests.
The submarine channel-fill system of the Cambrian Spurs Formation exhibits unique metre-scale cycles of breccia and diamictite. The studied sections, Eureka Spurs, are located at the Mariner Glacier in the central-eastern part of northern Victoria Land, Antarctica. A facies analysis of the channel-fill deposit has led to the recognition of four main lithofacies: breccia, diamictite, thin-bedded sandstone and mudstone. The channel-fill deposit consists of two architectural elements: hollow-fill (HF) and sheet-like (SL) elements. The SL has wide convex-up geometry and consists solely of a very thick bed of diamictite, and is interpreted as a submarine channel lobe. The HF has a concave-up erosional base and flat upper surface. The HF consists of nine cyclic alternations of underlying breccia (cohesionless debris flow) and overlying diamictite (cohesive debris flow). The deposition of breccia is interpreted to have been controlled by repeated allogenic processes such as earthquakes. In contrast, the abrupt vertical transition from breccia to diamictite in each cycle is interpreted to have resulted from an autogenic, slope instability-related process. The interaction of the allogenic and autogenic factors recorded in the metre-scale unique cyclic deposits provides new criteria to interpret cycles of submarine debris flow.
Little is known about the combined use of benzodiazepines and antidepressants in older psychiatric patients. This study examined the prescription pattern of concurrent benzodiazepines in older adults treated with antidepressants in Asia, and explored its demographic and clinical correlates.
The data of 955 older adults with any type of psychiatric disorders were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Demographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. Both univariate and multiple logistic regression analyses were performed.
The proportion of benzodiazepine and antidepressant combination in this cohort was 44.3%. Multiple logistic regression analysis revealed that higher doses of antidepressants, younger age (<65 years), inpatients, public hospital, major comorbid medical conditions, antidepressant types, and country/territory were significantly associated with more frequent co-prescription of benzodiazepines and antidepressants.
Nearly, half of the older adults treated with antidepressants in Asia are prescribed concurrent benzodiazepines. Given the potentially adverse effects of benzodiazepines, the rationale of benzodiazepines and antidepressants co-prescription needs to be revisited.
Respiratory syncytial virus (RSV) can cause serious respiratory infections, second only to influenza virus. In order to know RSV's genetic changes we examined 4028 respiratory specimens from local hospital outpatients in Gyeonggi Province, South Korea over six consecutive years by real-time one-step RT–PCR; 183 patients were positive for RSV infection. To investigate the specific distribution of RSV genotypes, we performed partial sequencing of the glycoprotein gene. Of the 131 RSV-A specimens sequenced, 61 (43·3%) belonged to the ON1 genotype, 66 (46·8%) were NA1 genotype, 3 (2·1%) were GA5 genotype, and 1 (0·7%) belonged to the GA1 genotype. Of the 31 RSV-B specimens sequenced, 29 were BA9 genotype (87·9%) and 2 were BA10 genotype (6·1%). The most common clinical symptoms were fever, cough, nasal discharge, and phlegm; multiple logistic regression analysis showed that RSV-positive infection on pediatric patients was strongly associated with cough (OR = 2·8, 95% CI 1·6–5·1) and wheezing (OR = 2·8, 95% CI 1·7–4·4). The ON1 genotype was significantly associated with phlegm (OR = 11·8, 95% CI 3·8–46·7), while the NA1 genotype was associated with the pediatric patients’ gender (males, OR = 2·4, 95% CI 1·1–5·4) and presence of chills (OR = 5·1, 95% CI 1·1–27·2). RSV subgroup B was showed association with nasal obstruction (OR = 4·6, 95% CI 1·2–20·0). The majority of respiratory virus coinfections with RSV were human rhinovirus (47·2%). This study contributes to our understanding of the molecular epidemiological characteristics of RSV, which promotes the potential for improving RSV vaccines.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
The surface carbon abundances of Algol secondaries are known to be low compared to field stars of similar type. The C and N anomalies of these G and K subgiants are undoubtedly due to the exposure of CN cycle processed material as mass transfer removes the outer layers of the star. Therefore the carbon abundance is a promising tool for helping fix the evolutionary state of Algols, particularly the amount of mass which has been lost from the secondary. We report here the carbon abundance of 12 Algol secondaries as deduced from the g-band in spectra obtained during photometric totality. We compare the abundances to those from models of single stars of appropriate age and mass. The values of log ∊(C) for this sample fall 0.25–0.75 dex below field G and K giants, and 1.25–1.75 dex above “stripped” single star models. This larger sample supports the conclusions of Parthasarthy et al. regarding mixing and mass loss, which they deduced from a smaller sample of carbon abundances.
Shumardiid trilobites had a small, unique morphology, and formed a key constituent in trilobite faunas during the Cambrian–Ordovician. Because of their unusual morphology, they have been the subject of research s, into various aspects such as their life habit, functional morphology, evolutionary origin and ontogeny. Originally, a flat, adult-like protaspid morphology was suggested for shumardiids, but subsequently a bulbous protaspid morphology interpreted to be associated with metamorphosis was also suggested for this unique trilobite group. This article documents the ontogeny of the two co-occurring shumardiid trilobites, Akoldinioidia latus Park and Kihm and Koldinioidia choii Park and Kihm, from the middle Furongian Hwajeol Formation, Taebaeksan Basin, Korea. Interestingly, protaspides of the two shumardiids have a bulbous morphology. Given the stratigraphic occurrences of the two shumardiids, it can be inferred that commutavi protaspis appeared quite early in the shumardiid evolution. The co-occurrence of the two closely related trilobites is reminiscent of sexual dimorphism, although further evidence is required to prove it. The appearance of metamorphosis-undergoing protaspides in the Furongian shumardiids may have been due to the onset of increasing ecological pressure in the early phase of the Great Ordovician Biodiversification Event.
Classical studies of accreting white dwarfs have assumed spherical symmetry. However, it is believed that in close binary systems the transfered matter carries angular momentum to spin up the accreting star. Here, we present preliminary results of CO white dwarf models which accrete helium rich matter with effects of rotation considered, in the context of the Sub-Chandrasekhar mass scenario for Type Ia supernovae.
We discuss the first available binary evolution models which include up-to-date rotational physics for both components, as well as angular momentum accretion and spin-orbit coupling. These models allow a self-consistent computation of the mass transfer efficiency during Roche-lobe overflow phases, and a determination of the transition from quasi-conservative to non-conservative evolution. Applications to massive binary systems lead to predictions for the spin rates of compact objects in binaries, and for the occurrence of gamma-ray bursts from collapsars in binaries. Rotational effects in accreting white dwarfs are found to stabilise the shell burning and decrease the carbon abundance in progenitor models for Chandrasekhar-mass Type Ia supernovae, and to potentially avoid a detonation of the white dwarf within the sub-Chandrasekhar mass scenario.
We report on the results of CCD photometric observations of the open cluster NGC 2539. Eight new variable stars have been found in the observed field of this cluster. However, no γ Doradus-type variability was found among the member stars.
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
An acute gastroenteritis (AGE) outbreak was reported in May 2013 in Gyeonggi Province, South Korea. Eight students who had eaten breakfast on 21 May 2013 at a high-school restaurant exhibited AGE symptoms. Our case-control study showed that a strong association was observed between AGE symptoms and fermented oyster consumption. Virological studies also indicated that noroviruses (NoVs) were detected from both clinical samples and fermented oyster samples, and multiple different genotypes (genogroups GII.4, GII.11 and GII.14) of NoVs were present in both samples. The nucleotide sequence similarity between the strains found in the clinical samples and those in the fermented oysters was more than 99·5%. Therefore, to prevent further outbreaks, proper management of raw oysters is necessary and the food industry should be aware of the risk of viral gastroenteritis posed by fermented oysters contaminated with NoVs.
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.
Cerebral white matter hyperintensities (WMH) are prevalent incident findings on brain MRI scans among elderly people and have been consistently implicated in cognitive dysfunction. However, differential roles of WMH by region in cognitive function are still unclear. The aim of this study was to ascertain the differential role of regional WMH in predicting progression from mild cognitive impairment (MCI) to different subtypes of dementia.
Participants were recruited from the Clinical Research Center for Dementia of South Korea (CREDOS) study. A total of 622 participants with MCI diagnoses at baseline and follow-up evaluations were included for the analysis. Initial MRI scans were rated for WMH on a visual rating scale developed for the CREDOS. Differential effects of regional WMH in predicting incident dementia were evaluated using the Cox proportional hazards model.
Of the 622 participants with MCI at baseline, 139 patients (22.3%) converted to all-cause dementia over a median of 14.3 (range 6.0–36.5) months. Severe periventricular WMH (PWMH) predicted incident all-cause dementia (Hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.43–3.43) and Alzheimer's disease (AD) (HR 1.86; 95% CI 1.12–3.07). Subcortical vascular dementia (SVD) was predicted by both PWMH (HR 16.14; 95% CI 1.97–132.06) and DWMH (HR 8.77; 95% CI 1.77–43.49) in more severe form (≥ 10 mm).
WMH differentially predict dementia by region and severity. Our findings suggest that PWMH may play an independent role in the pathogenesis of dementia, especially in AD.
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.