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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.
Healthcare organizations are required to provide workers with respiratory protection (RP) to mitigate hazardous airborne inhalation exposures. This study sought to better identify gaps that exist between RP guidance and clinical practice to understand issues that would benefit from additional research or clarification.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
As the initial part of a research programme to assess the importance of geochemical factors in livestock production, a survey has been conducted on the copper (Cu) content of whole blood samples from cattle analyzed by the Veterinary Investigation Service over the period 1977-1980 inclusive. The area covered was restricted to England and the Welsh borders; data for Wales were not included, as they were not of a strictly comparable form, being based on plasma rather than on whole blood analysis.
To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms.
IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms.
Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose–response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68–0.95); that for IL-6 was 1.20 (95% CI, 1.03–1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship.
The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people.
We performed a spatial-temporal analysis to assess household risk factors for Ebola virus disease (Ebola) in a remote, severely-affected village. We defined a household as a family's shared living space and a case-household as a household with at least one resident who became a suspect, probable, or confirmed Ebola case from 1 August 2014 to 10 October 2014. We used Geographic Information System (GIS) software to calculate inter-household distances, performed space-time cluster analyses, and developed Generalized Estimating Equations (GEE). Village X consisted of 64 households; 42% of households became case-households over the observation period. Two significant space-time clusters occurred among households in the village; temporal effects outweighed spatial effects. GEE demonstrated that the odds of becoming a case-household increased by 4·0% for each additional person per household (P < 0·02) and 2·6% per day (P < 0·07). An increasing number of persons per household, and to a lesser extent, the passage of time after onset of the outbreak were risk factors for household Ebola acquisition, emphasizing the importance of prompt public health interventions that prioritize the most populated households. Using GIS with GEE can reveal complex spatial-temporal risk factors, which can inform prioritization of response activities in future outbreaks.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.
To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.
This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
Mental health research funding priorities in high-income countries must balance longer-term investment in identifying neurobiological mechanisms of disease with shorter-term funding of novel prevention and treatment strategies to alleviate the current burden of mental illness. Prioritising one area of science over others risks reduced returns on the entire scientific portfolio.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
Do DSM-IV diagnostic criteria for major depression (MD) in Chinese and Western women perform in a similar manner?
The CONVERGE study included interview-based assessments of women of Han Chinese descent with treated recurrent MD. Using Mplus software, we investigated the overall degree of between-sample measurement invariance (MI) for DSM-IV diagnostic criteria for MD in the CONVERGE sample and samples selected from four major Western studies from the USA and Europe matched to the inclusion criteria of CONVERGE. These analyses were performed one pair at a time. We then compared the results from CONVERGE paired with Western samples to those obtained when examining levels of MI between pairs of the Western samples.
Assuming a single factor model for the nine diagnostic criteria for MD, the level of MI based on global fit indexes observed between the CONVERGE and the four Western samples was very similar to that seen between the Western samples. Comparable results were obtained when using a two-factor structure for MI testing when applied to the 14 diagnostic criteria for MD disaggregated for weight, appetite, sleep, and psychomotor changes.
Despite differences in language, ethnicity and culture, DSM criteria for MD perform similarly in Chinese women with recurrent MD and comparable subjects from the USA and Europe. The DSM criteria for MD may assess depressive symptoms that are relatively insensitive to cultural and ethnic differences. These results support efforts to compare findings from depressed patients in China and Western countries.
Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
Psychotic phenomena are common in the general population but are excluded from diagnostic criteria for mild to moderate depression and anxiety despite their co-occurrence and shared risk factors. We used item response theory modelling to examine whether the co-occurrence of depressive, anxiety and psychotic phenomena is best explained by: (1) a single underlying factor; (2) two separate, uncorrelated factors; (3) two separate yet linked factors; or (4) two separate domains along with an underlying ‘common mental distress’ (CMD) factor. We defined where, along any latent continuum, the psychopathological items contributed most information.
We performed a secondary analysis of cross-sectional, item-level information from measures of depression, anxiety and psychotic experiences in 6617 participants aged 13 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and 977 participants aged 18 years from the ROOTS schools-based sample. We replicated results from one sample in the other and validated the latent factors against an earlier parental measure of mental state.
In both cohorts depression, anxiety and psychotic items were best represented as a bi-factor model with a single, unitary CMD factor on which psychotic items conveyed information about the more severe end (model 4); residual variation remained for psychotic items. The CMD factor was significantly associated with the prior parental measure.
Psychotic phenomena co-occur with depression and anxiety in teenagers and may be a marker of severity in a single, unitary dimension of CMD. Psychotic phenomena should be routinely included in epidemiological assessments of psychiatric morbidity, otherwise the most severe symptomatology remains unmeasured.
To study the natural course of vestibular schwannomas 15 to 31 mm in diameter.
A retrospective study of 45 patients conservatively managed with interval scanning was performed. Outcome measures were: changes in tumour size, clinical features and hearing. A tumour was considered to be growing if it increased in size by more than 2 mm.
Initial tumour sizes ranged from 15 to 31 mm, with a mean (± standard deviation) diameter of 20.1 ± 4.3 mm. The duration of follow up ranged from 6 months to 14 years (median, 3 years). Tumours grew in 11 cases (24.4 per cent), remained stable in 30 cases (66.7 per cent) and regressed in 4 cases (8.9 per cent). The overall mean tumour growth rate was 0.9 ± 2.2 mm per year; in growing tumours, it was 3.6 ± 2.9 mm per year.
Outcomes were similar to those reported for smaller tumours. These findings suggest that patients with medium or moderately large tumours can be safely offered an initial period of conservative management before intervention is considered.
We present the KMOS (K-band Multi-Object Spectrograph) Cluster and VIRIAL (VLT IRIFU Absorption Line) Guaranteed Time Observation (GTO) programs. KMOS provides 24 arms each feeding an integral field unit (14×14 spaxels of 0.2″ pixels) for IZ, YJ, H and K band near infrared (NIR) medium resolution spectroscopy (R ∼ 3500). Targets are selected from a 7.2′ diameter patrol field. Ultra-deep spectroscopy of ∼ 80 early-type cluster galaxies (∼ 20hr on source) and ∼ 200 (∼ 10hr on source) early-type field galaxies at 1 < z < 2 will dramatically improve the situation at z > 1 for which measurements of stellar velocity dispersions and absorption indices are limited to a few, often relatively young passively evolving galaxies (e.g. Bezanson 2013). In ESO Periods P92 and P93, 15 nights worth of data has been collected for KMOS-Clusters and 6 nights for VIRIAL: this will be supplemented with more data in upcoming semesters. All galaxies have multiband HST imaging including existing or upcoming WFC3 IR imaging, providing stellar mass maps and sizes. Combined with our dispersion measurements, this will allow us to examine the fundamental plane and the dynamical mass of a large sample of z > 1 galaxies for the first time, for both cluster and field galaxies.
Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression.
A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses.
At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) –0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (–0.29, 95% CI –3.04 to 2.46, p = 0.84) or the other mental health outcomes.
There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.
The cold, dry, and stable air above the summits of the Antarctic plateau provides the best ground-based observing conditions from optical to sub-millimetre wavelengths to be found on the Earth. Pathfinder for an International Large Optical Telescope (PILOT) is a proposed 2 m telescope, to be built at Dome C in Antarctica, able to exploit these conditions for conducting astronomy at optical and infrared wavelengths. While PILOT is intended as a pathfinder towards the construction of future grand-design facilities, it will also be able to undertake a range of fundamental science investigations in its own right. This paper provides the performance specifications for PILOT, including its instrumentation. It then describes the kinds of projects that it could best conduct. These range from planetary science to the search for other solar systems, from star formation within the Galaxy to the star formation history of the Universe, and from gravitational lensing caused by exo-planets to that produced by the cosmic web of dark matter. PILOT would be particularly powerful for wide-field imaging at infrared wavelengths, achieving near diffraction-limited performance with simple tip–tilt wavefront correction. PILOT would also be capable of near diffraction-limited performance in the optical wavebands, as well be able to open new wavebands for regular ground-based observation, in the mid-IR from 17 to 40 μm and in the sub-millimetre at 200 μm.