•Functional IL6R variant Asp358Ala (IL6R rs2228145; A > C) is associated with decreased risk of severe depression and/or psychosis.•The variant exerts anti-inflammatory effect downstream of ...IL-6.•rs2228145 is associated with increased serum IL-6 but decreased serum CRP levels.•rs2228145 is not associated with common confounders of IL-6, depression and psychosis relationship.
Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders.
We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score.
Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15–0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10−22) but decreased serum CRP levels (P = 3.5 × 10−5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20).
The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.
Abstract Objective A premorbid IQ deficit supports a developmental dimension to schizophrenia and its cognitive aspects that are crucial to functional outcome. Better characterisation of the ...association between premorbid IQ and the disorder may provide further insight into its origin and etiology. We aimed to quantify premorbid cognitive function in schizophrenia through systematic review and meta-analysis of longitudinal, population-based studies, and to characterize the risk of schizophrenia across the entire range of premorbid IQ. Method Electronic and manual searches identified general population-based cohort or nested case–control studies that measured intelligence before onset of schizophrenic psychosis using standard psychometric tests, and that defined cases using contemporaneous ICD or DSM. Meta-analyses explored dose–response relationships between premorbid cognitive deficit (using full-scale, verbal and performance IQ) and risk of schizophrenia. Meta-regression analyses explored relationships with age of illness onset, change in premorbid intelligence over time and gender differences. Results Meta-analysis of 4396 cases and over 745 000 controls from 12 independent studies confirmed significant decrements in premorbid IQ (effect size − 0.43) among future cases. Risk of schizophrenia operated as a consistent dose–response effect, increasing by 3.7% for every point decrease in IQ (p < 0.0001). Verbal and nonverbal measures were equally affected. Greater premorbid IQ decrement was associated with earlier illness onset (p < 0.0001). There was no evidence of a progressively increasing deficit during the premorbid period toward illness onset. Conclusions Strong associations between premorbid IQ and risk for schizophrenia, and age of illness onset argue for a widespread neurodevelopmental contribution to schizophrenia that operates across the entire range of intellectual ability. This also suggests higher IQ may be protective in schizophrenia, perhaps by increasing active cognitive reserve.
Study has been made of the thermoluminescence (TL) response of silica-based Ge-doped cylindrical, flat and photonic crystal fibres (referred to herein as PCF-collapsed) to electron (6, 12 and 20 MeV) ...and photon (6, 10 MV) irradiation and 1.25 MeV γ-rays, for doses from 0.1 Gy to 100 Gy. The electron and photon irradiations were delivered through use of a Varian Model 2100C linear accelerator located at the University of Malaya Medical Centre and γ-rays delivered from a 60Co irradiator located at the Secondary Standard Dosimetry Laboratory (SSDL), Malaysian Nuclear Agency. Tailor-made to be of various dimensions and dopant concentrations (6-10% Ge), the fibres were observed to provide TL yield linear with radiation dose, reproducibility being within 1-5%, with insensitivity to energy and angular variation. The sensitivity dependency of both detectors with respect to field size follows the dependency of the output factors. For flat fibres exposed to 6 MV X-rays, the 6% Ge-doped fibre provided the greatest TL yield while PCF-collapsed showed a response 2.4 times greater than that of the 6% Ge-doped flat fibres. The response of cylindrical fibres increased with core size. The fibres offer uniform response, high spatial resolution and sensitivity, providing the basis of promising TL systems for radiotherapy applications.
This investigation was carried out to study the effects of using a replacement percentage of saturated lightweight fine aggregate (LWA) as an internal curing agent on the shrinkage and mechanical ...behavior of Engineered Cementitious Composites (ECC). ECC is a micromechanically-based, designed high-performance, fiber-reinforced cementitious composite with high ductility and improved durability due to tight crack width. Standard ECC mixtures are typically produced with micro-silica sand (200
µm maximum aggregate size). Two replacement levels of silica sand with saturated LWA (fraction 0.59–4.76
mm) were adopted: the investigation used 10 and 20% by weight of total silica sand content, respectively. For each LWA replacement level, two different ECC mixtures with a fly ash-to-Portland cement ratio (FA/PC) of 1.2 and 2.2 were cast. In a control test series, two types of standard ECC mixtures with only silica sand were also studied. To investigate the effect of replacing a portion of the silica sand with saturated LWA on the mechanical properties of ECC, the study compared the results of uniaxial tensile, flexure and compressive strength tests, crack development, autogenous shrinkage and drying shrinkage. The test results showed that the autogenous shrinkage strains of the control ECCs with a low water-to-cementitious material ratio (W/CM) (0.27) and high volume FA developed rapidly, even at early ages. The results also showed that up to a 20% replacement of normal-weight silica sand with saturated LWA was very effective in reducing the autogenous shrinkage and drying shrinkage of ECC. On the other hand, the partial replacement of silica sand with saturated LWA with a nominal maximum aggregate size of 4.76
mm is shown to have a negative effect, especially on the ductility and strength properties of ECC. The test results also confirm that the autogenous shrinkage and drying shrinkage of ECC significantly decreases with increasing FA content. Moreover, increasing FA content is shown to have a positive effect on the ductility of ECC.
This study investigated the dual effect of freeze–thaw cycles with sodium sulfate solution on the performance of non-air-entrained Engineering Cementitious Composites (ECCs) with high volumes of ...slag. ECC specimens containing three different levels of slag content as a replacement for cement (55%, 69% and 81% by weight of total cementitious material) were exposed to aggressive sodium sulfate solution under freezing–thawing cycles. The load–deflection response associated with ultimate mid-span deflection and flexural strength/stiffness was determined, along with crack development behavior. For comparison purposes, the freezing–thawing resistance (in water) of control ECC specimens was also evaluated. Modified point count method air-void parameters, compressive strength, porosity, water absorption and sorptivity tests were also conducted on the virgin ECC specimens (those not exposed to freezing–thawing cycles in water or aggressive sodium sulfate solution). The test results for the virgin specimens revealed that increased slag content (S/PC) improved the ductility, hardened air content, water absorption, porosity and sorptivity of ECC, while marginally decreasing the compressive and flexural strengths. Freeze–thaw cycles in water or sodium sulfate solution showed that the ductility of ECC specimens decreased remarkably, irrespective of slag content and applied freezing–thawing process. Reduction in mass loss was at minimal levels and no significant behavior change was monitored between the specimens undergoing freeze–thaw cycling in water and the aggressive sodium sulfate solution. Moreover, the decrease in flexural stiffness was more evident than the reduction of the flexural strength for all ECC mixtures.
Lightweight self-consolidating concrete (LWSCC) has evolved to combine the excellent benefits of self-consolidating concrete (SCC) and lightweight concrete (LWC). However, investigation on structural ...performance of LWSCC-made structural components is quite limited. In this study, the shear behavior of LWSCC beams (with and without shear reinforcement) made of slag aggregates was investigated and compared with normalweight SCC beams. It was observed that LWSCC beams with stirrups showed similar shear behavior compared to their non-shear-reinforced counterparts until the formation of diagonal cracks. Compared to normalweight SCC beams without shear reinforcement, non-shear-reinforced LWSCC beams showed lower post-cracking shear resistance. It was also found that shear strength of LWSCC/SCC beams increased with the decrease in shear span-depth ratio. Moreover, American, Canadian, and British codes were found to be conservative in predicting shear strength of shear/non-shear-reinforced LWSCC beams. Keywords: diagonal cracks; ductility; lightweight self-consolidating concrete; post-cracking shear resistance; shear behavior; slag aggregates; ultimate shear resistance.
Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate ...IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.
We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.
IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.
Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. ...We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (OR
= 2.01, 95% CI 1.71-2.37, p < 0.001; OR
= 1.09, 95% CI 1.06-1.13, p < 0.001), CRP levels and IL-6 activity (OR
= 1.40, 95% CI 1.21-1.55, p < 0.001; OR
= 1.03, 95% CI 1.02-1.05, p < 0.001, OR
= 1.06 (1.03-1.09), p < 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using > 500 genetic instruments for CRP) and depression (OR
= 1.01, 95% CI 0.99-1.04; OR
= 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.
Study has been made of the thermoluminescence yield of various novel tailor-made silica fibres, 6 and 8 mol % Ge-doped, with four differing outer dimensions, comprised of flat and cylindrical shapes, ...subjected to electron irradiation. Main thermoluminescence dosimetric characteristics have been investigated, including the glow curve, dose response, energy dependence, minimum detectable dose, effective atomic number, linearity of index and sensitivity of the fibres. The studies have also established the uncertainties involved as well as the stability of response in terms of fading effect, reproducibility and annealing. In addition, dose-rate dependence was accounted for as this has the potential to be a significant factor in radiotherapy applications. The 6 and 8 mol % fibres have been found to provide highly linear dose response within the range 1 to 4 Gy, the smallest size flat fibre, 6 mol% Ge-doped, showing the greatest response by a factor of 1.1 with respect to the highly popular LiF phosphor-based medium TLD100. All of the fibres also showed excellent reproducibility with a standard deviation of < 2% and < 4% for 6 and 8 mol % Ge-doped fibres respectively. For fading evaluation, the smallest 6 mol% Ge-doped dimension flat fibre, i.e., 85 × 270 μm displayed the lowest signal loss within 120 days post-irradiation, at around 26.9% also showing a response superior to that of all of the other fibres. Moreover, all the fibres and TLD-100 chips showed independence with respect to electron irradiation energy and dose-rate. Compared with the 8 mol% Ge-doped optical fibres, the 6 mol% Ge-doped flat optical fibres have been demonstrated to possess more desirable performance features for passive dosimetry, serving as a suitable alternative to TLD-100 for medical irradiation treatment applications.
Schizophrenia has a neurodevelopmental component to its origin, and may share overlapping pathogenic mechanisms with childhood neurodevelopmental disorders (NDs). Nevertheless, longitudinal studies ...of psychotic outcomes among individuals with NDs are limited. We report a population-based prospective study of six common childhood NDs, subsequent neurocognitive performance and the risk of psychotic experiences (PEs) in early adolescence.
PEs were assessed by semi-structured interviews at age 13 years. IQ and working memory were measured between ages 9 and 11 years. The presence of six NDs (autism spectrum, dyslexia, dyspraxia, dysgraphia, dysorthographia, dyscalculia) was determined from parent-completed questionnaires at age 9 years. Linear regression calculated the mean difference in cognitive scores between children with and without NDs. Associations between NDs and PEs were expressed as odds ratios (ORs) with 95% confidence intervals (CIs); effects of cognitive deficits were examined. Potential confounders included age, gender, father's social class, ethnicity and maternal education.
Out of 8220 children, 487 (5.9%) were reported to have NDs at age 9 years. Children with, compared with those without, NDs performed worse on all cognitive measures; the adjusted mean difference in total IQ was 6.84 (95% CI 5.00-8.69). The association between total IQ and NDs was linear (p < 0.0001). The risk of PEs was higher in those with, compared with those without, NDs; the adjusted OR for definite PEs was 1.76 (95% CI 1.11-2.79). IQ (but not working memory) deficit partly explained this association.
Higher risk of PEs in early adolescence among individuals with childhood ND is consistent with the neurodevelopmental hypothesis of schizophrenia.
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