A cluster randomised, 16-week, parallel-group multicentre trial to compare the effectiveness of a digital school-based cognitive behavioural resilience/wellbeing-building intervention targeting emotional and behavioural problems in vulnerable Year 4 primary school children in whole classes, to the usual school curriculum: a study protocol to the "CUES for Schools" trial.

BACKGROUND: Around 10% of school-aged children experience mental health difficulties. Many more are 'vulnerable': experiencing emotional and/or behavioural problems reaching clinical levels, and thus at greatest risk of future mental illness. The trial aim is to evaluate the effectiveness of the CUES for schools programme in reducing emotional and behavioural problems in vulnerable children. METHODS: The "CUES for Schools" study is a multicentre cluster randomised controlled trial in primary schools in south east England. Schools will be randomised to receive the usual school curriculum, or the CUES programme (1:1). We aim to enrol 74 schools (5550 children including 2220 vulnerable children). CUES is a whole-class teacher-facilitated interactive digital cognitive-behavioural intervention, delivered as 24 short (20-min) modules over 12 weeks, targeting emotional/behavioural regulation skills. Children self-report emotional/behavioural problems at baseline, 8, and 16 weeks, and wellbeing and cognitive vulnerability at 0 and 16 weeks. Adverse events are assessed at 8 and 16 weeks. Teachers rate classroom behaviour at baseline and 16 weeks. School senior leadership teams and individual teachers consent to involvement in the study; parents can opt their child out of CUES sessions, assessments, or research. Children can similarly opt out and assent to research participation. The primary objective of this trial is to evaluate the effectiveness of CUES for schools compared to the usual school curriculum in improving emotional/behavioural problems for vulnerable Year 4 (8-9 years old) children at 16 weeks post-randomisation, as measured using a standardised questionnaire designed for primary schools. The secondary objective is to investigate the impact of the CUES for schools programme on both vulnerable and non-vulnerable children on wellbeing and teacher-rated classroom behaviour. DISCUSSION: The study will show whether CUES for schools is more effective than the usual curriculum in reducing emotional and behavioural problems in vulnerable Year 4 children, and thus reducing the risk of mental health difficulties in later adolescent and adult life. As a digital, teacher-facilitated intervention, CUES for schools can be readily implemented, at minimal cost. If effective, CUES for schools therefore has the potential to reduce the impact of emotional/behavioural difficulties on children's learning, behaviour, and relationships and the burden of future mental health morbidity. TRIAL REGISTRATION: Trial Registration ISRCTN11445338. Registered on September 12, 2022.

Demonstration of a 120° hybrid based simplified coherent receiver on SOI for high speed PON applications.

We demonstrate the first simplified coherent receiver using a 120° hybrid on silicon-on-insulator (SOI) for high speed PON applications. This coherent receiver integrates an inverse taper edge coupler for the received signal, a vertical grating coupler for the local oscillator input, a polarization splitter and rotator (PSR), a 120° hybrid based on a 3×3 multimode interference (MMI) coupler, and three germanium photodetectors. We achieved 25 Gbit/s two-level pulse amplitude modulation (PAM-2) transmission over 30 km standard single mode fiber (SMF) in the C-band without any digital signal processing (DSP) (e.g., pre-emphasis, pulse shaping, equalization, nonlinearity compensation) and dispersion compensation (e.g., optical or digital) either at the transmitter or at the receiver. The requirements for frequency and phase locking of the local oscillator (LO) were avoided due to the use of intensity modulated signals. Receiver sensitivities of -23.70 dBm, -20.30 dBm, and -15.10 dBm are achieved at a bit error rate (BER) below the hard-decision forward error correction (HD-FEC) threshold (i.e., 3.8 × 10-3) in back-to-back (B2B), after 21 km and 30 km, respectively. We also demonstrate 25 Gbit/s PAM-4 transmission achieving receiver sensitivities of -15.30 dBm, -13.90 dBm, and -9.50 dBm below the HD-FEC threshold in B2B, after 10.5 km and 21 km, respectively.

Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study.

Animal studies and a handful of prospective human studies have demonstrated that young offspring exposed to maternal prenatal stress show abnormalities in immune parameters and hypothalamic-pituitary-adrenal (HPA) axis function. No study has examined the effect of maternal prenatal depression on offspring inflammation and HPA axis activity in adulthood, nor the putative role of child maltreatment in inducing these abnormalities. High-sensitivity C-reactive protein (hs-CRP) and awakening cortisol were measured at age 25 in 103 young-adult offspring of the South London Child Development Study (SLCDS), a prospective longitudinal birth cohort of mother-offspring dyads recruited in pregnancy in 1986. Maternal prenatal depression was assessed in pregnancy at 20 and 36 weeks; offspring child maltreatment (birth 17 years) was assessed at offspring ages 11, 16 and 25; and offspring adulthood depression (18-25 years) was assessed at age 25. Exposure to maternal prenatal depression predicted significantly elevated offspring hs-CRP at age 25 (odds ratio=11.8, 95% confidence interval (CI) (1.1, 127.0), P=0.041), independently of child maltreatment and adulthood depression, known risk factors for adulthood inflammation. In contrast, maternal prenatal depression did not predict changes in offspring adulthood cortisol; however, offspring exposure to child maltreatment did, and was associated with elevated awakening cortisol levels (B=161.9, 95% CI (45.4, 278.4), P=0.007). Fetal exposure to maternal depression during pregnancy has effects on immune function that persist for up to a quarter of a century after birth. Findings are consistent with the developmental origins of health and disease (DOHaD) hypothesis for the biological embedding of gestational psychosocial adversity into vulnerability for future physical and mental illness.

Segmented silicon MZM for PAM-8 transmissions at 114 Gb/s with binary signaling.

We experimentally demonstrate PAM-8 generation from binary electrical signals driving a silicon multi-electrode Mach-Zehnder modulator acting as an optical digital-to-analog converter. Measured BER in back-to-back configuration is used to evaluate signal quality. We demonstrate 38 GBd PAM-8 transmission below the forward error correction (FEC) threshold using minimum mean square error (MMSE) equalization. The results show that modulators with segmented phase shifters can be advantageously used to eliminate the need for high bandwidth electronic digital-to-analog converters in the generation of multilevel signals. These modulators, that can be designed and fabricated with standard CMOS compatible tools and processes, are of high interest for short range high-speed data links.

Perinatal depression and child development: exploring the economic consequences from a South London cohort.

BACKGROUND: Depression in mothers during pregnancy and in the postnatal period has been recognized to have wide-ranging adverse impacts on offspring. Our study examines some of the outcomes and long-term economic implications experienced by offspring who have been exposed to perinatal depression. METHOD: We analysed the effects of perinatal depression on child development outcomes of children at ages 11 and 16 years from the community-based South London Child Development Study. Economic consequences were attached to those outcomes through simple decision-analytic techniques, building on evidence from studies of epidemiology, health-related quality of life, public sector costs and employment. The economic analysis takes a life-course perspective from the viewpoints of the public sector, individual and society. RESULTS: Additional risks that children exposed to perinatal depression develop emotional, behavioural or cognitive problems ranged from 5% to 21%. In addition, there was a high risk (24%) that children would have special educational needs. We present results in the form of cost consequences attached to adverse child outcomes. For each child exposed to perinatal depression, public sector costs exceeded £3030, costs due to reduced earnings were £1400 and health-related quality of life loss was valued at £3760. CONCLUSIONS: Action to prevent or treat mothers' depression during pregnancy and after birth is likely to reduce public sector costs, increase earnings and improve quality of life for children who were exposed to the condition.

Gene transfer of arginine kinase to skeletal muscle using adeno-associated virus.

In this study, we tested the feasibility of non-invasively measuring phosphoarginine (PArg) after gene delivery of arginine kinase (AK) using an adeno-associated virus (AAV) to murine hindlimbs. This was achieved by evaluating the time course, regional distribution and metabolic flux of PArg using (31)phosphorus magnetic resonance spectroscopy ((31)P-MRS). AK gene was injected into the gastrocnemius of the left hindlimb of C57Bl10 mice (age 5 weeks, male) using self-complementary AAV, type 2/8 with desmin promoter. Non-localized (31)P-MRS data were acquired over 9 months after injection using 11.1-T and 17.6-T Bruker Avance spectrometers. In addition, (31)P two-dimensional chemical shift imaging and saturation transfer experiments were performed to examine the spatial distribution and metabolic flux of PArg, respectively. PArg was evident in each injected mouse hindlimb after gene delivery, increased until 28 weeks, and remained elevated for at least 9 months (P<0.05). Furthermore, PArg was primarily localized to the injected posterior hindimb region and the metabolite was in exchange with ATP. Overall, the results show the viability of AAV gene transfer of AK gene to skeletal muscle, and provide support of PArg as a reporter that can be used to non-invasively monitor the transduction of genes for therapeutic interventions.

Association of a complement receptor 1 gene variant with baseline erythrocyte sedimentation rate levels in patients starting anti-TNF therapy in a UK rheumatoid arthritis cohort: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort.

Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (SNPs) rs7527798 (CR1L), rs6691117 (CR1), rs10903129 (TMEM57) and rs1043879 (C1orf63). The association between SNPs and baseline ESR, baseline DAS28-ESR, and change in DAS28-ESR was evaluated. Baseline ESR was significantly associated with CR1 rs6691117 genotype (P=0.01). No correlation was identified between baseline DAS28-ESR or change in DAS28-ESR. In conclusion, genetic variation in the gene encoding CR1 may alter ESR levels but not DAS28-ESR, indicating no adjustment for CR1 genotype is required in the assessment of patients with severe active RA.

Intergenerational transmission of maltreatment and psychopathology: the role of antenatal depression.

BACKGROUND: Maternal experience of childhood maltreatment and maternal antenatal depression are both associated with offspring childhood maltreatment and offspring adjustment problems. We have investigated the relative impact of maternal childhood maltreatment and exposure to depression in utero on offspring maltreatment and psychopathology. METHOD: The sample included 125 families from the South London Child Development Study. A prospective longitudinal design was used. Data on maternal childhood maltreatment, maternal antenatal depression (36 weeks of pregnancy), offspring childhood maltreatment (age 11 years) and offspring adolescent antisocial behaviour and depression (ages 11 and 16 years) were obtained from parents and offspring through clinical interview. RESULTS: Mothers who experienced childhood maltreatment were significantly more likely to be depressed during pregnancy [odds ratio (OR) 10.00]. Offspring of mothers who experienced only childhood maltreatment or only antenatal depression were no more at risk of being maltreated or having psychopathology; however, offspring of mothers who experienced both maternal childhood maltreatment and antenatal depression were exposed to significantly greater levels of childhood maltreatment and exhibited significantly higher levels of adolescent antisocial behaviour compared with offspring not so exposed. Furthermore, maternal childhood maltreatment accounted for a significant proportion of the variance in offspring childhood maltreatment in only those offspring exposed to depression in utero. CONCLUSIONS: Maternal childhood maltreatment and maternal antenatal depression are highly associated. The co-occurrence of both insults significantly increases the risk of offspring adversity. The antenatal period is an optimum period to identify vulnerable women and to provide interventions.

A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in early inflammatory polyarthritis: results from the Norfolk Arthritis Register.

Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.

Hip protectors: recommendations for conducting clinical trials--an international consensus statement (part II).

INTRODUCTION: While hip protectors are effective in some clinical trials, many, including all in community settings, have been unable to demonstrate effectiveness. This is due partly to differences in the design and analysis. The aim of this report is to develop recommendations for subsequent clinical research. METHODS: In November of 2007, the International Hip Protector Research Group met to address barriers to the clinical effectiveness of hip protectors. This paper represents a consensus statement from the group on recommended methods for conducting future clinical trials of hip protectors. RESULTS AND CONCLUSIONS: Consensus recommendations include the following: the use of a hip protector that has undergone adequate biomechanical testing, the use of sham hip protectors, the conduct of clinical trials in populations with annual hip fracture incidence of at least 3%, a run-in period with demonstration of adequate adherence, surveillance of falls and adherence, and the inclusion of economic analyses. Larger and more costly clinical trials are required to definitively investigate effectiveness of hip protectors.

Functional autoantibodies against serpin E2 in rheumatoid arthritis.

OBJECTIVE: To search for novel autoantibodies in patients with rheumatoid arthritis (RA) in an effort to better understand the processes of joint destruction in this disease. METHODS: Using a modified SEREX technique and complementary DNA derived from RA synovium, serpin E2 was identified as a novel autoantigen and was analyzed by immunohistochemistry. Levels of anti-serpin E2 autoantibodies in serum and synovial fluid from patients with RA, osteoarthritis (OA), psoriatic arthritis, and ankylosing spondylitis, and/or from healthy individuals were assessed by enzyme-linked immunosorbent assay. Since serpin E2 is an inhibitor of serine proteases, we studied the inhibitory activity of serpin E2 toward its target, urokinase plasminogen activator (uPA), in vitro in the presence of isolated anti-serpin E2 autoantibodies and in vivo using the uPA activity assay. RESULTS: We identified autoantibodies against serpin E2 by the SEREX technique. Serpin E2 was overexpressed in RA synovial tissues as compared with OA synovial tissues. Significantly higher levels of anti-serpin E2 autoantibodies were present in samples of synovial fluid (28%) and serum (22%) from RA patients as compared with OA patients (0 and 6%, respectively) or with healthy individuals (6% of sera). Most importantly, anti-serpin E2 autoantibodies isolated from RA sera reversed the inhibitory activity of serpin E2 by 70%. Furthermore, the levels of anti-serpin E2 autoantibodies correlated with the uPA activity in vivo. CONCLUSION: This study characterizes a functional property of a novel autoantibody in RA. Since anti-serpin E2 autoantibodies interfere with the inhibitory activity of serpin E2 toward serine proteases, they might facilitate the joint destruction in RA.

Hip protectors: recommendations for biomechanical testing--an international consensus statement (part I).

INTRODUCTION: Hip protectors represent a promising strategy for preventing fall-related hip fractures. However, clinical trials have yielded conflicting results due, in part, to lack of agreement on techniques for measuring and optimizing the biomechanical performance of hip protectors as a prerequisite to clinical trials. METHODS: In November 2007, the International Hip Protector Research Group met in Copenhagen to address barriers to the clinical effectiveness of hip protectors. This paper represents an evidence-based consensus statement from the group on recommended methods for evaluating the biomechanical performance of hip protectors. RESULTS AND CONCLUSIONS: The primary outcome of testing should be the percent reduction (compared with the unpadded condition) in peak value of the axial compressive force applied to the femoral neck during a simulated fall on the greater trochanter. To provide reasonable results, the test system should accurately simulate the pelvic anatomy, and the impact velocity (3.4 m/s), pelvic stiffness (acceptable range: 39-55 kN/m), and effective mass of the body (acceptable range: 22-33 kg) during impact. Given the current lack of clear evidence regarding the clinical efficacy of specific hip protectors, the primary value of biomechanical testing at present is to compare the protective value of different products, as opposed to rejecting or accepting specific devices for market use.

Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis.

OBJECTIVE: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents. METHODS: UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). RESULTS: Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. CONCLUSION: The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22.

Investigating the role of the HLA-Cw*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis.

OBJECTIVE: Psoriasis of early onset (type I; age of onset 40 years). HLA-DRB1*07, in linkage disequilibrium with HLA-Cw*06, was also associated with patients with PsA having type I psoriasis (OR 2.7, 95% CI 2.1, 3.7, p<0.00001). HLA-DRB1*04 alleles and the SE were associated with undifferentiated inflammatory arthritis but not with PsA. CONCLUSIONS: The SE is not a PsA susceptibility locus. HLA-Cw*06 and HLA-DRB1*07 are associated with patients with PsA having type I psoriasis, suggesting that the primary association is with age of onset of psoriasis. Patients with PsA having type I psoriasis, therefore, have a genetic background different to those with type II psoriasis, and adjustment for this is necessary in future studies that investigate the genetic susceptibility of PsA.

Cation occupancies in Mg, Co, Ni, Zn, Al ferrite spinels: a multi-element EXAFS study.

The distribution of cations between tetrahedral (A) sites and octahedral (B) sites in ferrite spinels has been studied using K-edge x-ray absorption spectroscopy. The samples include natural and synthetic end-member magnetites (Fe3O4), a natural Mn- and Zn-rich magnetite (franklinite) and synthetic binary, ternary and quaternary ferrites of stoichiometry M(²+)M2(³+)O4, where M(²+) = Mg, Co, Ni, Zn and M(³+) = Fe, Al. XAS data were obtained for all metals. Complete, unfiltered, EXAFS spectra were refined to determine the percentage distribution of each element over the A and B sites and these data were combined with microprobe analyses to quantify the tetrahedral occupancy for each element in each sample. Measured site occupancies and an internally consistent set of (M-O)(A) and (M-O)(B) bond lengths were used to calculate unit-cell parameters, which show excellent agreement with measured values, pointing to the reliability of the measured occupancy factors. The average occupancies determined for the tetrahedral sites in ferrites are (atoms per formula unit) Mg 0.44, Co 0.24, Ni 0.11, Zn 0.76, Al 0.11 and Fe(³+) 0.92-0.19. The wide range found for Fe(³+) is consistent with it playing a relatively passive role by making good any A-site deficit left by the other competing cations.

Cation migration upon adsorption of methanol in NaY and NaX faujasite systems: a molecular dynamics approach.

Molecular dynamics simulations have been carried out to address the question of cation migration upon adsorption of methanol in NaY and NaX faujasite systems as a function of the loading. For NaY, it has been shown that, at low and intermediate loadings, SII cations can migrate toward the center of the supercage due to strong interactions with the adsorbates, followed by a hopping of SI' from the sodalite cage into the supercage to fill the vacant SII site. A SI' cation can also migrate across the double six ring and takes a SI' vacant position. SI cations mainly remain trapped in their initial sites whatever the loading. At high loading, only limited motions are observed for SII cations due to steric effects induced by the presence of adsorbates within the supercage. For NaX, the SIII' cations which occupy the most accessible adsorption sites are significantly moving upon coordination to the methanol molecules; the extent of this mobility exhibits a maximum for 48 methanol molecules per unit cell before decreasing at higher loadings due to steric hindrance. In addition, the SI' and SII cations remain almost trapped in their initial sites whatever the loading. Indeed, the most probable migration mechanism involves SIII' cation displacements into nearby SIII' sites.

Modeling the concentration dependence of the methanol self-diffusivity in faujasite systems: comparison with the liquid phase.

Molecular dynamics simulations were performed to understand further the concentration dependence of the self-diffusion of methanol in the faujasite zeolite systems. The evolution of the self-diffusivity was investigated as a function of coverage for DAY and NaY systems to study the effect of both the pore confinement and the presence of the extraframework cations within the supercage. It was found that the self-diffusivity decreases with loading for DAY, whereas for NaY it passes through a maximum at intermediate coverage, in agreement with pulse-field gradient NMR and quasi elastic neutron scattering data reported in similar systems. The activation energies of the methanol diffusion corresponding to a combination of both intra- and intercage motions were evaluated as a function of the coverage. The simulated trends are interpreted on the basis of the predominant interactions which take place in both systems. Finally, the preferential arrangement of the adsorbate molecules are provided and compared with those simulated in the liquid phase. For the fully loaded materials, it was seen that the methanol molecules form a one-dimensional hydrogen-bonded chain along the channels in DAY whereas only dimers are present in NaY.

Molecular dynamics simulation of the cation motion upon adsorption of CO2 in Faujasite zeolite systems.

Molecular Dynamics simulations have been carried out in NaX and NaY Faujasite systems to deepen understanding of the cation rearrangement during the CO2 adsorption process suggested by our recent diffusivity measurements. This study is a major contribution since the rearrangement of the cations in Faujasite, the most promising adsorbent for CO2 storage, can represent a significant breakthrough in understanding the adsorption and diffusion processes at the mircroscopic scale. For NaY, it has been shown that at low and intermediate loadings, SII cations can migrate toward the center of the supercage due to strong interactions with the adsorbates, followed by a hopping of SI'cation from the sodalite cage into the supercage to fill the vacant SII site. The SI cations are only displaced at a higher loading, leading to cation de-trapping out of the double six rings into the vacant SI' sites. For NaX, the SIII' cations which occupy the most accessible adsorption sites move significantly upon coordination to the carbon dioxide molecules. The SI' and SII cations remain consistently located in their initial sites whatever the loading. Indeed, the most probable migration mechanism involves SIII' cation displacements into nearby vacant SIII' sites.