Why does early childhood deprivation increase the risk for depression and anxiety in adulthood? A developmental cascade model

Abstract Background: Using data from the English & Romanian Adoptees (ERA) study we recently reported that early time-lmited exposure to severe institutional deprivation is associated with early onset and persistent neurodevelopmental problems and later onset emotional problems. Here we examine possible reasons for the late emergence of emotional problems in this cohort. Our main focus is on testing a developmental cascade mediated via the functional impact of early-appearing neurodevelopmental problems on late adolescent functioning. We also explore a second putative pathway via sensitization to stress. Methods: The ERA study includes 165 Romanian individuals who spent their early lives in grossly depriving institutions and were subsequently adopted into UK families, along with 52 UK adoptees with no history of deprivation. Age six years symptoms of neurodevelopmental problems and age 15 anxiety/depression symptoms were assessed via parental reports. Young adult symptoms of depression and anxiety were assessed by both parent and self-reports; young adults also completed measures of stress reactivity , exposure to adverse life events and functioning in work and interpersonal relationships. Results: The path between early institutional deprivation and adult emotional problems was mediated via the impact of early neurodevelopmental problems on unemployment and poor friendship functioning during the transition to adulthood. The findings with regard to early deprivation, later life stress reactivity and emotional problems were inconclusive. Conclusions: Our analysis suggests that the risk for adult depression and anxiety following extreme institutional deprivation is explained through the effects of early neurodevelopmental problems on later social and vocational functioning. Future research should more fully examine the role of stress susceptibility in this model

Non-perturbative measurement of low-intensity charged particle beams

Non-perturbative measurements of low-intensity charged particle beams are particularly challenging to beam diagnostics due to the low amplitude of the induced electromagnetic fields. In the low-energy antiproton decelerator (AD) and the future extra low energy antiproton rings at CERN, an absolute measurement of the beam intensity is essential to monitor the operation efficiency. Superconducting quantum interference device (SQUID) based cryogenic current comparators (CCC) have been used for measuring slow charged beams in the nA range, showing a very good current resolution. But these were unable to measure fast bunched beams, due to the slew-rate limitation of SQUID devices and presented a strong susceptibility to external perturbations. Here, we present a CCC system developed for the AD machine, which was optimised in terms of its current resolution, system stability, ability to cope with short bunched beams, and immunity to mechanical vibrations. This paper presents the monitor design and the first results from measurements with a low energy antiproton beam obtained in the AD in 2015. These are the first CCC beam current measurements ever performed in a synchrotron machine with both coasting and short bunched beams. It is shown that the system is able to stably measure the AD beam throughout the entire cycle, with a current resolution of $30\,\mathrm{nA}$

Auditory network connectivity in tinnitus patients: a resting-state fMRI study

Objective: Resting-state functional magnetic resonance imaging (fMRI) uncovers correlated activity between spatially distinct functionally related brain regions and offers clues about the integrity of functional brain circuits in people with chronic subjective tinnitus. We chose to investigate auditory network connectivity, adopting and extending previously used analyses methods to provide an independent evaluation of replicability. Design: Independent components analysis (ICA) was used to identify coherent patterns arising from spontaneous brain signals within the resting-state data. The auditory network component was extracted and evaluated. Bivariate and partial correlation analyses were performed on pre-defined regions of bilateral auditory cortex to assess functional connectivity. Study sample: Our design carefully matched participant groups for possible confounds, such as hearing status. Twelve patients (seven male, five female; mean age 66 years) all with chronic constant tinnitus and eleven controls (eight male, three female; mean age 68 years) took part. Results: No significant differences were found in auditory network connectivity between groups after correcting for multiple statistical comparisons in the analysis. This contradicts previous findings reporting reduced auditory network connectivity; albeit at a less stringent statistical threshold. Conclusions: Auditory network connectivity does not appear to be reliably altered by the experience of chronic subjective tinnitus

Safety and Tolerability of Sitagliptin in Type 2 Diabetes: Pooled Analysis of 25 Clinical Studies

INTRODUCTION: In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the sitagliptin clinical development program continues, additional studies with sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of sitagliptin by examining pooled data from 25 double-blind clinical studies. METHODS: The present analysis included data from 14,611 patients in 25 studies with T2DM who received either sitagliptin 100 mg/day (n = 7,726; sitagliptin group) or a comparator agent (n = 6,885; non-exposed group). These studies represent all randomized, double-blind trials conducted by Merck that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years, and for which results were available as of December 2011. These studies assessed sitagliptin, versus comparator agents, taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or metformin + pioglitazone or rosiglitazone). Patient-level data from each study were used to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events (AEs). RESULTS: Overall incidence rates of AEs and drug-related AEs were higher in the non-exposed group compared with the sitagliptin group. Incidence rates of specific AEs were generally similar between the two groups, except for higher incidence rates of hypoglycemia related to the greater use of a sulfonylurea and diarrhea related to the greater use of metformin in the non-exposed group, and of constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events, malignancy, or pancreatitis. CONCLUSION: In this updated pooled safety analysis of data from 14,611 patients with T2DM, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration

Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis

OBJECTIVE: To compare the incidence of cardiovascular events and mortality in patients with type 2 diabetes mellitus treated with sitagliptin or non-sitagliptin comparators. METHODS: A post hoc assessment of cardiovascular safety in 14,611 patients was performed by pooling data from 25 double-blind studies, which randomised patients at baseline to sitagliptin 100 mg/day or a non-sitagliptin comparator (i.e., non-exposed). Included studies were limited to those at least 12 weeks in duration (range: 12 to 104 weeks). Patient-level data were used in this analysis of major adverse cardiovascular events (MACE) including ischaemic events and cardiovascular deaths. Analyses were performed in three cohorts: the entire 25-study cohort, the cohort from placebo-controlled portions of studies (n=19), and the cohort from studies comparing sitagliptin to a sulphonylurea (n=3). RESULTS: In the entire cohort analysis, 78 patients had at least 1 reported MACE-related event, with 40 in the sitagliptin group and 38 in the non-exposed group. The exposure-adjusted incidence rate was 0.65 per 100 patient-years in the sitagliptin group and 0.74 in the non-exposed group (incidence rate ratio = 0.83 [95% confidence interval (CI): 0.53, 1.30]). In the analysis comparing sitagliptin to placebo, the exposure-adjusted incidence rate was 0.80 per 100-patient-years with sitagliptin and 0.76 with placebo (incidence rate ratio = 1.01 [95% CI: 0.55, 1.86]). In the analysis comparing sitagliptin to sulphonylurea, the exposure-adjusted incidence rate was 0.00 per 100 patient-years with sitagliptin and 0.86 with sulphonylurea (incidence rate ratio = 0.00 [95% CI: 0.00, 0.31]). CONCLUSION: A pooled analysis of 25 randomised clinical trials does not indicate that treatment with sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus. In a subanalysis, a higher rate of cardiovascular-related events was associated with sulphonylurea relative to sitagliptin

Wide-band full-wave electromagnetic modal analysis of the coupling between dark-matter axions and photons in microwave resonators

The electromagnetic coupling axion-photon in a microwave cavity is revisited with the Boundary Integral - Resonant Mode Expansion (BI-RME) 3D technique. Such full-wave modal technique has been applied for the rigorous analysis of the excitation of a microwave cavity with an axion field. In this scenario, the electromagnetic field generated by the axion-photon coupling can be assumed to be driven by equivalent electrical charge and current densities. These densities have been inserted in the general BI-RME 3D equations, which express the RF electromagnetic field existing within a cavity as an integral involving the Dyadic Green functions of the cavity (under Coulomb gauge) as well as such densities. This method is able to take into account any arbitrary spatial and temporal variation of both magnitude and phase of the axion field. Next, we have obtained a simple network driven by the axion current source, which represents the coupling between the axion field and the resonant modes of the cavity. With this approach, it is possible to calculate the extracted and dissipated RF power as a function of frequency along a broad band and without Cauchy-Lorentz approximations, obtaining the spectrum of the electromagnetic field generated in the cavity, and dealing with modes relatively close to the axion resonant mode. Moreover, with this technique we have a complete knowledge of the signal extracted from the cavity, not only in magnitude but also in phase. This can be an interesting issue for future analysis where the axion phase is an important parameter.Comment: 37 pages, 14 figures, 40 reference