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To assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders.
We conducted a retrospective follow-up study with a nested case-control analysis using data from the U.K.-based Clinical Practice Research Datalink. We estimated incidence rates (IRs) with 95% confidence intervals (CIs) of seizures in depressed patients who used no antidepressant treatment or who used selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), or ‘other antidepressants’. To better adjust for potential confounding, we estimated odds ratios (ORs) of antidepressant drug use among cases with seizures and matched controls in a nested case-control analysis.
Of 151,005 depressed patients, 619 had an incident seizure during follow-up. IRs per 10,000 person-years were 9.33 (95% CI, 6.19-12.46) in non-users of antidepressants, 12.44 (95% CI, 10.67-14.21) in SSRI users, 15.44 (95% CI, 8.99-21.89) in SNRI users, 8.33 (95% CI, 4.68-11.98) in TCA users, and 5.05 (95% CI, 4.49-5.62) in past users of antidepressants. Across single antidepressants, the highest IR per 10,000 person-years (17.06 [95% CI, 7.41-26.72]) was observed in mirtazapine users. In the case-control analysis we observed the highest risks of seizure in male users of other antidepressants (OR 3.90, 95% CI 1.85-8.26), and in female users of SNRIs (2.70, 95% CI 1.33-5.48) compared with non-use.
With the exception of TCAs, antidepressant use in depressed patients was associated with an increased risk of seizures compared to non-use. Risk estimates differed across antidepressants and depended on timing of therapy, dose, and sex.
Infectious diseases, such as Helicobacter pylori, which produce systemic inflammation may be one key factor in the onset of autoimmunity. The association between H. pylori and antinuclear antibodies (ANA), a marker of autoimmunity, has been understudied. Data from the 1999–2000 National Health and Nutrition Examination Survey were used to evaluate the cross-sectional association between H. pylori seroprevalence and ANA positivity in US adults aged ≥20 years. ANA was measured in a 1:80 dilution of sera by indirect immunofluorescence using HEp-2 cells (positive ⩾3). H. pylori immunoglobulin G enzyme-linked immunosorbent assays were used to categorise individuals as seropositive or seronegative. H. pylori seropositivity and ANA positivity were common in the adult US population, with estimated prevalences of 33.3% and 9.9%, respectively. Both were associated with increasing age. H. pylori seropositivity was associated with higher odds of ANA (prevalence odds ratio = 1.89, 95% confidence interval = 1.08–3.33), adjusted for age, sex, race/ethnicity, educational attainment and body mass index. H. pylori infection may be one key factor in the loss of self-tolerance, contributing to immune dysfunction.
Nitrogen (N) leached into groundwater from urine patches of cattle grazing in situ is an environmental problem in pasture-based dairy industries. One potential mitigation is to breed cattle for lower urinary nitrogen (UN) excretion. Urinary nitrogen is difficult to measure, while milk urea nitrogen concentration (MUN) is relatively easy to measure. For animals fed diets of differing N content in confinement, MUN is moderately heritable and is positively related to UN. However, there is little information on the heritability of MUN, and its relationship with other traits such as milk yield and composition, for animals grazing fresh pasture. Milk urea nitrogen concentration data together with milk yield, fat, protein and lactose composition and somatic cell count was collected from 133 624 Holstein-Friesian (HF), Jersey (J) and HF×J (XBd) cows fed predominantly pasture over three full lactations and one part lactation. Mean MUN was 14.0; and 14.4, 13.2 and 13.9 mg/dl for HF, J and XBd cows, respectively. Estimates of heritability of MUN were 0.22 using a repeatability model that fitted year-of-lactation by month-of-lactation by cow-age with days-in-milk within month-of-lactation and cow-age, and 0.28 using a test-day model analysis with Gibbs sampling methods. Sire breeding values (BVs) ranged from −2.8 to +3.2 indicating that MUN could be changed by selection. The genetic correlation between MUN and percent true protein in milk was −0.22; −0.29 for J cows and −0.16 for HF cows. Should the relationship between MUN and UN observed in dietary manipulation studies hold similarly when MUN is manipulated by genetic selection, UN excretion could be reduced by 6.6 kg/cow per year in one generation of selection using sires with low MUN BVs. Although J cows had lower MUN than HF, total herd UN excretion may be similar for the same fixed feed supply because more J cows are required to utilise the available feed. The close relationship between blood plasma urea N concentration and MUN may enable early selection of bulls to breed progeny that excrete less UN.
Lentil (Lens culinaris Medik.) is an important and expanding crop in southern Australia and a significant crop in western Canada. Currently, production in both countries is limited by an inability to effectively control weeds, due in part to a lack of registered safe and effective herbicides. Metribuzin is a broad-spectrum herbicide providing an alternative weed control option to the imidazolinones, but it has low crop safety in lentil. Two methods, germplasm screening using a hydroponic sand assay and field screening of a large mutated population of the Australian cultivar ‘PBA Flash’ were initially used to identify lines with putative metribuzin tolerance over current cultivars. Dose–response experiments showed the germplasm line SP1333 had GR50 (the rate required to reduce dry weight 50%) values up to four times higher than PBA Flash. However, the mutation selections M043 and M009 had GR50 values more than 25 times higher than PBA Flash. A field study in Canada, under conditions of induced shade and no shade 72 h before POST application of metribuzin, confirmed the intermediate level of tolerance in SP1333 and the high level in the two mutant lines compared with 20 Canadian and Australian genotypes. This relative increase in metribuzin tolerance of the two mutant lines over the parent cultivar is higher than all previous reports in a range of crop species. The development of large mutant populations combined with large M2 field screens was a successful method for developing high levels of metribuzin tolerance in lentil. The estimated mutation rate of the mutant lines was 9.4×10−8. All three lines are currently being used as parents in lentil breeding programs.
Outflows from AGB stars enrich the Galactic environment with metals and inject mechanical energy into the ISM. Radio spectroscopy can recover both properties through observations of molecular lines. We present results from SWAG: “Survey of Water and Ammonia in the Galactic Center”. The survey covers the entire Central Molecular Zone (CMZ), the inner 3.35° × 0.9° (∼480 × 130 pc) of the Milky Way that contains 5 × 107 M⊙ of molecular gas. Although our survey primarily targets the CMZ, we observe across the entire sightline through the Milky Way. AGB stars are revealed by their signature of double peaked 22 GHz water maser lines. They are distinguished by their spectral signatures and their luminosities, which reach up to 10−7 L⊙. Higher luminosities are usually associated with Young Stellar Objects located in CMZ star forming regions. We detect a population of ∼600 new water masers that can likely be associated with AGB outflows.
Aurochs played a prominent role in mortuary and feasting practices during the Neolithic transition in south-west Asia, although evidence of these practices is diverse and regionally varied. This article considers a new concentration of aurochs bones from the southern Levantine Pre-Pottery Neolithic site of Kfar HaHoresh, situating it in a regional context through a survey of aurochs remains from other sites. Analysis shows a change in the regional pattern once animal domestication began from an emphasis on feasting to small-scale practices. These results reveal a widely shared practice of symbolic cattle use that persisted over a long period, but shifted with the beginning of animal management across the region.
Several infections have been linked to telomere shortening and in some cases these associations have varied by sex. We assessed the association between seropositivity to four persistent pathogens (cytomegalovirus (CMV), herpes simplex virus-1, Helicobacter pylori, Chlamydia pneumoniae), and total pathogen burden on leukocyte telomere length in a diverse US sample. Data came from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study. We utilized cross-sectional survey data, and biological samples from participants tested for pathogens and telomere length (N = 163). Linear regression was used to examine the association between seropositivity for individual pathogens as well as total pathogen burden and telomere length, adjusting for various confounders. CMV seropositivity and increased total pathogen burden level were significantly associated with shorter telomere length among females (β = −0·1204 (standard error (s.e.) 0·06), P = 0·044) and (β = −0·1057 (s.e. = 0·05), P = 0·033), respectively. There was no statistically significant association among males. Our findings suggest that prevention or treatment of persistent pathogens, in particular CMV, may play an important role in reducing telomere shortening over the life course among women. Future research is needed to confirm these novel findings in larger longitudinal samples.
Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation.
We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding.
At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22–1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20–1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94–1.30; anxiety disorders: HRR 0.94, 95% CI 0.80–1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75–1.89; anxiety disorders: HRR 0.87, 95% CI 0.55–1.36).
The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP.
As ruminants are able to digest fibre efficiently and assuming that competition for feed v. food use would intensify in the future, cereals and other field crops should primarily be destined to cover the dietary needs of humans and monogastric animals such as poultry and pigs. Farming systems with a reduced or absent concentrate supplementation, as postulated by organic agriculture associations, require adapted dairy cows. The aim of this experiment was to examine the impact of concentrate supplementation on milk production, grazing and rumination behaviour, feed intake, physical activity and blood traits with two Holstein-Friesian cow strains and to conclude the consequences for sustainable and organic farming. The experiment was a cross-over study and took place on an organic farm in Switzerland. In all, 12 Swiss Holstein-Friesian (HCH) cows and 12 New Zealand Holstein-Friesian (HNZ) cows, which were paired according to lactation number, days in milk and age for primiparous cows, were used. All cows grazed full time and were supplemented either with 6 kg/day of a commercial, organic cereal-grain mix or received no supplement. After an adaptation period of 21 days, a measurement period of 7 days followed, where milk yield and composition, pasture dry matter intake estimated with the n-alkane double-indicator technique, physical activity based on pedometer measurements, grazing behaviour recorded by automatic jaw movement recorder and blood samples were investigated. Non-supplemented cows had a lower milk yield and supplemented HCH cows produced more milk than supplemented HNZ cows. Grazing time and physical activity were greater for non-supplemented cows. Supplementation had no effect on rumination behaviour, but HNZ cows spent longer ruminating compared with HCH cows. Pasture dry matter intake decreased with the concentrate supplementation. Results of blood analysis did not indicate a strong negative energy balance for either non-supplemented or supplemented cows. Minor differences between cow strains in this short-term study indicated that both cow strains are equally suited for an organic pasture-based production system with no concentrate supplementation. Many factors such as milk yield potential, animal welfare and health, efficiency, grazing behaviour and social aspects influence the decision to supplement grazing dairy cows with concentrates.
SWAG (“Survey of Water and Ammonia in the Galactic Center”) is a multi-line interferometric survey toward the Center of the Milky Way conducted with the Australia Telescope Compact Array. The survey region spans the entire ~400 pc Central Molecular Zone and comprises ~42 spectral lines at pc spatial and sub-km/s spectral resolution. In addition, we deeply map continuum intensity, spectral index, and polarization at the frequencies where synchrotron, free-free, and thermal dust sources emit. The observed spectral lines include many transitions of ammonia, which we use to construct maps of molecular gas temperature, opacity and gas formation temperature (see poster by Nico Krieger et al., this volume). Water masers pinpoint the sites of active star formation and other lines are good tracers for density, radiation field, shocks, and ionization. This extremely rich survey forms a perfect basis to construct maps of the physical parameters of the gas in this extreme environment.
Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.
Several epidemiological studies suggest a possible involvement of viral infection in the development of epilepsy. While recent research from in vitro studies increasingly supports the role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of epilepsy, little is known about the role of other viral infections such as influenza. Using data from the Clinical Practice Research Datalink (CPRD), we conducted a matched case-control analysis to assess the association between GP-diagnosed influenza infections and the risk of developing an incident diagnosis of epilepsy. During the study period 11 244 incident epilepsy cases and 44 976 matched control patients were identified. Prior exposure to influenza was reported in 7·5% of epilepsy cases and 6·7% of controls [adjusted odds ratio (aOR) 1·12, 95% confidence interval (CI) 1·03–1·22]. Prior history of ‘complicated influenza’, i.e. influenza associated with a possible super-infection, was associated with a slightly increased epilepsy risk (aOR 1·64, 95% CI 1·10–2·46), particularly if recorded within the 2 months preceding the epilepsy diagnosis (aOR 6·03, 95% CI 1·10–33·2). Our findings suggest that prior influenza exposure does not appear to materially alter the risk of developing epilepsy. By contrast, influenza episodes accompanied by complications were associated with a slightly increased epilepsy risk.