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Radiocarbon (14C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric 14C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international 14C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable 14C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the 14C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine 14C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.
The model of PGE describes the emergence of new systems based on reference by the activities carryover, embodiment and principle variation - qualitatively different manifestations of a transfer process. We investigate indicators which constitute these different manifestations measurably for different types of systems. We propose generalized variation operators to describe system development with respect to different product elements and system types. We use case studies from automotive, production systems and simulation models.
Age-of-onset (AO) seems to be a phenotypic variable with a strong genetic component and therefore useful in molecular analysis of bipolar disorder (BP). A debate about the cut-off point for defining early AO has developed over the last few years. Using an Expectation-Maximization algorithm Bellivier et al. (2001) found the best fit for a model with three onset-groups, proposing the age 20-21 as cut-off for early onset, while using the same algorithm Kennedy et al. (2005) found the best fit for a two onset-group model with age 40 as cut-off with an incidence peak for mania in the age-band 21-25. Based on segregation analysis, we proposed a two AO-group model with cut-off age 25 for early onset (Grigoroiu-Serbanescu et al. 2001). The present study aimed at investigating the best AO-model in 500 Romanian BPI and 1458 German BPI patients using commingling analysis (SAGEv6.01-software) (Elston et al, 2009). The best model was selected according to Akaike's Information Criterion (AIC).
The two AO-group and three AO-group models provided similar AIC-values both in the Romanian and the German sample. The Romanian early-onset group (40% cases) had means around 18 years, SDs=6-7, while in the German early-onset group the mean AO was around 20 years (SDs=9-11) (50% cases). Thus the cut-off for early-onset (X +1SD) was different.
Our results overlapped with the findings of Kennedy et al (2005) showing that two-curve and three-curve AO mixtures similarly fit the AO-distribution in BPI disorder and the cut-offs for early-onset differ by sample.
To evaluate open-label treatment with olanzapine in patients with borderline personality disorder (BPD).
In two concurrent studies, patients received 12 weeks of open-label olanzapine after completing 12-weeks of double-blind treatment with either olanzapine or placebo. Open-label olanzapine dosing started at 2.5 or 5mg/day and could be increased up to 20mg/day (Study 1) or 15mg/day (Study 2).
Mean ZAN-BPD total scores decreased from approximately 17 points to approximately 8-10 points during the acute phase. After 12 weeks of open-label olanzapine treatment, mean ZAN-BPD total scores were approximately 6-7 points. Patients treated with placebo during the acute phase and then open-label olanzapine showed changes in weight, prolactin, and other laboratory values similar in magnitude to those seen in acutely olanzapine-treated patients. Patients treated with olanzapine during the acute phase showed smaller changes in weight and laboratory values during the open-label extension.
Overall BPD symptom severity was low by the end of the open-label olanzapine treatment period. The types of treatment emergent adverse events appeared to be consistent with those seen previously in patients treated with olanzapine. The direction and magnitude of effects on safety measures depended on the treatment received during the prior double-blind period.
Neuropsychological deficits are considered endophenotypes for schizophrenia, because they are not only found in patients but also in many of their unaffected relatives, albeit in attenuated form. It is not yet clear which of these deficits in relatives are related to genetic or to environmental causes. We tested effects of inferred genetic liability for schizophrenia on neurocognitive variables to address this problem.
Twenty-eight patients with schizophrenia, 129 non-affected biological parents and 143 matched controls were assessed with an extensive neuropsychological test battery including tests of attention, memory, executive functioning and motor soft signs. Twenty-two parents had an ancestral history of schizophrenia and therefore were hypothesized to be more likely than their spouses without such a history (n = 17) to carry a genetic risk for schizophrenia.
Unaffected parents of schizophrenic patients showed significant deficits in a wide array of neuropsychological tasks and task domains. However, comparison of more likely and less likely carriers of illness-related genes showed specifically attentional and executive functioning, but not memory, to vary with degree of inferred genetic loading.
Attentional and executive (frontal) impairments vary with genetic loading for schizophrenia and can be considered true endophenotypes for this disorder. Consequently, these functions are particularly suited to evaluate the functional impact of candidate genes for schizophrenia in future studies.
We examined the efficacy and safety of flexibly-dosed olanzapine for the treatment of borderline personality disorder (BPD).
In this 12-week double-blind trial, patients 18-65 years of age with a diagnosis of DSM-IV BPD received olanzapine (2.5-20mg/day; N=155) or placebo (N=159). The primary efficacy measure was the change from baseline to last-observation carried forward endpoint (LOCF) on the Zanarini Rating Scale for BPD (ZAN-BPD) total score. Rate of response and time to response were also examined, with response defined as a >=50% reduction in ZAN-BPD total score.
Mean baseline ZAN-BPD total scores were indicative of moderate symptom severity (olanzapine 17.01 vs. placebo 17.70, p=0.156). Both treatment groups showed significant improvements in overall symptom severity, based on mean changes from baseline to LOCF endpoint in ZAN-BPD total score, but did not differ in the magnitude of improvement at endpoint (olanzapine -6.56 vs. placebo -6.25, p=.661). Response rates did not differ between treatment groups (olanzapine 64.7% vs. placebo 53.5%, p=.062); however, time to response was significantly shorter for the olanzapine treatment group (p=.022). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, sedation, increased appetite and weight increase. Mean weight change from baseline to endpoint was significantly different for olanzapine- relative to placebo-treated patients (2.86vs. -0.35kg, p<.001).
Both the olanzapine- and placebo-treated patients showed significant but not statistically different improvement on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment were similar to those seen previously in adult populations.
Neurocognitive and functional neuroimaging studies point to frontal lobe abnormalities in schizophrenia. Molecular and behavioural genetic studies suggest that the frontal lobe is under significant genetic influence. We carried out structural magnetic resonance imaging (MRI) of the frontal lobe in monozygotic (MZ) twins concordant or discordant for schizophrenia and healthy MZ control twins.
The sample comprised 21 concordant pairs, 17 discordant affected and 18 discordant unaffected twins from 19 discordant pairs, and 27 control pairs. Groups were matched on sociodemographic variables. Patient groups (concordant, discordant affected) did not differ on clinical variables. Volumes of superior, middle, inferior and orbital frontal gyri were calculated using the Cavalieri principle on the basis of manual tracing of anatomic boundaries. Group differences were investigated covarying for whole-brain volume, gender and age.
Results for superior frontal gyrus showed that twins with schizophrenia (i.e. concordant twins and discordant affected twins) had reduced volume compared to twins without schizophrenia (i.e. discordant unaffected and control twins), indicating an effect of illness. For middle and orbital frontal gyrus, concordant (but not discordant affected) twins differed from non-schizophrenic twins. There were no group differences in inferior frontal gyrus volume.
These findings suggest that volume reductions in the superior frontal gyrus are associated with a diagnosis of schizophrenia (in the presence or absence of a co-twin with schizophrenia). On the other hand, volume reductions in middle and orbital frontal gyri are seen only in concordant pairs, perhaps reflecting the increased genetic vulnerability in this group.
We examined the efficacy and safety of low vs. moderate olanzapine doses for the treatment of borderline personality disorder (BPD) in the largest controlled clinical trial ever conducted in this population.
This 12-week, double-blind trial involved patients 18-65 years with a diagnosis of DSM-IV BPD randomized to receive 2.5mg/day olanzapine (N=150), 5-10mg/day olanzapine (N=148), or placebo (N=153). The primary efficacy measure was the change from baseline-to-endpoint (last-observation-carried-forward) on the Zanarini Rating Scale for BPD (ZAN-BPD) total score. Rate of response and time-to-response were also examined (response defined as a >=50% reduction in ZAN-BPD total score).
Mean baseline ZAN-BPD total scores ranged from 17.01 to 17.42, indicating moderate symptom severity. Treatment with OLZ5-10 was associated with significantly greater mean change from baseline-to-endpoint in ZAN-BPD total score than placebo (-8.50 vs. -6.79, p=.010). Response rates were significantly higher for OLZ5-10 (73.6%) than for OLZ2.5 (60.1%, p=.018) and placebo (57.8%, p=.006). Time-to-response was significantly shorter for OLZ5-10 than placebo (p=.028). Treatment-emergent adverse events seen more frequently in the olanzapine groups included somnolence, increased appetite, and weight gain. Mean weight change from baseline-to-endpoint was 2.09kg for OLZ 2.5, 3.17kg for OLZ5-10, and 0.02kg for placebo.
The results of this study suggest that moderate doses of olanzapine (5-10mg/day) are effective in the treatment of overall borderline psychopathology. Also, the types of adverse events observed with olanzapine treatment were similar to those seen previously in adult populations.
Significant alterations of cardiac autonomic function were shown for patients with schizophrenia and their first-degree relatives, implying a genetic association. Cardio-respiratory function, although a core physiological regulatory component, has never been assessed.
To test the hypothesis of altered patterns of breathing in patients with acute schizophrenia, we assessed breathing rate, rhythm and depth, as well as heart rate variability (HRV) and cardio-respiratory coupling in patients (n = 23), their first-degree relatives (n = 20) and controls (n = 30). Control subjects were matched for age, gender, smoking and physical fitness, and were investigated a second time by means of a stress task to identify stress-related changes of cardio-respiratory function.
Patients breathe faster (p < .001) and shallower (p < .001) than controls most pronouncedly during exhalation. Patients' breathing is characterized by an increased amount of middle- (p < .001), high- (p < .001), and very high fluctuations (p < .001). These measures correlated with positive symptoms. Shallow breathing of patients is mirrored by a smaller tidal volume (p < .001) without variability changes. Cardio-respiratory coupling was reduced in patients only, while HRV was decreased in patients and healthy relatives.
Changes of respiratory regulation and decreased cardio-respiratory coupling mirror profound alterations of core physiological function. In contrast to HRV changes, respiratory alterations were observed in patients only and might reflect arousal in acutely ill patients. This assumption is supported by observed changes of breathing and cardiac regulation in healthy subjects during stress. Findings are of high relevance for other research areas such as functional imaging.
Smoking-behaviour is influenced by environmental and genetic risk factors. Established epidemiological risk factors include early age at onset (AaO), depression, positive family history (FH+) of depression/alcohol-dependence, low education, older birth cohort, and male gender. Genomewide-association-studies (GWAS) have identified genetic risk variants for smoking-behaviour. In the present study we investigated correlations between these epidemiological and genetic risk factors and smoking-behaviour in a large population-based German sample. Genetic risk was defined in terms of a polygenic score – the accumulated effect of seven independent genetic risk markers for smoking-behaviour identified through GWAS.
The sample comprised 1736 individuals (815 males, 921 females). Dependent variables were: smoking-duration, nicotine-dependence, cigarettes–per-day, ever-smoking, and smoking-cessation. The effect of the epidemiological risk factors, the polygenic risk score, and their combined effect on the smoking-behaviours was tested via linear or logistic regression analyses.
The following associations were detected: AaO and birth cohort with smoking-duration (p=0.004; p<0.001); AaO, education and FH+ depression with nicotine-dependence (p=0.002; p=0.092); sex and AaO with cigarettes–per-day (p=0.020; p<0.001); FH+ alcohol dependence with eversmoking (p=0.049); and birth cohort and education with smoking-cessation (p=0.001; p=0.029). The polygenic risk score showed a trend towards association with nicotine-dependence (p=0.113) and cigarettes–per-day (p=0.109). In the combined analyses, the polygenic risk score improved the regression model for nicotine-dependence, cigarettes–per-day, and smoking-cessation.
The addition of GWAS information concerning genetic risk factors explained an increased fraction of the smoking behaviours nicotine dependence, CPD, and smoking cessation. Future studies are warranted to elucidate the biological correlates of these genetic risk factors.
The COVID-19 pandemic has stunned the global community with marked social and psychological ramifications. There are key challenges for psychiatry that require urgent attention to ensure mental health well-being for all – COVID-19-positive patients, healthcare professionals, first responders, people with psychiatric disorders and the general population. This editorial outlines some of these challenges and research questions, and serves as a preliminary framework of what needs to be addressed. Mental healthcare should be an integral component of healthcare policy and practice towards COVID-19. Collaborative efforts from psychiatric organisations and their members are required to maximise appropriate clinical and educational interventions while minimising stigma.
Maternal systemic inflammation during pregnancy may restrict embryo−fetal growth, but the extent of this effect remains poorly established in undernourished populations. In a cohort of 653 maternal−newborn dyads participating in a multi-armed, micronutrient supplementation trial in southern Nepal, we investigated associations between maternal inflammation, assessed by serum α1-acid glycoprotein and C-reactive protein, in the first and third trimesters of pregnancy, and newborn weight, length and head and chest circumferences. Median (IQR) maternal concentrations in α1-acid glycoprotein and C-reactive protein in the first and third trimesters were 0.65 (0.53–0.76) and 0.40 (0.33–0.50) g/l, and 0.56 (0.25–1.54) and 1.07 (0.43–2.32) mg/l, respectively. α1-acid glycoprotein was inversely associated with birth size: weight, length, head circumference and chest circumference were lower by 116 g (P = 2.3 × 10−6), and 0.45 (P = 3.1 × 10−5), 0.18 (P = 0.0191) and 0.48 (P = 1.7 × 10−7) cm, respectively, per 50% increase in α1-acid glycoprotein averaged across both trimesters. Adjustment for maternal age, parity, gestational age, nutritional and socio-economic status and daily micronutrient supplementation failed to alter any association. Serum C-reactive protein concentration was largely unassociated with newborn size. In rural Nepal, birth size was inversely associated with low-grade, chronic inflammation during pregnancy as indicated by serum α1-acid glycoprotein.
The electrical reliability of multilayer high density interconnection printed circuit boards (HDI-PCBs) is mainly affected by the thermo-mechanical stability of stacked micro via interconnections. Here, a critical failure mode is the stress related crack between the electrolytically filled via and the target pad, commonly known as target pad separation. The junction includes two Cu-Cu-interfaces, one between the target Cu pad and the thin electroless Cu layer and the second between electroless Cu and electrolytic Cu. In this paper we will show that state-of-the-art electroless Cu plating processes are able to provide solid, completely recrystallized and highly reliable stacked via junctions. Defect free interfaces were achieved by using ionic Pd-activators and electroless Cu baths with a cyanide based stabilizer system. Cyanide free electroless Cu baths tend more to the formation of nanometer sized defects, discovered via Transmission Electron Microscopy (TEM). In this case a precise adjustment of single stabilizer components is mandatory to achieve defect free layers. The defects are hollow and were identified as “nano voids”. A critical density of these nano voids weakens the interface, predefines the crack path and reduces the overall reliability of the junction. A precise localization of the nano voids within the junction was enabled by detecting the Ni-containing electroless Cu layer via TEM-Ni mapping. Slower volume exchange of the electroless Cu solution within the blind micro via (BMV) substantially increases the nano void density. The ability of nano voids to migrate and coalesce at elevated temperatures was investigated as well.
The replacement of the finite and costly resource fish oil is an important task for aquaculture nutrition. A promising approach could be the use of plant bioactives that may have the potential to influence the metabolism and the synthesis of n-3 long chain polyunsaturated fatty acids, especially EPA (20:5n-3) and DHA (22:6n-3). In this study, the two phytochemicals resveratrol (RV) and genistein (G) were investigated for their effects on fish growth, nutrient utilization and body nutrient composition alongside their effects on whole body fatty acid (FA) composition. In a feeding trial lasting 8 weeks, rainbow trout (initial BW: 81.4±0.5 g) were held in a recirculating aquaculture system and fed six experimental diets with varying fish oil levels as plain variants or supplemented with 0.3% of dry matter (DM) of either RV or G. The six diets were as follows: diet F4 had 4% DM fish oil, diet F0 had 0% DM fish oil, diets F4+RV, F4+G, F0+RV and F0+G were equal to the diets F4 and F0, respectively, and supplemented with the phytochemicals RV and G. The feeding of the F0+RV diet resulted in reduced feed intake, growth rate and slightly reduced whole body lipid levels. At the same time, the amount of polyunsaturated FA and the n-3/n-6 ratio were significantly increased in whole body homogenates of rainbow trout fed diet F0+RV in comparison to the F0 control. The feeding of the F0+G diet led to reduced feed intake, slightly increased protein utilization but did not significantly affect the whole body FA composition. Overall, feeding the fish oil-free diet supplemented with the phytochemicals resulted in more pronounced effects on fish performance and FA composition than the single factors per se (dietary fish oil level or phytochemical). Present data indicate that G might not be of profitable use for trout nutrition. In terms of FA composition, RV could be a potentially useful complement for fish oil. However, the impairment of growth and performance parameters as observed in the present study discourages its use in trout diets.
Based on the vulnerability–stress model, we aimed to (1) determine new onset of depression in individuals who had not shown evidence of depression at baseline (5 years earlier) and (2) identify social, psychological, behavioral, and somatic predictors.
Longitudinal data of N = 10 036 participants (40–79 years) were evaluated who had no evidence of depression at baseline based on Patient Health Questionnaire (PHQ-9), no history of depression, or intake of antidepressants. Multivariate logistic regression models were used to predict the onset of depression.
Prevalence of new cases of depression was 4.4%. Higher rates of women (5.1%) than men (3.8%) were due to their excess incidence <60 years of age. Regression analyses revealed significant social, psychological, behavioral, and somatic predictors: loneliness [odds ratio (OR) 2.01; 95% confidence interval (CI) 1.48–2.71], generalized anxiety (OR 2.65; 1.79–3.85), social phobia (OR 1.87; 1.34–2.57), panic (OR 1.67; 1.01–2.64), type D personality (OR 1.85; 1.47–2.32), smoking (OR 1.35; 1.05–1.71), and comorbid cancer (OR 1.58; 1.09–2.24). Protective factors were age (OR 0.88; 0.83–0.93) and social support (OR 0.93; 0.90–0.95). Stratified by sex, cancer was predictive for women; for men smoking and life events. Entered additionally, the PHQ-9 baseline score was strongly predictive (OR 1.40; 1.34–1.47), generalized anxiety became only marginally, and panic was no longer predictive. Other predictors remained significant, albeit weaker.
Psychobiological vulnerability, stress, and illness-related factors were predictive of new onset of depression, whereas social support was protective. Baseline subclinical depression was an additional risk weakening the relationship between anxiety and depression by taking their overlap into account. Vulnerability factors differed between men and women.
Cir X-1 is a young X-ray binary exhibiting X-ray flux changes of four orders of magnitude over several decades. It has been observed many times since the launch of the Chandra X-ray Observatory with high energy transmission grating spectrometer and each time the source gave us a vastly different look. At its very lowest X-ray flux we found a single 1.7 keV blackbody spectrum with an emission radius of 0.5 km. Since the neutron star in Cir X-1 is only few thousand years old we identify this as emission from an accretion column since at this youth the neutron star is assumed to be highly magnetized. At an X-ray flux of 1.8×10−11 erg cm−2 s−1 this implies a moderate magnetic field of a few times of 1011 G. The photoionized X-ray emission line properties at this low flux are consistent with B5-type companion wind. We suggest that Cir X-1 is a very young Be-star binary.