Impact and extinction signatures in complete Cretaceous-Tertiary (K-T) boundary sections

The Zumaya, Caravaca and Agost sections in Spain, the El Kef section in Tunisia and the Negev (Nahal Avdat) sections in Israel are among the most continuous, expanded and complete K-T boundary sections. The distribution patterns of the planktic faunas were quantitatively analyzed in closely spaced samples across the K-T boundary in these sections, in conjuction with the geochemistry, stable isotopes, mineralogy and magnetostratigraphy. Three hundred foraminiferal specimens were randomly selected and determined. Reliable estimates for the foraminiferal productivity changes across the K-T boundary and for the 1 to 2 Ma interval preceding the K-T boundary were made from the numbers of individuals/gram of sediment corrected for the sedimentation rates (calculated from magnetic reversals and lithology). No gradual or stepwise extinction is seen below the K-T boundary nor any productivity decrease. Stable isotope analyses show a warming just after deposition of the ejecta layer, not cooling as predicted by nuclear winter scenarios, although the duration of such cooling may be too short to be observed even in these complete sections. Low REE values and cpx spherules with quench textures idential to quench-textures in diagenetically altered spherules, strongly indicate an oceanic site of (one of) the impactor(s)

The Circular Dispersion Spectrum

AbstractLet ϑ be a real irrational number and N a positive integer. The one-dimensional torus T is divided by the N points nϑ mod 1, n = 1, 2, ..., N, into N arcs. Denote the length of the longest of these arcs by dN. Define the circular dispersion constant of ϑ, notation C(ϑ), by C(ϑ) ≔ lim supN → ∞NdN. The set of numbers C(ϑ) is called the circular dispersion spectrum. This paper determines the smallest accumulation point of this spectrum and all points below this accumulation point

Stability of boundaries between response options of response scales: Does 'very happy' remain equally happy over the years?

__Abstract__ The differences between response scales in number and wording of response options make it hard to compare data from survey research and to perform research syntheses. A recent method that we have developed to tackle this problem is rooted in the idea that the transition points on a bounded continuum, on which verbal response options from a primary scale transit from one point to another, for instance from ‘happy’ to ‘very happy’, remain unchanged over time. The idea behind this is that although people may change their perception of, for example, their own happiness intensity over time, they are assumed not to change the degree of appreciation they attribute to the terms used to label response options. This is an important assumption for research syntheses that requires that everything remains unchanged, except for the change of interest. It means that if our method is applied to measurements at distinct points in time, differences in estimates of the mean and standard deviation can be attributed solely to changes in the frequency distributions on the primary scale. In this paper we apply the method to happiness and show that it is reasonable to assume that the transition points between the response options are stable over time

The Effects of Ketone Supplementation on Recovery in Collegiate Male Soccer Players: Pilot Trial

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Conversion of Verbal Response Scales: Robustness Across Demographic Categories

Happiness and life satisfaction have traditionally been measured using verbal response scales, however, these verbal scales have not kept up with the present trend to use numerical response scales. A switch from a verbal scale to a numerical scale, however, causes a severe problem for trend analyses, due to the incomparability of the old and new measurements. The Reference Distribution Method is a method that has been developed recently to deal with this comparison problem. In this method use is made of a reference distribution based on responses to a numerical scale which is used to decide at which point verbally labelled response options transit from one state to another, for example from ‘happy’ to ‘very happy’. Next, for each wave of the time series in which the verbal scale is used, a population mean is estimated for the beta distribution that fits best to these transition points and the responses in this wave. These estimates are on a level that is comparable to that of the mean of the reference distribution and are appropriate for use in an extended time series based on the responses measured using a verbal and a numerical scale. In this paper we address the question of whether the transition points derived for the general population can be used for demographic categories to produce reliable, extended time series to monitor differences in trends among these categories. We conclude that this is possible and that it is not necessary to derive transition points for each demographic category separately

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p Z 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4e4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3e1.6) for placebo (HR Z 0.64, 95% CI: 0.38e1.07; p Z 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6e4.2) months for brivanib and 2.0 months (95% CI: 1.2e2.7) for placebo (HR: 0.56, 95% CI: 0.26e1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6e4.2) and was 2.0 months (95% CI: 1.2e2.7) in those randomised to placebo (HR Z 0.54, 95% CI: 0.25e1.17; p Z 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat

Proof-of-concept of a data-driven approach to estimate the associations of comorbid mental and physical disorders with global health-related disability

Objective: The standard method of generating disorder-specific disability scores has lay raters make rankings between pairs of disorders based on brief disorder vignettes. This method introduces bias due to differential rater knowledge of disorders and inability to disentangle the disability due to disorders from the disability due to comorbidities. Methods: We propose an alternative, data-driven, method of generating disorder-specific disability scores that assesses disorders in a sample of individuals either from population medical registry data or population survey self-reports and uses Generalized Random Forests(GRF) to predict global (rather than disorder-specific) disability assessed by clinician ratings or by survey respondent self-reports. This method also provides a principled basis for studying patterns and predictors of heterogeneity in disorder-specific disability. We illustrate this method by analyzing data for 16 disorders assessed in the World Mental Health Surveys(n=53,645).Results: Adjustments for comorbidity decreased estimates of disorder-specific disability substantially. Estimates were generally somewhat higher with GRF than conventional multivariable regression models. Heterogeneity was nonsignificant. Conclusions: The results show clearly that the proposed approach is practical, and that adjustment is needed for comorbidities to obtain accurate estimates of disorder-specific disability. Expansion to a wider range of disorders would likely find more evidence for heterogeneity

Vascular disrupting agents in clinical development

Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given