The Early to Middle Triassic continental-marine transition of NW Bulgaria:sedimentology, palynology and sequence stratigraphy

Sedimentary facies and cycles of the Triassic continental–marine transition of NW Bulgaria are documented in detail from reference sections along the Iskar river gorge between the villages of Tserovo and Opletnya. The depositional environments evolved from anastomosing and meandering river systems in the Petrohan Terrigenous Group to mixed fluvial and tidal settings in the Svidol Formation, and to peritidal and shallow-marine conditions in the Opletnya Member of the Mogila Formation. For the first time, the palynostratigraphic data presented here allow for dating the transitional interval and for the precise identification of a major sequence boundary between the Petrohan Terrigenous Group and the Svidol Formation (Iskar Carbonate Group). This boundary most probably corresponds to the major sequence boundary Ol4 occurring in the upper Olenekian of the Tethyan realm and thus enables interregional correlation. The identification of regionally traceable sequence boundaries based on biostratigraphic age control is a first step towards a more accurate stratigraphic correlation and palaeogeographic interpretation of the Early to early Middle Triassic in NW Bulgaria

MAGIC MOORE-PENROSE INVERSES AND PHILATELIC MAGIC SQUARES WITH SPECIAL EMPHASIS ON THE DANIELS–ZLOBEC MAGIC SQUARE

We study singular magic matrices in which the numbers in the rows and columns and in the two main diagonals all add up to the same sum. Our interest focuses on such magic matrices for which the Moore– Penrose inverse is also magic. Special attention is given to the “Daniels–Zlobec magic square’’ introduced by the British magician and television performer Paul Daniels (b. 1938) and considered by Zlobec (2001); see also Murray (1989, pp. 30–32). We introduce the concept of a “philatelic magic square” as a square arrangement of images of postage stamps so that the associated nominal values form a magic square. Three philatelic magic squares with stamps especially chosen for Sanjo Zlobec are presented in celebration of his 70th birthday; most helpful in identifying these stamps was an Excel checklist by Männikkö (2009)

Integrated bio- and cyclostratigraphy of Middle Triassic (Anisian) ramp deposits, NW Bulgaria

A cyclostratigraphic interpretation of peritidal to shallow-marine ramp deposits of the early Middle Triassic (Anisian) Opletnya Member exposed in outcrops along the Iskar River gorge, NW Bulgaria, is presented. Based on facies trends and bounding surfaces, depositional sequences of several orders can be identified. New biostratigraphic data provide a time frame of the studied succession with placement of the boundaries of the Anisian substages and show that the Aegean (early Anisian) substage lasted about 1.6 Myr. In the corresponding interval in the two studied sections, 80 elementary sequences are counted. Five elementary sequences compose a small-scale sequence. The prominent cyclic pattern of the Opletnya Member can thus be interpreted in terms of Milankovitch cyclicity: elementary sequences represent the precession (20-kyr) cycle and small-scale sequences the short eccentricity (100-kyr) cycle in the Milankovitch frequency band. Medium-scale sequences are defined based on lithology but only in two cases can be attributed to the long eccentricity cycle of 405 kyr. The transgressive-regressive facies trends within the sequences of all scales imply that they were controlled by sea-level changes, and that these were in tune with the climate changes induced by the orbital cycles. However, the complexity of facies and sedimentary structures seen in the Opletnya Member also implies that additional factors such as lateral migration of sediment bodies across the ramp were active. In addition, three major sequence boundaries have been identified in the studied sections, which can be correlated with the boundaries Ol4, An1, and An2 of the Tethyan realm

Independent external validation of a stroke recurrence score in patients with embolic stroke of undetermined source

Abstract Background Embolic stroke of undetermined source (ESUS) accounts for a substantial proportion of ischaemic strokes. A stroke recurrence score has been shown to predict the risk of recurrent stroke in patients with ESUS based on a combination of clinical and imaging features. This study aimed to externally validate the performance of the ESUS recurrence score using data from a randomized controlled trial. Methods The validation dataset consisted of eligible stroke patients with available magnetic resonance imaging (MRI) data enrolled in the PreDAFIS sub-study of the MonDAFIS study. The score was calculated using three variables: age (1 point per decade after 35 years), presence of white matter hyperintensities (2 points), and multiterritorial ischaemic stroke (3 points). Patients were assigned to risk groups as described in the original publication. The model was evaluated using standard discrimination and calibration methods. Results Of the 1054 patients, 241 (22.9%) were classified as ESUS. Owing to insufficient MRI quality, three patients were excluded, leaving 238 patients (median age 65.5 years [IQR 20.75], 39% female) for analysis. Of these, 30 (13%) patients experienced recurrent ischaemic stroke or transient ischemic attack (TIA) during a follow-up period of 383 patient-years, corresponding to an incidence rate of 7.8 per 100 patient-years (95% CI 5.3–11.2). Patients with an ESUS recurrence score value of ≥ 7 had a 2.46 (hazard ratio (HR), 95% CI 1.02–5.93) times higher risk of stroke recurrence than patients with a score of 0–4. The cumulative probability of stroke recurrence in the low-(0–4), intermediate-(5–6), and high-risk group (≥ 7) was 9%, 13%, and 23%, respectively (log-rank test, χ2 = 4.2, p = 0.1). Conclusions This external validation of a published scoring system supports a threshold of ≥ 7 for identifying ESUS patients at high-risk of stroke recurrence. However, further adjustments may be required to improve the model’s performance in independent cohorts. The use of risk scores may be helpful in guiding extended diagnostics and further trials on secondary prevention in patients with ESUS. Trial registration: Clinical Trials, NCT02204267. Registered 30 July 2014, https://clinicaltrials.gov/ct2/show/NCT02204267

Regulatory delays in a multinational clinical stroke trial

INTRODUCTION: The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. MATERIALS AND METHODS: We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. RESULTS: The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02). DISCUSSION: CONCLUSION: In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials

Precision of genetic parameters and breeding values estimated in marker assisted BLUP genetic evaluation

In practical implementations of marker-assisted selection economic and logistic restrictions frequently lead to incomplete genotypic data for the animals of interest. This may result in bias and larger standard errors of the estimated parameters and, as a consequence, reduce the benefits of applying marker-assisted selection. Our study examines the impact of the following factors: phenotypic information, depth of pedigree, and missing genotypes in the application of marker-assisted selection. Stochastic simulations were conducted to generate a typical dairy cattle population. Genetic parameters and breeding values were estimated using a two-step approach. First, pre-corrected phenotypes (daughter yield deviations (DYD) for bulls, yield deviations (YD) for cows) were calculated in polygenic animal models for the entire population. These estimated phenotypes were then used in marker assisted BLUP (MA-BLUP) evaluations where only the genotyped animals and their close relatives were included

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment

BackgroundInfections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. MethodsWe conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR 1 harm). This trial is registered (ISRCTN82217627). FindingsFrom April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81–1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77–1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96–1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. InterpretationWe observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. FundingThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No: 634809

Axis internationalism: Spanish health experts and the Nazi ‘New Europe’, 1939–1945

Many of the forms and practices of interwar internationalism were recreated under the auspices of the Nazi ‘New Europe’. This article will examine these forms of ‘Axis internationalism’ by looking at Spanish health experts' involvement with Nazi Germany during the Second World War. Despite the ambiguous relationship between the Franco regime and the Axis powers, a wide range of Spanish health experts formed close ties with colleagues from Nazi Germany and across Axis and occupied Europe. Many of those involved were relatively conservative figures who also worked with liberal international health organisations in the pre- and post-war eras. Despite their political differences, their opposing attitudes towards eugenics and the tensions caused by German hegemony, Spanish experts were able to rationalise their involvement with Nazi Germany as a mutually-beneficial continuation of pre-war international health cooperation amongst countries united by a shared commitment to modern, ‘totalitarian’ forms of public health. Despite the hostility of Nazi Germany and its European collaborators to both liberal and left-wing forms of internationalism, this phenomenon suggests that the ‘New Europe’ deserves to be studied as part of the wider history of internationalism in general and of international health in particular

The Guinea Pig as a model for sporadic Alzheimer's Disease (AD): the impact of cholesterol intake on expression of AD-related genes

Extent: 12p.We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer’s disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high cholesterol intake. Unlike rats and mice, guinea pigs possess an Aβ peptide sequence identical to human Aβ. Consistent with the commonality between cardiovascular and AD risk factors in humans, we saw that a high cholesterol diet leads to up-regulation of BACE1 (β-secretase) transcription and down-regulation of ADAM10 (α-secretase) transcription which should increase release of Aβ from APP. Significantly, guinea pigs possess isoforms of AD-related genes found in humans but not present in mice or rats. For example, we discovered that the truncated PS2V isoform of human PSEN2, that is found at raised levels in AD brains and that increases γ-secretase activity and Aβ synthesis, is not uniquely human or aberrant as previously believed. We show that PS2V formation is up-regulated by hypoxia and a high-cholesterol diet while, consistent with observations in humans, Aβ concentrations are raised in some brain regions but not others. Also like humans, but unlike mice, the guinea pig gene encoding tau, MAPT, encodes isoforms with both three and four microtubule binding domains, and cholesterol alters the ratio of these isoforms. We conclude that AD-related genes are highly conserved and more similar to human than the rat or mouse. Guinea pigs represent a superior rodent model for analysis of the impact of dietary factors such as cholesterol on the regulation of AD-related genes.Mathew J. Sharman, Seyyed H. Moussavi Nik, Mengqi M. Chen, Daniel Ong, Linda Wijaya, Simon M. Laws, Kevin Taddei, Morgan Newman, Michael Lardelli, Ralph N. Martins, Giuseppe Verdil

Order in Spontaneous Behavior

Brains are usually described as input/output systems: they transform sensory input into motor output. However, the motor output of brains (behavior) is notoriously variable, even under identical sensory conditions. The question of whether this behavioral variability merely reflects residual deviations due to extrinsic random noise in such otherwise deterministic systems or an intrinsic, adaptive indeterminacy trait is central for the basic understanding of brain function. Instead of random noise, we find a fractal order (resembling Lévy flights) in the temporal structure of spontaneous flight maneuvers in tethered Drosophila fruit flies. Lévy-like probabilistic behavior patterns are evolutionarily conserved, suggesting a general neural mechanism underlying spontaneous behavior. Drosophila can produce these patterns endogenously, without any external cues. The fly's behavior is controlled by brain circuits which operate as a nonlinear system with unstable dynamics far from equilibrium. These findings suggest that both general models of brain function and autonomous agents ought to include biologically relevant nonlinear, endogenous behavior-initiating mechanisms if they strive to realistically simulate biological brains or out-compete other agents