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Objective: We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status.
Results: Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients.
Trial registration: ISRCTN93732214 (http://www.isrctn.com)
Background: Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, prothrombin complex concentrate has been reported to be superior to other acute interventions, and many guidelines recommend prothrombin complex concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of prothrombin complex concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants.
Methods/design: A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, Science Citation Index, regulatory databases, and trial registers. We will include randomised clinical trials comparing prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients with oral anticoagulant-induced coagulopathy. Data extraction and risk of bias assessment will be handled by two independent review authors. Meta-analysis will be performed as recommended by Cochrane Handbook for Systematic Reviews of Interventions, bias will be assessed with domains, and trial sequential analysis will be conducted to control random errors. Certainty will be assessed by GRADE.
Discussion: As critical bleeding in patients treated with oral anticoagulants is an increasing problem, an up-to-date systematic review evaluating the benefits and harms of prothrombin complex concentrate is urgently needed. It is the hope that this review will be able to guide best practice in treatment and clinical research of these critically bleeding patients.
Systematic review registration: PROSPERO CRD42018084371
Background: In intensive care units (ICU) octogenarians become a routine patients group with aggravated therapeutic and diagnostic decision-making. Due to increased mortality and a reduced quality of life in this high-risk population, medical decision-making a fortiori requires an optimum of risk stratification. Recently, the VIP-1 trial prospectively observed that the clinical frailty scale (CFS) performed well in ICU patients in overall-survival and short-term outcome prediction. However, it is known that healthcare systems differ in the 21 countries contributing to the VIP-1 trial. Hence, our main focus was to investigate whether the CFS is usable for risk stratification in octogenarians admitted to diversified and high tech German ICUs.
Methods: This multicentre prospective cohort study analyses very old patients admitted to 20 German ICUs as a sub-analysis of the VIP-1 trial. Three hundred and eight patients of 80 years of age or older admitted consecutively to participating ICUs. CFS, cause of admission, APACHE II, SAPS II and SOFA scores, use of ICU resources and ICU- and 30-day mortality were recorded. Multivariate logistic regression analysis was used to identify factors associated with 30-day mortality.
Results: Patients had a median age of 84 [IQR 82–87] years and a mean CFS of 4.75 (± 1.6 standard-deviation) points. More than half of the patients (53.6%) were classified as frail (CFS ≥ 5). ICU-mortality was 17.3% and 30-day mortality was 31.2%. The cause of admission (planned vs. unplanned), (OR 5.74) and the CFS (OR 1.44 per point increase) were independent predictors of 30-day survival.
Conclusions: The CFS is an easy determinable valuable tool for prediction of 30-day ICU survival in octogenarians, thus, it may facilitate decision-making for intensive care givers in Germany.
Trial registration: The VIP-1 study was retrospectively registered on ClinicalTrials.gov (ID: NCT03134807) on May 1, 2017.
Vor dem Hintergrund des globalen Klimawandels und der Diskussion menschlicher Einflussnahme („anthropogener Treibhauseffekt“) ist anhand von Beobachtungsdaten der bodennahen Lufttemperatur und des Niederschlags untersucht worden, welche Strukturen die Klimaveränderungen in Hessen erkennen lassen. Dabei umfasst das betrachtete Gebiet den Bereich 49°- 52° Nord / 7°-11° Ost und schließt somit auch Teilgebiete der angrenzenden Bundesländer mit ein. Zeitlich lag der Schwerpunkt der Betrachtung auf dem Intervall 1951-2000, da aus dieser Zeit bei weitem die meisten Daten verfügbar sind (Temperatur 53, Niederschlag 674 Stationen). Darüber hinaus wurden aber auch Untersuchungen für die Zeit 1901 bis 2000 bzw. 2003 sowie für 30-jährige Subintervalle durchgeführt. Die Analysemethodik umfasst die Berechnung linearer Trends, einschließlich ihrer räumlichen Strukturen (Trendkarten), Aufdeckung von Fluktuationen (spektrale Varianzanalyse), Extremwertanalysen und die Diskussion natürlicher bzw. anthropogener Einflussfaktoren (Signalanalyse mittels multipler schrittweiser Regression). Die aus Tages-, Monats-, jahreszeitlichen und jährlichen Daten gewonnenen Ergebnisse sind überaus vielfältig und heterogen. Für das Flächenmittel Hessen ergibt sich 1951-2000 insgesamt (Jahresdaten) ein Temperaturanstieg von 0,9 °C mit dem Schwerpunkt im Winter (1,6 °C) und der geringsten Erwärmung im Herbst (0,2 °C). 1901-2003 liegen an den erfassten Stationen die jährlichen Erwärmungen bei 0,7 bis 1,8 °C; 30-jährig treten zum Teil auch Abkühlungen auf, insbesondere wenn die regional-jahreszeitlichen bzw. monatlichen Strukturen erfasst werden. Diese Strukturen sind beim Niederschlag noch weit ausgeprägter. Im Flächenmittel Hessen beträgt 1951-2000 der jährliche Niederschlagsanstieg 8,5 %, mit Maxima im Herbst (25 %) und Winter (22 %; Frühling 20%), während im Sommer ein Rückgang um 18 % eingetreten ist (mit Schwerpunkten im Juni und insbesondere August). Bei den Fluktuationen dominieren mittlere Perioden von ca. 2,2, 3,3, 5,5 und 7,5-8 Jahren, beim Niederschlag auch ca. 4,5 Jahre. Der Sonnenfleckenzyklus spiegelt sich in den analysierten Klimadaten nicht wider. Zusammen mit den Extremwerten sorgen diese Fluktuationen für zeitliche Instabilitäten der Klimatrends, insbesondere wenn relativ kurze (z.B. 30-jährige) Zeitabschnitte betrachtet werden. Die wiederum sehr vielfältigen und unterschiedlichen Ergebnisse der Extremwertanalyse spiegeln bei der Temperatur weitgehend die Trends wider, da sich die Streuung der Daten kaum verändert hat: d.h. Zunahme der Überschreitungswahrscheinlichkeit extrem warmer Ereignisse (insbesondere Frühling, überwiegend auch Sommer und Winter, am wenigsten im Herbst) und Abnahme der Unterschreitungswahrscheinlichkeit extrem kalter Ereignisse (dies im Winter bei den Tagesdaten jedoch sehr uneinheitlich). Beim Niederschlag sind die Abnahme extrem feuchter Monate im Sommer und die Zunahme extrem feuchter Tage im Herbst und Winter am auffälligsten. Langfristig folgen daraus ganz markante Änderungen der Jährlichkeiten. So ist beispielsweise 1901-2001 in Alsfeld die Jährlichkeit eines extrem feuchten Winters von 100 auf 5,6 Jahre zurückgegangen, die entsprechende Jährlichkeit eines extrem feuchten Sommers in Bad Camberg dagegen fast bis zur Unmöglichkeit angestiegen. Bei der Ursachendiskussion lässt sich in den Temperaturdaten ein deutlicher anthropogener Einfluss („Treibhauseffekt“) ausfindig machen. Abschließend wird diskutiert, inwieweit es sinnvoll ist, die beobachteten Trends, im Vergleich mit Modellprojektionen, in die Zukunft zu extrapolieren.
Questions about how human-environment-relations can be conceptualized in a non-dualistic way have been intensively discussed throughout the last decades. The majority of the established realist and constructivist perspectives aim at explaining a given situation by analytically dissecting it. Unfortunately, such an interactionist perspective systematically reproduces the dualistic division between humans, environment and nature.
In contrast, this paper offers a transactive perspective origin in classical pragmatism and discusses its meta-theoretical consequences for human-environment-research. A transactionist perspective interprets the world as a flow of unique and entangled events. Instead of ontologically separating humans and environment, it advocates to look at their relations as being part of a "connatural world". Such a point of view raises new ethical and political questions for geographical human-environment research, argues for a renaissance of ideographic methodologies and hints to a fruitful unity of geographical inquiry.
Introduction: Ischemic and hemorrhagic strokes in the brainstem and cerebellum with injury to the functional loop of the Guillain-Mollaret triangle (GMT) can trigger a series of events that result in secondary trans-synaptic neurodegeneration of the inferior olivary nucleus. In an unknown percentage of patients, this leads to a condition called hypertrophic olivary degeneration (HOD). Characteristic clinical symptoms of HOD progress slowly over months and consist of a rhythmic palatal tremor, vertical pendular nystagmus, and Holmes tremor of the upper limbs. Diffusion Tensor Imaging (DTI) with tractography is a promising method to identify functional pathway lesions along the cerebello-thalamo-cortical connectivity and to generate a deeper understanding of the HOD pathophysiology. The incidence of HOD development following stroke and the timeline of clinical symptoms have not yet been determined in prospective studies—a prerequisite for the surveillance of patients at risk. Methods and Analysis: Patients with ischemic and hemorrhagic strokes in the brainstem and cerebellum with a topo-anatomical relation to the GMT are recruited within certified stroke units of the Interdisciplinary Neurovascular Network of the Rhine-Main. Matching lesions are identified using a predefined MRI template. Eligible patients are prospectively followed up and present at 4 and 8 months after the index event. During study visits, a clinical neurological examination and brain MRI, including high-resolution T2-, proton-density-weighted imaging, and DTI tractography, are performed. Fiberoptic endoscopic evaluation of swallowing is optional if palatal tremor is encountered. Study Outcomes: The primary endpoint of this prospective clinical multicenter study is to determine the frequency of radiological HOD development in patients with a posterior fossa stroke affecting the GMT at 8 months after the index event. Secondary endpoints are identification of (1) the timeline and relevance of clinical symptoms, (2) lesion localizations more prone to HOD occurrence, and (3) the best MR-imaging regimen for HOD identification. Additionally, (4) DTI tractography data are used to analyze individual pathway lesions. The aim is to contribute to the epidemiological and pathophysiological understanding of HOD and hereby facilitate future research on therapeutic and prophylactic measures.
The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.