The analysis tool and software package Fast-NPS can be used to analyse smFRET data to obtain quantitative structural information about macromolecules in their natural environment. In the algorithm a ...Bayesian model gives rise to a multivariate probability distribution describing the uncertainty of the structure determination. Since Fast-NPS aims to be an easy-to-use general-purpose analysis tool for a large variety of smFRET networks, we established an MCMC based sampling engine that approximates the target distribution and requires no parameter specification by the user at all. For an efficient local exploration we automatically adapt the multivariate proposal kernel according to the shape of the target distribution. In order to handle multimodality, the sampler is equipped with a parallel tempering scheme that is fully adaptive with respect to temperature spacing and number of chains. Since the molecular surrounding of a dye molecule affects its spatial mobility and thus the smFRET efficiency, we introduce dye models which can be selected for every dye molecule individually. These models allow the user to represent the smFRET network in great detail leading to an increased localisation precision. Finally, a tool to validate the chosen model combination is provided.
Programme Title : Fast-NPS
Programme Files doi:http://dx.doi.org/10.17632/7ztzj63r68.1
Licencing provisions: Apache-2.0
Programming language: GUI in MATLAB (The MathWorks) and the core sampling engine in C++
Nature of problem: Sampling of highly diverse multivariate probability distributions in order to solve for macromolecular structures from smFRET data.
Solution method: MCMC algorithm with fully adaptive proposal kernel and parallel tempering scheme.
Animal models of obesity and diabetes mellitus Kleinert, Maximilian; Clemmensen, Christoffer; Hofmann, Susanna M ...
Nature reviews. Endocrinology,
03/2018, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Odprti dostop
More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent ...therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.
Manufacturing companies are increasingly confronted with the challenge of adapting components that are already established on the market. As a result, the existing manufacturing process sequences of ...the corresponding components must also be adapted. Due to the complex technical interdependencies of manufacturing process sequences, adaptations potentially cause change propagation. The change propagation must be considered to ensure the component’s functionality and to enable the selection of the most economical adaptation for the established manufacturing process sequence to implement the required component change. As a contribution to considering change propagation in manufacturing process sequences, a methodology for the deterministic and cost-efficient change propagation analysis is introduced. A case study from medical technology is presented to supplement the explanation of the methodology’s steps and to validate its applicability.
Zusammenfassung
Hintergrund
Der deutsche Rettungsdienst wird jährlich zu ca. 7,3 Mio. Einsätzen alarmiert, welche zu einem Großteil (ca. 59 %) ohne Arzt ablaufen. Da kaum Daten zur Qualität der ...medizinischen Versorgung und Dokumentation von Rettungsdiensteinsätzen ohne Arzt vorliegen, sollen diese anhand der Einsatzprotokolle im Rahmen dieser Studie überprüft werden.
Methode
Es erfolgte eine retrospektive Analyse von Protokollen der Rettungsdiensteinsätze ohne Arzt aus den Monaten Juni und Juli 2018. Unter Einbezug von Verfahrensanweisungen wurden die Dokumentations- und Behandlungsqualität der Einsätze analysiert. Primäre Endpunkte waren Dokumentationshäufigkeit, Vollständigkeit, die korrekte Notarzt- oder Telenotarztindikationsstellung, die Entwicklung von kritischen Vitalparametern im Einsatzverlauf sowie die mediane Behandlungszeit.
Ergebnisse
Insgesamt wurden 1935 Protokolle ausgewertet. Die Verdachtsdiagnose wurde in 1323 (68,4 %), die Anamnese in 456 (23,6 %), der Erstbefund in 350 (18,1 %) und der Letztbefund in 52 (2,7 %) der Fälle vollständig dokumentiert. Anhand der Dokumentation bestand bei 531 (27 %) Patienten eine Telenotarzt- bzw. Notarztindikation, jedoch kein Arztkontakt. Bei diesen Patienten wurden 410 kritische Vitalparameter im Erstbefund dokumentiert. Von diesen Vitalwerten verbesserten sich 69 (16,8 %); bei 217 (52,9 %) wurde kein Übergabebefund dokumentiert. Die mediane Behandlungsdauer vor Ort war bei Patienten mit eigentlicher Notarztindikation (15:02 min) signifikant länger als bei Patienten ohne Indikation (13:05 min).
Schlussfolgerung
Die Dokumentation der Einsätze ist defizitär. Zudem könnte ein Viertel der Patienten von einem prähospitalen Arztkontakt profitieren. Eine juristisch bedenkliche Übergabedokumentation besteht bei ca. der Hälfte aller Protokolle.
By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using ...high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.
Synopsis
This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.
Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.
Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.
Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy.
This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.
Each year there are 7.3 million emergencies for the German rescue service, trend rising and around 59% of the emergency patients are treated by paramedics only; however, most of the studies focus on ...physicians, while their practical skills at the scene are rarely necessary. Accordingly, the responsibility for the patient lies with the paramedics most of the time. Their duty is to execute life-saving measures, stabilize the patient for the transport and the regular documentation of the operation. Retrospectively, the emergencies can only be analyzed based on the emergency protocols, which are mostly paper-based and handwritten. That causes an increased effort in the evaluation, which makes studies for the whole country hardly feasible. As of now there are only few data on quality of healthcare and documentation by the paramedics. Both were analyzed in this survey based on the emergency protocols.
A retrospective analysis of emergency protocols from June to July 2018 took place in Aachen, a major German city. A specific feature of Aachen is a 24‑h available emergency physician via telemedicine. The quality of documentation and healthcare was analyzed by including standard operating procedures. Primary endpoints were the frequency of documentation, the achievement of complete documentation, the correct indications for a physician, the development of critical vital signs and the average on-scene time of the ambulance.
Overall, 1935 protocols were analyzed. A complete documentation was achieved in 1323 (68.4%) suspected diagnoses, 456 (23.6%) anamneses, 350 (18.1%) initial and 52 (2.7%) vital signs at handover. Based on the documentation, there were 531 cases (27%) of patients treated by paramedics only, even though a physician would have been indicated. Out of those patients 410 critical initial vital signs were documented of which 69 (16.8%) improved, while there was no documentation of vital signs at handover in 217 (52.9%). Also, there was a significantly prolonged on-scene time for patients with belated indications for an emergency physician with 15:02 min in comparison to 13:05 min for patients without indications.
Deficient documentation was found in multiple cases and several important vital signs for a complete differential diagnosis were missing. Furthermore, a quarter of all patients might have benefited from an emergency physician as they were taken to hospital with no or insufficient treatment, despite standard operating procedures. From a forensic point of view there is an alarmingly incomplete documentation of vital signs at handover. The on-scene time in general was within the predetermined time frame, but can still be reduced in different scenarios. Overall, we recommend strict adherence to the standard operating procedures and algorithms, to remove unnecessary documentation and implement a structured quality assurance. Moreover, the quality of treatment might benefit from the rising number of more specialized paramedics and an increasing use of telemedicine.
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