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Oberflächen des Neoliberalismus: Technik, Ästhetik und Kritik bei Jia Zhangke, im Dritten Kino und im postkinematografischen Film
Full text linkIn der vorliegenden Dissertation wird die Digitalisierung von Film und Kino zum Ausgangspunkt einer Auseinandersetzung mit dem Verhältnis von technologischen Veränderungen, ästhetischen Formen und politischer Programmatik in verschiedenen historisch und geografisch divergierenden Filmkorpora gemacht: den Filmen des zeitgenössischen chinesischen Regisseurs Jia Zhangke, den Filmen des Dritten Kinos Lateinamerikas sowie dem sogenannten postkinematografischen Film. In allen Untersuchungen zeigen sich dabei Verbindungen zwischen medialen und wirtschaftlichen Verhältnissen. Eine kritische Medienästhetik muss folglich beides im Blick behalten und die Relevanz technologischer und gesellschaftlicher Bedingtheit im Einzelfall prüfen. Der Verweis auf die Unhintergehbarkeit technologischer Bedingungen wird nicht als Gegenvorschlag zu einer sozio-ökonomischen Perspektive aufgefasst, sondern als Anlass für eine weitere Radikalisierung der Kritik
TBX3 restricts anterior gene expression from the posterior mesenchyme to protect posterior identity that is promoted by HAND2
Full text linkEmbryonic development and organogenesis depend on precise spatial and temporal control of gene expression, which is regulated by cis-regulatory modules (CRMs). The signalling pathways and transcription factors form a robust gene regulatory network (GRN) to control growth and cell differentiation patterns.
The establishment of limb anterior-posterior (A-P) polarity requires the genetic interaction between Tbx3, Hand2, and Gli3. The interaction involves posterior Tbx3 working with Hand2 to genetically antagonise Gli3. This results in the segregation of an anterior-distal Gli3 and a posterior Hand2 and Tbx3 signal. This distinction in A/P patterning will control other transcription factors and establish early A/P polarisation. Hand2 and Tbx3 are required to prevent posterior expansion of Gli3 expression in early limb buds and maintain posterior gene expression. Hand2 has been shown to be important for ulna and autopod formation; in the absence of Hand2, the ulna is completely lost, leaving only a digit that appears to develop independently of SHH signalling. Meanwhile, the deletion of Tbx3 in the limb results in the loss of digit 5 and a mild downregulation of posterior gene expression. Hand2 and Tbx3 maintain each other's expression; deletion of Hand2 results in complete loss of posterior Tbx3, whereas mutation of Tbx3 leads to downregulation of Hand2.
How Tbx3 and Hand2 restrict Gli3 expression and the observed differential roles of Tbx3 and Hand2 in maintaining posterior gene expression remain to be elucidated.
Here, we have identified the role of posterior TBX3 in restricting anterior gene expression in the posterior. In doing so, TBX3 supports HAND2 in promoting posterior gene expression, setting the stage for Shh to be properly expressed.
TBX3 binds to three out of four Gli3 enhancers active in the limb, whereas Hand2 only binds to one. This suggests that TBX3 may be essential to exclude the high expression of Gli3 in the posterior limb buds. Indeed, our results show that mutation of Tbx3 leads to an expansion of the Gli3 enhancers mm1179 and mm-hs1586 activity in the posterior limb buds. TBX3 binds several CRMs associated with anterior genes. We propose that TBX3, by interacting with CRMs of anterior gene, would restrict Irx3/5, Alx4, and Hand1 expression and exclude from the posterior limb bud.
We've also investigated the anterior role of Tbx3 using the genetic interaction between Tbx3 and Gli3. As reported in previous studies, Tbx3 cooperates with Gli3 to restrict digit 1 development and prevent preaxial polydactyly (PPD). The combined mutation of Tbx3 and heterozygous Gli3 increases PPD. Observations of the Hand2-Tbx3 combined mutants versus Gli3-Tbx3 and our late-stage HCR data highlight a digit 1 development that relies only on anterior Tbx3 and Gli3 but would be independent of Hand2. Since Tbx3 has been shown to play a role in both anterior and posterior limb development, the mild downregulation of posterior genes seen in a Tbx3 mutant may be due to a buffering effect caused by the deletion of anterior and posterior Tbx3.
TBXs would also play a role in promoting Gli3 expression, as deletion of the T-box binding motif resulted in a partial loss of spatial Gli3 enhancer activity. By examining the literature and TBXs gene expression concerning Tbx3 mutation, we propose that TBX15, TBX18 and TBX5 could be candidates for the activation and promotion of Gli3 expression in the mouse limb bud. Interestingly, Tbx15 expression largely overlaps with Gli3 and extends to the posterior mesenchyme in Tbx3 deficient limb buds. On the other hand, TBX5 shares phenotypic limb changes and binds Gli3 enhancers, which suggests that TBXs may function in maintaining Gli3 enhancer activities and expression, which raises new questions about how TBXs might compete to regulate the expression of shared target genes
Non-territorial arrangements in interwar Soviet Ukraine: The development of the judicial network for minority populations
No full textIn the 1920s, in Soviet Union ethnicity became territorially institutionalised, meaning that every Soviet nationality was promised a territory of their own, either in the form of a separate or an autonomous Soviet republic, national region or a separate national town or village council (soviet). Within those national-territorial units, the Soviet state strove to provide access to state institutions, political representation, police and judicial protection, healthcare, education and cultural opportunities in the minority language. Ukraine's minorities, however, were often linguistically assimilated and territorially dispersed, making the Bolshevik territorial solutions, with some exceptions, ill-suited to serve the republic's non-Ukrainian population. Using the development of judicial network for minorities in early Soviet Ukraine as a case study, this article demonstrates how in the Soviet context, non-territorial arrangements, despite conceptual resentment, were incorporated into everyday practices in parallel with national territorialisation. By doing so, this article aims to examine some overlooked aspects of the early Soviet minorities experiment and determine a correlation between hard-line Ukrainisation - a policy of linguistic and bureaucratic de-Russification of the republic and minority policies. Secondly, this study aims to introduce the Soviet case into the context of non-territorial autonomy developed and implemented throughout postwar Europe
Why grasses grow better after drought: Mechanisms driving post-drought recovery and productivity outperformance in temperate grasslands
Full text linkDespite 2023 being with a 1.4 K higher global surface temperature compared to the 1850-1900 average the warmest year ever recorded, it will likely once be among the coldest years measured in this century. According to the Intergovernmental Panel on Climate Change, the increase in earth’s surface temperature will reach 1.4 K to 4.4 K compared to the 1850-1900 reference period by 2100, depending on the future emission scenario. With every temperature increment, the capacity and demand of the atmosphere to hold water increases. Increased amounts of water vapor in the atmosphere will affect large-scale atmospheric circulation processes and ultimately lead to more frequent extreme climatic events such as drought. Drought has been a common threat to terrestrial ecosystems. Nonetheless, the projected increase in its frequency and intensity will doubtlessly transform our ecosystems and pose new challenges to human societies. Yet, certain ecosystems seem to cope better with drought than others. Some grasslands have a remarkable capacity to regrow after drought with formerly drought-stressed grasslands even outperforming non-stressed controls once drought is released. The processes and factors underlying this capacity have, however, not yet been identified. In this PhD thesis, I delve into drought recovery mechanisms in temperate perennial grasslands and identify the key drivers that lead to post-drought outperformance in plant aboveground productivity
Large vessel vasculitis in giant cell arteritis and polymyalgia rheumatica – prevalence, outcome and associated factors
Full text linkBackground: Giant cell arteritis (GCA) is the most common primary vasculitis of the elderly and is closely related to polymyalgia rheumatica (PMR). Both conditions may occur separately, simultaneously, or sequentially over time. GCA classically manifests as cranial arteritis, but large vessel vasculitis (LVV) has been recognized as part of the disease spectrum. Diagnosing LVV remains challenging as symptoms may be non-specific and imaging is necessary to establish the diagnosis. Furthermore, PMR may be the only clinical manifestation of GCA. However, the understanding of subclinical GCA in patients with PMR, including its prevalence, risk factors and prognostic significance, is limited.
GCA is associated with severe vascular and ischemic complications such as stroke, arterial stenosis, and the development of aortic aneurysms. The most feared complication of GCA is permanent vision loss, and timely diagnosis and treatment of GCA are crucial to prevent acute and chronic complications. Although fast-track clinics for GCA have reduced the delay in diagnosis, permanent vision loss is still reported in up to 13% of cases.
Established imaging modalities for the diagnosis of LVV include ultrasound, [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), CT, or magnetic resonance imaging (MRI). However, standardized criteria defining vasculitis on MRI are lacking. While imaging is well established in the diagnostic work-up of patients with suspected GCA, its role in monitoring disease activity during follow-up and predicting the disease course in GCA after treatment discontinuation remains unclear. As relapses are common in patients with GCA after treatment withdrawal, imaging biomarkers for guiding the timing of treatment stop would be helpful.
Objectives: We first aimed to investigate the prevalence of subclinical GCA in patients with newly diagnosed PMR in the literature and to identify potential patient characteristics associated with subclinical GCA in published cohorts. In a next step, we aimed to explore the hypothesis that undiagnosed subclinical GCA in patients with PMR may lead to GCA-associated vascular damage. In our second manuscript, we aimed to study the risk factors and incidence of permanent vision loss in patients with GCA and to identify obstacles which caused a delay in diagnosis. The third manuscript aimed to identify which parameters on MRI correspond to vasculitis in patients with newly diagnosed large vessel (LV-) GCA. Finally, we addressed the role of PET/CT and MRI to predict relapses after treatment stop in patients with large vessel LV-GCA.
Methods: We systematically searched PubMed, Embase, and Web of Science Core Collection for consecutively recruited cohort studies reporting the prevalence of GCA in steroid-naïve patients with PMR. Potential predictors of subclinical GCA were identified using individual patient data from seven cohorts.
In the frame of our retrospective cohort of patients with GCA, we investigated the hypothesis that a proportion of patients with newly diagnosed GCA and a history of PMR may have already had subclinical GCA at the time of PMR manifestation and compared vascular ultrasound findings (extent of vessel involvement and stenoses) between GCA patients with and without prior PMR. Furthermore, we used our retrospective cohort to examine patient and referral characteristics and trends in the incidence of permanent vision loss over the past 15 years at the University Hospital Basel.
To identify which parameters on MRI correspond to vasculitis in patients with newly diagnosed LV-GCA, we compared MRI findings to PET/CT and/or ultrasound findings on a segment level (axillary segment per side, and the thoracic aorta).
Lastly, in an exploratory cohort study, patients with LV-GCA underwent imaging at the time of treatment discontinuation. Imaging findings of patients who relapsed within 4 months after treatment discontinuation were compared to those who remained in remission.
Results: The pooled prevalence of subclinical GCA across all identified studies was 23%, and 29% in the studies using PET/CT. Inflammatory back pain and absence of lower limb pain remained weak predictors of subclinical GCA after multivariable analysis.
Newly diagnosed patients with GCA and a prior history of PMR had significantly more often LVV (51.0% vs. 25.0%, p<0.001) and stenosis within the vasculitic segments (18.4% vs. 3.1%, p<0.001) on ultrasound compared to patients without prior PMR in our retrospective cohort.
The incidence of permanent vision loss was 17.4% in our institution and did not decline over 15 years. More than half of the patients who suffered from vision loss had experienced non-ocular symptoms related to GCA for a median of 21 days but did not seek medical help until the onset of visual impairment. In multivariable analysis, patients with vision loss were older and reported more frequently jaw claudication.
Vessel wall oedema on diffusion-weighted sequences on MRI corresponded to vasculitic PET/CT findings while pathological vessel segments on MRI had a low agreement with vasculitic ultrasound findings.
None of the examined imaging parameters predicted subsequent relapse after treatment withdrawal in patients with LV-GCA. The number of segments with vasculitic findings on PET/CT and the sum of all maximum standardized uptake value (SUVmax) artery/liver ratios showed a slight tendency to be higher in patients who relapsed; however, this did not reach statistical significance.
Conclusion: The high prevalence of subclinical GCA and the accumulating evidence of the potential impact of subclinical GCA on disease outcome advocates a paradigm shift in the assessment of patients with PMR and supports the implementation of screening strategies for large vessel involvement. Our findings underscore the need to increase public and physician awareness of the potentially devastating consequences of GCA and the importance of early detection and timely medical treatment to further reduce the incidence of ischemic and vascular complications. Lastly, we did not find any parameter on imaging performed at the time of treatment discontinuation which predicted future relapse in patients with LV-GCA. The relevance of vasculitic imaging findings in patients in clinical remission of GCA for the development of aortic aneurysms should be further studied
The Expressive Body as Revolution: Art and the Problem of Abstraction in the Philosophy of Gilles Deleuze
No full textEndovascular Treatment for Stroke Due to Occlusion of Medium or Distal Vessels
Full text linkBACKGROUND Endovascular treatment (EVT) of stroke with large-vessel occlusion is known to be safe and effective. The effect of EVT for occlusion of medium or distal vessels is unclear. METHODS We randomly assigned participants with an isolated occlusion of medium or distal vessels (occlusion of the nondominant or codominant M2 segment of the middle cerebral artery [MCA]; the M3 or M4 segment of the MCA; the A1, A2, or A3 segment of the anterior cerebral artery; or the P1, P2, or P3 segment of the posterior cerebral artery) to receive EVT plus best medical treatment or best medical treatment alone within 24 hours after the participant was last seen to be well. The primary outcome was the level of disability at 90 days, as assessed with the modified Rankin scale score. RESULTS A total of 543 participants (women, 44%; median age, 77 years) were included in the analysis: 271 were assigned to receive EVT plus best medical treatment and 272 to receive best medical treatment alone. The median score on the National Institutes of Health Stroke Scale (range, 0 to 42, with higher scores indicating more severe symptoms) at admission was 6 (interquartile range, 5 to 9). Intravenous thrombolysis was given to 65.4% of the participants. The predominant occlusion locations were the M2 segment (in 44.0% of the participants), M3 segment (in 26.9%), P2 segment (in 13.4%), and P1 segment (in 5.5%). In the comparison between EVT plus best medical treatment and best medical treatment alone, no significant difference in the distribution of modified Rankin scale scores was observed at 90 days (common odds ratio for improvement in the score, 0.90; 95% confidence interval, 0.67 to 1.22; P=0.50). All-cause mortality was similar in the two groups (15.5% with EVT plus best medical treatment and 14.0% with best medical treatment alone), as was the incidence of symptomatic intracranial hemorrhage (5.9% and 2.6%, respectively). CONCLUSIONS In persons with stroke with occlusion of medium or distal vessels, EVT did not result in a lower level of disability or a lower incidence of death than best medical treatment alone. (Funded by the Swiss National Science Foundation and others; DISTAL ClinicalTrials.gov number, NCT05029414.
Bioanalysis and metabolic investigation of psychoactive substances
Full text linkIn Part I, four liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods for the bioanalysis of psychoactive substances and their metabolites were developed and validated according to United States Food and Drug Administration (FDA) guidelines.
The first method was validated for the quantification of mescaline and its metabolites 3,4,5-trimethoxyphenylacetic acid (TMPAA), N-acetyl mescaline (NAM), and 3,5-dimethoxy-4-hydroxyphenethylamine (4-desmethyl mescaline). A linear range of 12.5 to 5,000 ng/mL for mescaline and TMPAA, and 1.25 to 500 ng/mL for NAM and 4-desmethyl mescaline was achieved. For optimal chromatographic separation, an Acquity Premier HSS T3 C18 column was employed. A single-step extraction procedure was implemented, enabling a non-laborious analysis of plasma samples with a runtime of 4.25 minutes per sample. The method satisfied all FDA validation criteria, including those on accuracy (85–106%), precision (coefficient of variation [CV] ≤ 7%), sensitivity and selectivity, matrix effect (92–100%), and extraction recovery (≥ 98%). Ultimately, the method was successfully employed for the analysis of mescaline, TMPAA, and NAM in pharmacokinetic samples from participants enrolled in a clinical phase I study. 4-desmethyl mescaline could not be selectively analyzed in pharmacokinetic samples due to interference and incomplete chromatographical separation with another metabolite, presumably 3,4-dimethoxy-5-hydroxyphenethylamine (3-desmethyl mescaline).
The second method was developed for the analysis of pharmacokinetic parameters in plasma samples from a clinical study involving diamorphine-dependent patients. The objective of the study was to investigate the feasibility of intranasal diamorphine administration as a component of diamorphine-assisted treatment. Analytes were separated using a Kinetex EVO C18 analytical column. The method is capable of quantifying the concentrations of diamorphine, 6-monoacetylmorphine (6-MAM), morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) in human plasma, spanning a linear range of 1 to 1,000 ng/mL. The total runtime for a single sample was four minutes. The method was demonstrated to be accurate (91–106%) and precise (CV ≤ 9%) while exhibiting a high extraction recovery (> 87%) and a negligible matrix effect (99–125%) for all analytes. No interferences with endogenous plasma compounds were observed and the method was successfully applied for the analysis of numerous clinical study samples.
In the third project, two methods for the quantification of racemic and chiral 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) in human plasma were developed and validated. A linear range of 0.5–500 ng/mL was achieved for racemic MDMA and MDA analysis, while linear ranges of 0.5–1,000 ng/mL and 1–1,000 ng/mL were achieved for chiral MDMA and MDA, respectively. The achiral chromatographic separation of the compounds was performed using a Luna PFP(2) column and the chiral analysis was conducted with a Lux AMP column. The total run times were 4.25 and 6 minutes for achiral and chiral sample analysis, respectively. Both methods met the FDA validation guidelines criteria for accuracy, precision, selectivity, sensitivity, matrix effect, and extraction recovery. Finally, a subset of clinical plasma samples from a study involving R-, S-, and racemic MDMA was analyzed to demonstrate the method’s functionality.
In conclusion, four sensitive, non-laborious, highly reliable, and robust LC–MS/MS methods for the bioanalysis of mescaline, diamorphine, racemic MDMA, and chiral MDMA plus their respective metabolites were developed and validated. These methods are applicable in pharmacokinetic investigations in a clinical setting as well as for forensic studies.
Part II of this thesis presents an investigation of the metabolic pathways of psilocybin’s active metabolite psilocin. The primary focus was on the phase I metabolism of psilocin through the cytochrome P450 (CYP) system, as well as the influence of monoamine oxidases (MAOs). Phase II metabolism, with a particular focus on UDP-glucuronosyltransferases (UGTs), was also examined. To conduct a comprehensive analysis of psilocin’s metabolism, enzymatic in vitro assays were performed using human liver microsomes (HLM) and recombinant CYP, MAO, and UGT enzymes. Moreover, plasma samples from C57BL/6J mice and humans were analyzed following psilocybin administration to obtain in vivo data.
After a 4-hour incubation period, approximately 29% of psilocin was metabolized by HLM. Recombinant CYP2D6 and CYP3A4 enzymes demonstrated even higher metabolic activity, with nearly 100% and 40% of psilocin being metabolized, respectively. The metabolites 4-hydroxyindole-3-acetic acid (4-HIAA) and 4-hydroxytryptophol (4-HTP) were identified in the presence of HLM, but not after incubation of psilocin with recombinant CYP enzymes. Nevertheless, trace amounts of 4-HIAA and 4-HTP were generated by MAO-A from psilocin, thereby substantiating its involvement in this metabolic pathway. In contrast to the in vivo data, where conjugated psilocin is one of the main metabolites, UGT1A10 did not extensively conjugate psilocin in vitro.
Furthermore, two potential metabolites were identified. In vitro and in vivo analyses identified N-methyl-4-hydroxytryptamine (norpsilocin) and an oxidized metabolite of psilocin. The former was detected following incubation with CYP2D6 and in the plasma of mice, while the latter was identified in CYP2D6 incubations, in mice, and in humans. However, the investigation into the influence of the CYP2D6 genotype on psilocin degradation yielded no significant results. While norpsilocin has never been described as a psilocin metabolite in mice before, the exact structure of the oxidized metabolite remains to be elucidated.
In conclusion, the phase I enzymes CYP2D6, CYP3A4, and MAO-A are implicated in psilocin’s metabolism. The identification of putative norpsilocin in mice and oxidized psilocin in humans offers further insight into the metabolic pathway of psilocybin and could contribute to the safety and efficacy of psilocybin application
Development and evaluation of a clinical decision support system for the reduction of medication errors
Full text linkMedication errors are preventable events that can lead to inappropriate drug use and patient harm. Clinical decision support systems (CDSSs) integrated into electronic health records (EHR) have the potential to significantly reduce medication errors. A major problem with CDSSs is alert fatigue, where clinicians ignore or override frequent alerts. Improving the specificity and relevance of CDSSs is critical to reduce alert fatigue. The Cantonal hospital of Aarau AG (KSA) has developed and implemented a CDSS (KPharm) with algorithms that focus on specificity by taking patient relevant data and medication chronology into account. To manage alerts more effectively, some are sent directly to prescribers, while others are initially assessed by clinical pharmacists.
The aim of the thesis was to scientifically guide the evaluation of existing algorithms and the development of new algorithms. The overarching question was whether the algorithms meet the requirements high specificity and other favorable performance parameters in practice, and how algorithms need to be designed to be specific.
Part 1: Evaluation of existing algorithms
In the first study, the performance of the CDSS was evaluated in terms of acceptance rate and alert burden. All alerts generated by the CDSS between January and December 2021 were included in a retrospective quantitative evaluation. Of 10,556 alerts generated, 619 triggered a direct notification to the physician and 2,231 notifications were send to the physician after evaluation by a clinical pharmacist. The acceptance rate was 89.8% for direct alerts and 68.4% for alerts pre-assessed by clinical pharmacists, which resulted in an overall acceptance rate of 72.4%. Clinical pharmacists handled an average of 17.2 alerts daily, while all hospital physicians combined received an average of 7.8 notifications daily. Moreover, a web-based survey was conducted amongst physicians of our hospital to assess their satisfaction with the CDSS. In the survey, 94.5% of physicians reported being satisfied or very satisfied. Algorithms addressing potential medication errors of anticoagulants received the highest usefulness ratings.
The second study investigated the performance of a specific algorithm in more detail, namely the triple whammy algorithm. The term triple whammy refers to the concomitant use of non-steroidal anti-inflammatory drugs, diuretics, and angiotensin system inhibitors; this combination significantly increases the risk of acute kidney injury. We identified all patients at the KSA who received a triple whammy prescription, had a triple whammy alert, or developed acute kidney injury during triple whammy therapy over the course of a year. Algorithm performance was evaluated by calculating the sensitivity and specificity as a primary endpoint and determining the acceptance rate among clinical pharmacists and physicians as a secondary endpoint. Out of 21,332 hospitalized patients, 290 patients had a triple whammy prescription, of which 12 patients experienced acute kidney injury. Overall, 216 patients were flagged by the algorithm, including 11 of 12 patients with acute kidney injury. The algorithm had a sensitivity of 88.3% and a specificity of 99.7%. Physician acceptance was high (77.7%), but clinical pharmacists were reluctant to forward the alerts to prescribers in some cases.
The third study focused on an algorithm to prevent anticoagulant duplications. This algorithm was developed in two phases, starting with an external algorithm that was run only once a day on weekdays and integrated into the hospital's EHR in the second phase. A retrospective analysis of three phases, one without CDSS and the two implementation phases, was performed to assess the impact of the CDSSs on the incidence and duration of anticoagulant duplications. The incidence of anticoagulant duplications in patients receiving two or more anticoagulants during the study period dropped from 91 anticoagulant duplications in 1581 patients in phase I, to 70 anticoagulant duplications in 1692 patients in phase II and 57 anticoagulant duplications in 1575 patients in phase III. The durations of anticoagulant duplications were also reduced over time, with anticoagulant duplications lasting a mean of 1.8, 1.4, and 1.1 calendar days during phases I, II, and III, respectively. Compared to the baseline in phase I, there was a 42% relative risk reduction for anticoagulant duplications in Phase III (relative risk (RR): 0.58, confidence interval (CI): 0.42 – 0.81). Phase III was analyzed in more detail regarding the acceptance rate, sensitivity, and specificity of the alerts. The acceptance rate was high at 97%; and the sensitivity and specificity of the algorithm was 87.4% and 87.9%, respectively.
The fourth study compared the performance of the final anticoagulant duplication algorithm described in study 3 to the performance of a CDSS with a different design in another cantonal hospital in Switzerland. While the CDSS at the KSA uses delayed expert alerts, the CDSS at the other hospital uses interruptive pop-up alerts during prescribing. To compare the performances of both CDSSs, we repeated the retrospective analysis in the other hospital one year before and after the implementation of its CDSS. The incidence of anticoagulant duplications was decreased in both hospitals after CDSS implementation, however, to a different extent. While the KSA had a relative risk reduction of 0.42 (RR = 0.58, CI = 0.42, 0.81), the relative risk reduction at the other hospital was less profound at 0.28 (RR = 0.72, CI = 0.52, 0.99). Moreover, the median duration of anticoagulant duplications was significantly reduced at the KSA, but not in the other hospital.
Part 2: Development of new algorithms
Three new algorithms were developed as part of this thesis. During the development phase, care was taken to ensure that not only the medical and technical aspects of the algorithms were adequately considered, but also the process level.
The Drug Duplication algorithm detects duplicate prescription both for same drugs and for therapeutic drug duplications. For this purpose, the principle of conventional CDSSs for recognizing drug duplications, which are often based on Anatomical Therapeutic Chemical codes, was expanded and refined. The algorithm has been in operation since May 2022 and has been well received by clinical pharmacists. In the first year, 366 interventions in patient medication were made on the basis of this algorithm, with an implementation rate of 75.7% by physicians. For certain drugs and in some departments, we observed a high false positive rate, which can be attributed to procedural peculiarities.
The HIT algorithm is used to recognize risk situations for heparin-induced thrombocytopenia. It recognizes patients who have a drop in platelets in temporal relation to heparin, patients who have received argatroban in the past (as indicator for previous HIT), and patients whose platelet levels are not being adequately monitored. The technical challenge with this algorithm was to correctly capture the chronology of HIT. The algorithm was integrated into the EHR in July 2023. A comprehensive evaluation of its performance has not yet been conducted. Given that the detection of an adverse drug reaction is a more challenging task than that of a medication error, this algorithm will likely exhibit a lower level of specificity than other KPharm algorithms.
The phenprocoumon algorithm was developed in response to a critical incident case, where a negative outcome was observed. The underlying problem was the declining use and consequently the decreasing medical experience with phenprocoumon. The objective of the algorithm is to compensate for this by improving the dosing and monitoring of phenprocoumon therapy in critical situations. The algorithm was integrated into the EHR in March 2024 and has already identified patients who have benefited from a pharmaceutical medication reconciliation.
Overall, the KPharm CDSS enhances patient safety at the KSA by demonstrating satisfactory performance across key parameters such as acceptance rates, sensitivity, specificity, and physician satisfaction. Furthermore, the introduction of the CDSS was accompanied by a risk reduction of critical medication errors. This confirms that KPharm meets its intended goals. The analyses also offer insights into the impact of different CDSS designs on CDSS effectiveness.
The development of new algorithms has enabled the detection and remediation of further potentially critical medication errors. A comprehensive evaluation of these algorithms regarding performance is yet to be conducted. The key findings from the development of context- and time-dependent algorithms, which emphasize the importance of considering medical, technical, and process-level factors, can contribute to the development and improvement of other complex CDSSs in different settings. Ultimately, the implementation of carefully designed context-based algorithms, tailored to hospital workflows, will help to reduce alert fatigue experienced by healthcare professionals when using CDSSs, thus increasing the effectiveness of CDSSs in preventing medication errors
Coupling a high impedance resonator to a Ge/Si nanowire
Full text linkThis thesis explores the development of quantum computing systems using Ge/Si core/shell nanowires, in particular coupled to high-impedance superconducting resonators. The work mainly addresses the challenges of scaling by improving qubit readout and remote coupling capabilities, but also by improving the coherence and speed of spin qubits. In particular, the fairly singular properties of Ge/Si nanowires, including a strong and tunable Rashba spin-orbit interaction, successfully coupled to high-impedance, magnetic field resilient, NbTiN superconducting resonators open up the possibility of strong spin-photon coupling in this system. In addition, the potential of using strontium titanate varactors for optimized readout through impedance matching is explored. Finally, a new operating regime that maximises coherence and speed in one-dimensional systems is shown and characterised. By providing insights into the design and optimisation of semiconductor-based spin qubit systems, this thesis contributes to ongoing efforts in the field of quantum computing