Dermatological emergencies and determinants of hospitalization in Switzerland: A retrospective study.

BACKGROUND: Dermatologic conditions are estimated to account worldwide for approximately 8% of all visits at emergency departments (EDs). Although rarely life-threatening, several dermatologic emergencies may have a high morbidity. Little is known about ED consultations of patients with dermatological emergencies and their subsequent hospital disposal. OBJECTIVE: We explore determinants and clinical variables affecting patients' disposal and hospitalization of people attending the ED at a Swiss University Hospital, over a 56-month observational period, for a dermatological problem. METHODS: De-identified patients' information was extracted from the hospital electronic medical record system. Generalized estimating equations were used to explore determinants of patient's disposition. RESULTS: Out of 5096 consecutive patients with a dermatological main problem evaluated at the ED, 79% of patients were hospitalized after initial assessment. In multivariable analyses, factors which were significantly associated with an increased admission rate included length of ED stay, age ≥ 45 years, male sex, distinct vital signs, high body mass index, low oxygen saturation, admission time in the ED and number and type of dermatological diagnoses. Only 2.2% of the hospitalized patients were admitted to a dermatology ward, despite the fact that they had dermatological diagnoses critically determining the diagnostic related group (DRG) payment. The number of patients managed by dermatologists during in-patient treatment significantly decreased over the study period. CONCLUSIONS: Our study identifies a number of independent predictors affecting the risk of hospital admission for patients with dermatological conditions, which may be useful to improve patients' disposal in EDs. The results indicate that the dermatological specialty is becoming increasingly marginalized in the management of patients in the Swiss hospital setting. This trend may have significant implications for the delivery of adequate medical care, outcomes and cost-effectiveness. Dermatologists should be more engaged to better position their specialty and to effectively collaborate with nondermatologists to enhance patient care.

Development and usability testing of a fully immersive VR simulation for REBOA training.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potentially life-saving procedure for bleeding trauma patients. Being a rare and complex procedure performed in extreme situations, repetitive training of REBOA teams is critical. Evidence-based guidelines on how to train REBOA are missing, although simulation-based training has been shown to be effective but can be costly and complex. We aimed to determine the feasibility and acceptance of REBOA training using a fully immersive virtual reality (VR) REBOA simulation, as well as assess the confidence in conducting the REBOA procedure before and after the training. METHODS: Prospective feasibility pilot study of prehospital emergency physicians and paramedics in Bern, Switzerland, from November 2020 until March 2021. Baseline characteristics of trainees, prior training and experience in REBOA and with VR, variables of media use (usability: system usability scale, immersion/presence: Slater-Usoh-Steed, workload: NASA-TLX, user satisfaction: USEQ) as well as confidence prior and after VR training were accessed. RESULTS: REBOA training in VR was found to be feasible without relevant VR-specific side-effects. Usability (SUS median 77.5, IQR 71.3-85) and sense of presence and immersion (Slater-Usoh-Steed median 4.8, IQR 3.8-5.5) were good, the workload without under-nor overstraining (NASA-TLX median 39, IQR 32.8-50.2) and user satisfaction high (USEQ median 26, IQR 23-29). Confidence of trainees in conducting REBOA increased significantly after training (p < 0.001). CONCLUSIONS: Procedural training of the REBOA procedure in immersive virtual reality is possible with a good acceptance and high usability. REBOA VR training can be an important part of a training curriculum, with the virtual reality-specific advantages of a time- and instructor-independent learning.

Virtual Reality for Pain Relief in the Emergency Room (VIPER) - a prospective, interventional feasibility study.

BACKGROUND: Pain is one of the most common, yet challenging problems leading to emergency department (ED) presentation, despite the availability of a wide range of pharmacological therapies. Virtual reality (VR) simulations are well studied in a wide variety of clinical settings, including acute and chronic pain management, as well as anxiety disorders. However, studies in the busy environment of an adult ED are scarce. The aim of this study is to explore the feasibility and effectiveness of a VR simulation for pain and anxiety control in a convenience sample of adult ED patients presenting with traumatic and non-traumatic pain triaged 2-5 (i.e., urgent to non-urgent) with a pain rating of ≥ 3 on a numeric rating scale (NRS 0-10). METHODS: Prospective within-subject, repeated measures interventional feasibility pilot study at a Swiss University ED. The intervention consisted of a virtual reality simulation in addition to usual care. Pain and anxiety levels were measured using a verbally administered numeric rating scale (NRS) before and after the intervention. Information on patient experience was collected using established rating scales. RESULTS: Fifty-two patients were enrolled. The most common pain localisations were extremities (n = 15, 28.8%) and abdomen (n = 12, 23.1%). About one third of patients presented with trauma-associated pain (n = 16, 30.8%). Duration of pain was mainly acute (< 24 h) (n = 16, 30.8%) or subacute (> 24 h) (n = 32, 61.5%). The majority of patients were triage category 3, i.e. semi-urgent (n = 48, 92.3%). Significant reduction in pain (NRS median pre-VR simulation 4.5 (IQR 3-7) vs. median post-VR simulation 3 (IQR 2-5), p < 0.001), and anxiety levels (NRS median pre-VR simulation 4 (IQR 2-5) vs. median post-VR simulation 2 (IQR 0-3), p < 0.001) was achieved, yielding moderate to large effect sizes (Cohen's d estimate for pain reduction = 0.59 (95% CI 0.19-0.98), for anxiety level on NRS = 0.75 (95% CI 0.34-1.15). With medium immersion and good tolerability of the VR simulation, user satisfaction was high. CONCLUSIONS: Virtual reality analgesia for pain and anxiety reduction in the busy setting of an ED is feasible, effective, with high user satisfaction. Further randomized controlled studies are needed to better characterize its impact on pain perception and resource utilization.

[Dizziness and vertigo in a tertiary ENT emergency department]. / Schwindelerkrankungen in einem tertiären HNO-Notfallzentrum.

BACKGROUND: Although vestibular symptoms are amongst the most frequent reasons for seeking emergency medical help, many patients remain undiagnosed. OBJECTIVE: In this cross-sectional study, we investigated the spectrum of vertigo and dizziness in a tertiary ear, nose, and throat (ENT) emergency department (ED). Furthermore, we investigated the attendant symptoms, clinical signs, and the diagnostic tests performed. METHODS: We screened all ED reports from 01/2013 to 12/2013 for adult patients with vestibular symptoms referred to the ENT department. RESULTS: In total, we found 2596 cases with reported vestibular symptoms in the ED as a main or accompanying complaint. Of these, 286 were referred to the ENT specialist directly (n = 98) or via other major medical specialties (n = 188). Benign paroxysmal positional vertigo (BPPV) was the most frequent diagnosis in our study (n = 46, 16.1%), followed by vestibular neuritis (n = 44, 15.4%), otitis media (n = 20, 7%), and 9 patients (3.1%) had an ischemic stroke or a transient ischemic attack. In 70 (24.5%) cases, dizziness was not further specified. CONCLUSION: BPPV is the most frequent diagnosis seen in the ED; however, physicians need to document nystagmus more precisely and perform diagnostic tests systematically, in order to make an accurate diagnosis. To avoid misdiagnoses, ED physicians and ENT specialists should be able to recognize central signs in patients with an acute vestibular syndrome. Every fourth patient does not receive a definitive diagnosis. Diagnostic ED workup for patients with dizziness needs further improvement.

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear. METHODS: ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain- and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of activation of EGFR signalling as well as on exosome production and exosomal phospho-EGFR. RESULTS: ANXA1 was found to be downregulated in head and neck cancer tissues, both at mRNA and protein level. Its anti-proliferative effects were mediated through the intracellular form of the protein. Importantly, ANXA1 downregulation resulted in increased phosphorylation and activity of EGFR and its downstream PI3K-AKT signalling. Additionally, ANXA1 modulation affected exosome production and influenced the release of exosomal phospho-EGFR. CONCLUSIONS: ANXA1 acts as a tumour suppressor in HNSCC. It is involved in the regulation of EGFR activity and exosomal phospho-EGFR release and could be an important prognostic biomarker.

Epistaxis in anticoagulated patients: Fewer hospital admissions and shorter hospital stays on rivaroxaban compared to phenprocoumon.

OBJECTIVES: Treatment of epistaxis in patients on anticoagulants is challenging and associated with higher admission rates and longer hospital stays compared with patients without anticoagulation. However, there is little information about epistaxis in patients taking new direct oral anticoagulants such as rivaroxaban compared with patients on traditional vitamin K antagonists such as phenprocoumon. DESIGN: Retrospective cohort study. SETTING: The study was conducted at the emergency department of the University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS: All admissions to the emergency department of the University Hospital Inselspital, Bern, Switzerland from 1st July 2012 to 30th June 2016 with non-traumatic epistaxis on anticoagulant therapy with phenprocoumon or rivaroxaban were included. MAIN OUTCOME MEASURES: We compared clinical outcome parameters (admission rates, length of hospital stay and mortality) for both anticoagulant groups. RESULTS: We included 440 patients with epistaxis, 123 (28%) on rivaroxaban and 317 (72%) on phenprocoumon. Fewer hospital admissions and shorter hospital stays were found in patients under rivaroxaban (12 (10.4%) vs 57 (18.0%) patients, P=.033; 0.7±2.2 vs 1.5±3.7 days, P=.011) compared with phenprocoumon. Anterior epistaxis was more common in the rivaroxaban group in contrast to posterior epistaxis in patients on phenprocoumon (74 (60.2%) vs 139 (43.8%) patients, P=.002; 7 (5.7%) vs 39 (12.3%) patients, P=.042). CONCLUSIONS: Our data suggests that epistaxis on direct oral anticoagulation with rivaroxaban is associated with shorter hospital stays and fewer hospital admissions than epistaxis on vitamin K antagonist phenprocoumon.

Design of an implantable seismic sensor placed on the ossicular chain.

This paper presents a design guideline for matching a fully implantable middle ear microphone with the physiology of human hearing. The guideline defines the first natural frequency of a seismic sensor placed at the tip of the manubrium mallei with respect to the frequency-dependence hearing of the human ear as well as the deflection of the ossicular chain. A transducer designed in compliance with the guideline presented reduces the range of the output signal while preserving all information obtained by the ossicular chain. On top of a output signal compression, static deflections, which can mask the tiny motions of the ossicles, are reduced. For guideline verification, a microelectromechanical system (MEMS) based on silicon on insulator technology was produced and tested. This prototype is capable of resolving 0.4 pm/Hz with a custom made read-out circuit. For a bandwidth of 0.1 kHz, this deflection is comparable with the lower threshold of speech (≈ 40 phon).

Analysis of an apoptotic core model focused on experimental design using artificial data.

The activation of caspases is a central mechanism in apoptosis. To gain further insights into complex processes like this, mathematical modelling using ordinary differential equations (ODEs) can be a very powerful research tool. Unfortunately, the lack of measurement data is a common problem in building such kinetic models, because it practically constrains the identifiability of the model parameters. An existing mathematical model of caspase activation during apoptosis was used in order to design future experimental setups that will help to maximise the obtained information. For this purpose, artificial measurement data are generated in silico to simulate potential experiments, and the model is fitted to this data. The model is also analysed using observability gramian and sensitivity analyses. The used analysis methods are compared. The artificial data approach allows one to make conclusions about system properties, identifiability of parameters and the potential information content of additional measurements for the used caspase activation model. The latter facilitates to improve the experimental design of further measurements significantly. The performed analyses reveal that several kinetic parameters are not at all, or only scarcely, identifiable, and that measurements of activated caspase 8 will maximally improve the parameter estimates. Furthermore, we can show that many assays with inhibitor of apoptosis protein (IAP) knockout cells only provide redundant information for our needs and as such do not have to be carried out.

Modeling and experimental validation of the signal transduction via the Escherichia coli sucrose phospho transferase system.

Bacterial signal processing was investigated concerning the sucrose phosphotransferase system (sucrose PTS) in the bacterium Escherichia coli as an example. The about 20 different phosphotransferase systems (PTSs) of the cell fulfill besides the transport of various carbohydrates, also the function of one signal processing system. Extra- and intracellular signals are converted within the PTS protein chain to important regulatory signals affecting, e.g. carbon metabolism and chemotaxis. A detailed dynamical model of the sucrose PTS was developed describing transport and signal processing function. It was formulated using a detailed description of complex formation and phosphate transfer between the chain proteins. Model parameters were taken from literature or were identified with own experiments. Simulation studies together with experimental hints showed that the dynamic behavior of phosphate transfer in the PTS runs within 1 s. Therefore a description of steady state characteristics is sufficient for describing the signaling properties of the sucrose PTS. A steady state characteristic field describes the degree of phosphorylation of the PTS protein EIIACrr as a function of the input variables extracellular sucrose concentration and intracellular phosphoenolpyruvate (PEP):pyruvate ratio. The model has been validated with different experiments performed in a CSTR using a sucrose positive E. coli W3110 derivative. A method for determining intracellular metabolite concentrations has been developed. A sample preparation technique using a boiling ethanol buffer solution was successfully applied. The PTS output signal degree of phosphorylation of EIIACrr was also measured. Steady state conditions with varying dilution rate and dissolved oxygen concentration and dynamical variations applying different stimuli to the culture were considered. Pulse, and stop feeding experiments with limiting sucrose concentrations were performed. Simulation and experimental results matched well. The same holds for the expanded sucrose PTS and glycolysis model.

Time hierarchies in the Escherichia coli carbohydrate uptake and metabolism.

The analysis of metabolic pathways with mathematical models contributes to the better understanding of the behavior of metabolic processes. This paper presents the analysis of a mathematical model for carbohydrate uptake and metabolism in Escherichia coli. It is shown that the dynamic processes cover a broad time span from some milliseconds to several hours. Based on this analysis the fast processes could be described with steady-state characteristic curves. A subsequent robustness analysis of the model parameters shows that the fast part of the system may act as a filter for the slow part of the system; the sensitivities of the fast system are conserved. From these findings it is concluded that the slow part of the system shows some robustness against changes in parameters of the fast subsystem, i.e. if a parameter shows no sensitivity for the fast part of the system, it will also show no sensitivity for the slow part of the system.

Reduction of mathematical models of signal transduction networks: simulation-based approach applied to EGF receptor signalling.

Biological systems and, in particular, cellular signal transduction pathways are characterised by their high complexity. Mathematical models describing these processes might be of great help to gain qualitative and, most importantly, quantitative knowledge about such complex systems. However, a detailed mathematical description of these systems leads to nearly unmanageably large models, especially when combining models of different signalling pathways to study cross-talk phenomena. Therefore, simplification of models becomes very important. Different methods are available for model reduction of biological models. Importantly, most of the common model reduction methods cannot be applied to cellular signal transduction pathways. Using as an example the epidermal growth factor (EGF) signalling pathway, we discuss how quantitative methods like system analysis and simulation studies can help to suitably reduce models and additionally give new insights into the signal transmission and processing of the cell.

A phase II trial of pemetrexed in patients with metastatic renal cancer.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTAR) for the treatment of metastatic RCC. PATIENTS AND METHODS: Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600 mg/m2 as a 10 min infusion every 3 weeks. Patients did not receive folic acid or vitamin B12 supplementation. RESULTS: Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2-25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5-27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. CONCLUSION: Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.

[Minimally invasive bone anchor in therapy of female stress incontinence. A good concept?]. / Minimal-invasiver Knochenanker in der Therapie der weiblichen Stressinkontinenz. Ein gutes Konzept?

Transvaginal pubic bone anchoring represents a minimally invasive technique for cystourethropexy or urethral sling suspension. This study assesses the results of this procedure. Cystourethropexy was performed in 4 and a sling procedure in 13 of 17 patients. The stress incontinence showed a median improvement from grade 2 to 1.35 (p = 0.01). Nine patients had impaired vaginal wound healing with urge symptoms. Revision was necessary in eight of them. An unfavorable outcome could not be significantly correlated with the surgical technique, the surgeon, the patient's age or the number of previous operations. The technique of minimally invasive bone anchoring must be regarded as unsuitable in view of the largely poor wound healing associated with irritation symptoms.

Efficacy and tolerability of tolterodine in children with detrusor hyperreflexia.

OBJECTIVES: To investigate the urodynamic effects and tolerability of the new antimuscarinic drug tolterodine in children with detrusor hyperreflexia. METHODS: Twenty-two children (12 boys and 10 girls; age range 3 months to 15 years, mean age 5.7 years) with detrusor hyperreflexia resulting in maximum detrusor pressures exceeding 40 cm H(2)O during filling cystotonometry were enrolled to receive tolterodine tartrate (a total of 0.1 mg/kg orally daily, divided into two doses) either as a first-line therapy (n = 12, group 1) or replacing oxybutynin chloride therapy (n = 10, group 2). Within 3 months, all patients underwent urodynamic re-evaluation during ongoing tolterodine treatment. RESULTS: In group 1, the mean maximum bladder capacity increased from 120.2 to 173.0 mL (+44%), the mean detrusor compliance increased from 8.7 to 13.5 mL/cm H(2)O (+55%), and the mean maximum detrusor pressures decreased from 70.1 to 37.9 cm H(2)O (-46%); the differences were significant (P < 0.001). In group 2, no differences in the urodynamic effects of oxybutynin versus tolterodine were noted. Only 1 patient experienced a transient and moderately adverse effect with tolterodine. CONCLUSIONS: Although based on a limited number of subjects, these data indicate that in pediatric patients with detrusor hyperreflexia, tolterodine may be better tolerated than and equally effective as the standard drug oxybutynin chloride.

Quantitative detection of human complement factor H-related protein in transitional cell carcinoma of the urinary bladder.

OBJECTIVE: The purpose of this study was to assess a new quantitative urinary tumor marker for transitional cell carcinoma of the urinary bladder (TCC), human complement factor H-related protein (hCFHrp, BTA TRAK). METHODS: Urine samples of 298 individuals (76 healthy volunteers, 118 patients with benign urologic disorders, 104 patients with histologically proven bladder cancer) were examined for the presence of hCFHrp. Samples of all patients were obtained prior to therapy. RESULTS: In comparison to healthy volunteers, patients with TCC had significantly higher urinary levels of hCFHrp (117.60 vs. 2.05 U/ml; p < 0.001). HCFHrp levels were positively correlated with tumor grade and stage. Patients with invasive TCC had significantly higher levels of hCFHrp than patients with superficial TCC (p = 0.001). Marker levels in superficial bladder cancer at high risk of tumor progression (pT1G3) were significantly higher as compared to low and intermediate grade superficial cancers. Elevated levels of hCFHrp were also found in patients with benign urologic disorders (median: 72.65 vs. 117.60 U/ml in cancer patients). Using a cutoff of 17.1 U/ml, hCFHrp had a sensitivity of 72.1% and, due to a high rate of false-positive determinations in patients with benign urologic disorders, a total specificity of 50.5%. CONCLUSIONS: HCFHrp (BTA TRAK) is a sensitive test for detection of bladder cancer and for identification of patients at high risk. Due to a high rate of false-positive results in patients with benign urologic diseases, the test should not be used in an unselected population.

Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4.

1. The metabolism of Meloxicam (ME) and the cytochrome(s) P450 (CYPs) involved were analysed by using primary human hepatocytes, human liver microsomes and microsomes from recombinant human B-lymphoblastoid cell lines. 2. While human hepatocytes were capable of converting ME to a 5-hydroxymethyl metabolite (M7) and then to a 5-carboxyderivative (M5), human liver microsomes formed mostly only the 5-hydroxymethylderivative. The kinetics of the formation of M7 by human liver microsomes were biphasic with Km = 13.6 +/- 9.5 and 381 +/- 55.2 microM respectively. The corresponding Vmax were 33.7 +/- 24.2 and 143 +/- 83.9 pmol/min/mg protein respectively. 3. CYP2C9 and, to a much lesser extent, CYP3A4 were found to convert ME to M7. The involvement of 2C9 was demonstrated by inhibition of tolbutamide hydroxylase activity in the presence of ME, inhibition of ME metabolism by sulphaphenazole, correlation between ME metabolism and tolbutamide hydroxylase activity and active metabolism of ME by recombinant 2C9. The involvement of 3A4 was shown by inhibition of ME metabolism by ketoconazole, correlation between ME metabolism and nifedipine oxidase activity and metabolism of ME by recombinant 3A4. Kinetics of the formation of M7 by the individual enzymes resulted in a Km = 9.6 microM and Vmax = 8.4 pmol/min/mg protein for 2C9 and a Km = 475 microM and Vmax = 23 pmol/min/mg protein for 3A4.

Laparoscopic retroperitoneal lymph node dissection in clinical stage I nonseminomatous germ cell tumor: a minimal invasive alternative.

OBJECTIVE: To evaluate modified laparoscopic retroperitoneal lymph node dissection (LRPLND) performed for stage I nonseminomatous germ cell tumor. METHODS: Between December 1993 and January 1996, modified unilateral laparoscopic retroperitoneal lymph node dissection was performed on 13 patients with nonseminomatous germ cell tumor of the testis. In 8 patients, the tumor was on the right side, and in 5, on the left. RESULTS: The procedure was completed in 12 patients at a mean operating time of 292 min (range: 210-400 min). The mean estimated blood loss was 250 ml. The mean hospital stay was 6.4 days. Conversion to open surgery was required in one patient because of an uncontrollable venous bleeding. No other major complications occurred. Antegrade ejaculation was preserved in 10 patients, and the last 3 patients have not yet been addressed now. CONCLUSIONS: Our results demonstrate that LRPLND is an accurate and reliable staging procedure with low morbidity, which allows quick patient discharge and rapid return to normal activity. For further evaluation, long follow-up in larger groups of patients is required.

Rapid pharmacokinetic screening of salbutamol in plasma samples by column-switching high-performance liquid chromatography-electrospray mass spectrometry.

In order to obtain pharmacokinetic data from studies in humans, a sensitive and selective assay for the quantification of salbutamol in human plasma samples was required. This report describes an automated high-performance liquid chromatography-mass spectrometry assay with pre-column enrichment using internal standard calibration for the quantification of salbutamol and the validation of the assay. The lower limit of quantitation is 0.2 ng/ml with an accuracy and imprecision of less than 7%. The analysis time is 8 min per sample.