Bleach activates a redox-regulated chaperone by oxidative protein unfolding.

Hypochlorous acid (HOCl), the active ingredient in household bleach, is an effective antimicrobial produced by the mammalian host defense to kill invading microorganisms. Despite the widespread use of HOCl, surprisingly little is known about its mode of action. In this study, we demonstrate that low molar ratios of HOCl to protein cause oxidative protein unfolding in vitro and target thermolabile proteins for irreversible aggregation in vivo. As a defense mechanism, bacteria use the redox-regulated chaperone Hsp33, which responds to bleach treatment with the reversible oxidative unfolding of its C-terminal redox switch domain. HOCl-mediated unfolding turns inactive Hsp33 into a highly active chaperone holdase, which protects essential Escherichia coli proteins against HOCl-induced aggregation and increases bacterial HOCl resistance. Our results substantially improve our molecular understanding about HOCl's functional mechanism. They suggest that the antimicrobial effects of bleach are largely based on HOCl's ability to cause aggregation of essential bacterial proteins.

Clinical practice - latest insights in optimizing the care of children with Down syndrome.

An essential part of the care of children with Down syndrome is secondary screening for comorbidity. It is well known that comorbidity frequently occurs in these children. A new update of the Dutch Down syndrome medical guideline was developed to create a sound evidence base for several of these conditions. We present the latest insights and recommendations from this Dutch medical guideline which are based on the most relevant literature currently available and developed with rigorous methodology. The main focus of this revision of the guideline was on obstructive sleep apnea and other airway problems and hematologic disorders, such as transient abnormal myelopoiesis, leukemia, and thyroid disorders. Conclusion: This is a short summary of the latest insights and recommendations from the updated Dutch medical guideline for children with Down syndrome.

On Senders's Models of Visual Sampling Behavior.

OBJECTIVE: We review the sampling models described in John Senders's doctoral thesis on "visual sampling processes" via a ready and accessible exposition. BACKGROUND: John Senders left a significant imprint on human factors/ergonomics (HF/E). Here, we focus on one preeminent aspect of his career, namely visual attention. METHODS: We present, clarify, and expand the models in his thesis through computer simulation and associated visual illustrations. RESULTS: One of the key findings of Senders's work on visual sampling concerns the linear relationship between signal bandwidth and visual sampling rate. The models that are used to describe this relationship are the periodic sampling model (PSM), the random constrained sampling model (RCM), and the conditional sampling model (CSM). A recent replication study that used results from modern eye-tracking equipment showed that Senders's original findings are manifestly replicable. CONCLUSIONS: Senders's insights and findings withstand the test of time and his models continue to be both relevant and useful to the present and promise continued impact in the future. APPLICATION: The present paper is directed to stimulate a broad spectrum of researchers and practitioners in HF/E and beyond to use these important and insightful models.

Shared control versus traded control in driving: a debate around automation pitfalls.

A major question in human-automation interaction is whether tasks should be traded or shared between human and automation. This work presents reflections-which have evolved through classroom debates between the authors over the past 10 years-on these two forms of human-automation interaction, with a focus on the automated driving domain. As in the lectures, we start with a historically informed survey of six pitfalls of automation: (1) Loss of situation and mode awareness, (2) Deskilling, (3) Unbalanced mental workload, (4) Behavioural adaptation, (5) Misuse, and (6) Disuse. Next, one of the authors explains why he believes that haptic shared control may remedy the pitfalls. Next, another author rebuts these arguments, arguing that traded control is the most promising way to improve road safety. This article ends with a common ground, explaining that shared and traded control outperform each other at medium and low environmental complexity, respectively. Practitioner summary: Designers of automation systems will have to consider whether humans and automation should perform tasks alternately or simultaneously. The present article provides an in-depth reflection on this dilemma, which may prove insightful and help guide design. Abbreviations: ACC: Adaptive Cruise Control: A system that can automatically maintain a safe distance from the vehicle in front; AEB: Advanced Emergency Braking (also known as Autonomous Emergency Braking): A system that automatically brakes to a full stop in an emergency situation; AES: Automated Evasive Steering: A system that automatically steers the car back into safety in an emergency situation; ISA: Intelligent Speed Adaptation: A system that can limit engine power automatically so that the driving speed does not exceed a safe or allowed speed.

Evaluating the Tobii Pro Glasses 2 and 3 in static and dynamic conditions.

Over the past few decades, there have been significant developments in eye-tracking technology, particularly in the domain of mobile, head-mounted devices. Nevertheless, questions remain regarding the accuracy of these eye-trackers during static and dynamic tasks. In light of this, we evaluated the performance of two widely used devices: Tobii Pro Glasses 2 and Tobii Pro Glasses 3. A total of 36 participants engaged in tasks under three dynamicity conditions. In the "seated with a chinrest" trial, only the eyes could be moved; in the "seated without a chinrest" trial, both the head and the eyes were free to move; and during the walking trial, participants walked along a straight path. During the seated trials, participants' gaze was directed towards dots on a wall by means of audio instructions, whereas in the walking trial, participants maintained their gaze on a bullseye while walking towards it. Eye-tracker accuracy was determined using computer vision techniques to identify the target within the scene camera image. The findings showed that Tobii 3 outperformed Tobii 2 in terms of accuracy during the walking trials. Moreover, the results suggest that employing a chinrest in the case of head-mounted eye-trackers is counterproductive, as it necessitates larger eye eccentricities for target fixation, thereby compromising accuracy compared to not using a chinrest, which allows for head movement. Lastly, it was found that participants who reported higher workload demonstrated poorer eye-tracking accuracy. The current findings may be useful in the design of experiments that involve head-mounted eye-trackers.

Why human factors science is demonstrably necessary: historical and evolutionary foundations.

We review the theoretical foundation for the need for human factors science. Over the past 2.8 million years, humans and tools have co-evolved. However, in the last century, technology is introduced at a rate that exceeds human evolution. The proliferation of computers and, more recently, robots, introduces new cognitive demands, as the human is required to be a monitor rather than a direct controller. The usage of robots and artificial intelligence is only expected to increase, and the present COVID-19 pandemic may prove to be catalytic in this regard. One way to improve overall system performance is to 'adapt the human to the machine' via task procedures, operator training, operator selection, a Procrustean mandate. Using classic research examples, we demonstrate that Procrustean methods can improve performance only to a limited extent. For a viable future, therefore, technology must adapt to the human, which underwrites the necessity of human factors science. Practitioner Summary: Various research articles have reported that the science of Human Factors is of vital importance in improving human-machine systems. However, what is lacking is a fundamental historical outline of why Human Factors is important. This article provides such a foundation, using arguments ranging from pre-history to post-COVID.

[Autopneumonectomie. A Forgotten Disease]. / Autopneumonektomie. Ein vergessenes Krankheitsbild.

HISTORY: An 80-year old female was referred to our hospital with left internal carotid artery stenosis and a childhood history of hemoptysis. INVESTIGATIONS AND DIAGNOSIS: The ECG showed 2nd degree Mobitz atrio-ventricular block. The chest x-ray and computerized tomography identified a shift of the mediastinum and the heart to the left. The left lung was completely destroyed whilst the right lung was enlarged and crossed the midline. Pulmonary function tests revealed a moderate restrictive ventilation disorder. The diagnosis of autopneumonectomy was based on patient history together with radiological findings. TREATMENT AND COURSE: A pacemaker was implanted with two stimulation electrodes via a left cephalic venous cutdown. A carotid endarterectomy was also performed without any complication. CONCLUSION: After autopneumonectomy, postpneumonectomy like syndrome may occur in very rare cases, whereupon operative treatment is mandatory. Any respiratory infections should be treated with antibiotics. Pacemaker electrode placement via the subclavian vein is contraindicated due to the risk of a catastrophic pneumothorax.

Stimulation with Porphyromonas gingivalis enhances malignancy and initiates anoikis resistance in immortalized oral keratinocytes.

The aim of this study was to get new insights into molecular processes involved in tumor propagation of immortalized oral keratinocytes induced by the keystone pathogen Porphyromonas gingivalis. Cell culture experiments with immortalized OKF6 cells were performed to analyze cellular effects caused by bacterial stimulation focusing on altered gene expression, signaling pathways, proliferation rate, cell viability, migration and invasion behavior, and on the development of antiapoptotic pathways. Gene and protein expression were analyzed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blot, and protein arrays. Trypan blue staining was used to analyze proliferation and viability, transwell assays for cellular migration, Matrigel assays for invasion, and anoikis-assays for evaluating anoikis resistance. Stimulation of OKF6 cells with Porphyromonas gingivalis led to an alteration in the molecular repertoire of proteins which are involved in cell proliferation, epithelial-mesenchymal transition, stem cell formation, migration, invasion, and anoikis resistance. Higher proliferation rates were detected in conjunction with an activation of PI3K/Akt signaling and the mTOR-pathway. Additionally, inhibition of glycogen-synthase-kinase3-ß led to stabilization of ß-catenin and Snail, which resulted in a switch from predominant E-cadherin to N-cadherin expression and increased expression of the stem cell markers Oct3/4, Sox2, and Nanog. Enhanced biosynthesis and enzyme activity of matrix metalloproteinase-9 was accompanied by elevated invasion behavior. Finally, anoikis resistance was detected in stimulated keratinocytes by decreased apoptosis of nonadherent cells and elevated expression of epidermal growth factor receptor and c-Met. Hence, Porphyromonas gingivalis is able to induce a more aggressive tumor-like phenotype in immortalized oral keratinocytes, thus contributing to enhanced tumor features.

Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

BACKGROUND: Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. OBJECTIVE: To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. METHODS: This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. RESULTS: Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). CONCLUSION: Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.

Intermuscular implantation technique for subcutaneous cardioverter-defibrillators.

BACKGROUND: The conventional technique for subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation has been associated with pocket complications. The aim of this study was to evaluate the efficacy and safety of an alternative intermuscular technique for S­ICD implantation. METHODS: S-ICDs were implanted in ten consecutive patients (ten males, mean age: 46.8 ± 14.7 years). The pocket for the pulse generator was made above the serratus anterior muscular fascia and beneath the latissimus dorsi muscle by detaching the fibrous tissue between the muscles. Electrode implantation was performed using the three- (n = 4) or the two-incision technique (n = 6). RESULTS: All S­ICDs were successfully implanted in the absence of any procedure-related complications with a successful 65-J standard polarity defibrillation threshold testing, apart from one patient with Brugada syndrome who needed device repositioning more dorsally. During a mean follow-up of 16.5 ± 7.3 months, no major complications requiring surgical repair were encountered, while patients demonstrated high levels of comfort and satisfaction with the cosmetic result. One patient experienced an inappropriate shock due to noise detection, which was resolved after reprogramming to a different sensing vector. CONCLUSION: The intermuscular technique is a safe and efficacious approach for S­ICD implantation. This technique could lead to fewer pocket-related complications and better cosmetic results.

[Validation of the German translation of the ASAS health index : A questionnaire to assess functioning and health in patients with spondyloarthritis]. / Validierung der deutschen Version des ASAS-Gesundheitsindex : Ein Fragebogen zur Erfassung von Funktionsfähigkeit und Gesundheit bei Patienten mit Spondyloarthritis.

INTRODUCTION: The aim of this study was the validation of the German translation of the ASAS Health Index (ASAS HI), which measures functioning and health in patients with axial and peripheral spondyloarthritis (SpA). METHOD: Patients with SpA who fulfilled the ASAS classification criteria for axial (axSpA) or peripheral SpA (pSpA) were included in this study. Constuct validity of the ASAS HI was tested by using Spearman's correlation coefficients. Reliability was analyzed by intraclass correlation coefficients (ICC) in patients with stable disease. In patients requiring an important therapeutic change because of unacceptable high disease activity, the sensitivity to change was analyzed using standardized response mean (SRM). RESULTS: A total of 171 patients (57.9% male, age 44.4 ± 13.0 years) were included. The internal consistency was high with a Cronbach's alpha of 0.83. The reliability (n = 63) was good (ICC = 0.94; 95% confidence interval [CI] 0.90-0.96). The sensitivity to change of the ASAS HI was low for a relatively small number of cases (n = 33) with a SRM of -0.27 but showed a good ability to discriminate between various stages of disease activity and physical functioning. DISCUSSION: We showed that the German translation of the ASAS HI provide good psychometric properties to assess functioning and health in patients with SpA. This reliable and sensitive to change questionnaire therefore enables the assessment of disease-specific global functioning and severity in patients with all forms of SpA.

Intracellular free magnesium concentration in healthy horses.

Equine metabolic syndrome (EMS) is a worldwide disease in horses that parallels human diabetes mellitus type 2. In both diseases, patients show an altered peripheral insulin sensitivity as a key feature. In humans, multiple studies have demonstrated the beneficial effect of magnesium supplementation on insulin sensitivity. However, serum magnesium levels vary and are therefore not a reliable indicator of the patients' magnesium status. Determining the intracellular free magnesium concentration appears to be a more sensitive diagnostic indicator. In this study, the free intracellular magnesium concentration was measured using mag-fura 2 spectrophotometry in blood lymphocytes in 12 healthy, non-obese horses at 9 a.m., 12 a.m. and 4 p.m. to establish reference ranges according to a protocol designed for human blood lymphocytes. Additionally, the serum magnesium concentration was measured. In all horses, the total serum magnesium concentration was within the reference range. The mean free magnesium concentration in blood lymphocytes of all horses was 0.291 ± 0.067 mmol/L with no significant difference between the time points. The reference range for the free intracellular magnesium concentration in equine lymphocytes was set at 0.16-0.42 mmol/L. The established values are slightly lower than those in healthy humans. The designed protocol for the measurement of the intracellular free magnesium concentration might be an excellent research tool to assess the cellular magnesium status and to reliably diagnose an altered magnesium homeostasis in EMS. Further studies shall elucidate possible alterations in cellular magnesium status in horses with EMS.

Follow-up after curative treatment for colorectal cancer: longitudinal evaluation of patient initiated follow-up in the first 12 months.

PURPOSE: To compare patient-triggered follow-up (PTFU) for curatively treated colorectal cancer against traditional outpatient follow-up (OPFU). METHODS: Questionnaires were mailed at four time points over one-year post-treatment to two prospectively-recruited cohorts: A, patients entering follow-up and receiving OPFU pre-implementation of PTFU; B, patients entering follow-up (FU) and receiving either OPFU (B1) or PTFU (B2) post-implementation of PTFU. Bi-variate tests were used to compare patient characteristics and outcomes eight months after entering follow-up (generic and cancer-specific quality of life (QoL), satisfaction). Regression analysis explored associations between follow-up model and outcomes. Resource implications and costs of models were compared. RESULTS: Patients in Cohort B1 were significantly more likely to have received chemotherapy (p < 0.001), radiotherapy (p < 0.05), and reported poorer QoL (p = 0.001). Having a longstanding co-morbid condition was the most important determinant of QoL (p < 0.001); model of care was not significant. Patients were satisfied with their follow-up care regardless of model. Health service costs were higher in PTFU over the first year CONCLUSIONS: PTFU is acceptable to patients with colorectal cancer and can be considered to be a realistic alternative to OPFU for clinically suitable patients. The initial costs are higher due to provision of a self-management (SM) programme and remote surveillance. Further research is needed to establish long-term outcomes and costs.