Mediamusic (E-Journal)
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New developments in RiPP discovery, enzymology and engineering
No full textCovering: up to June 2020Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large group of natural products. A community-driven review in 2013 described the emerging commonalities in the biosynthesis of RiPPs and the opportunities they offered for bioengineering and genome mining. Since then, the field has seen tremendous advances in understanding of the mechanisms by which nature assembles these compounds, in engineering their biosynthetic machinery for a wide range of applications, and in the discovery of entirely new RiPP families using bioinformatic tools developed specifically for this compound class. The First International Conference on RiPPs was held in 2019, and the meeting participants assembled the current review describing new developments since 2013. The review discusses the new classes of RiPPs that have been discovered, the advances in our understanding of the installation of both primary and secondary post-translational modifications, and the mechanisms by which the enzymes recognize the leader peptides in their substrates. In addition, genome mining tools used for RiPP discovery are discussed as well as various strategies for RiPP engineering. An outlook section presents directions for future research.</p
Sialendoscopy increases saliva secretion and reduces xerostomia up to 60 weeks in Sjogren's syndrome patients:a randomized controlled study
No full textOBJECTIVE: To assess the effect of sialendoscopy of the major salivary glands on salivary flow and xerostomia in patients with Sjögren's syndrome (SS).METHODS: Forty-five patients with SS were randomly assigned to a control group (no irrigation, control, n = 15), to irrigation of the major salivary glands with saline (saline, n = 15) or to irrigation with saline followed by corticosteroid application (triamcinolone acetonide in saline, saline/TA, n = 15). Unstimulated whole saliva flow (UWSF), chewing-stimulated whole saliva flow (SWSF), citric acid-stimulated parotid flow, Clinical Oral Dryness Score (CODS), Xerostomia Inventory (XI) and EULAR SS Patient Reported Index (ESSPRI) scores were obtained 1 week before (T0), and 1, 8, 16, 24, 36, 48 and 60 weeks after sialendoscopy. Data were analysed using linear mixed models.RESULTS: Irrespective of the irrigation protocol used, sialendoscopy resulted in an increased salivary flow during follow-up up to 60 weeks. Significant between-group differences in the longitudinal course of outcomes were found for UWSF, SWSF, XI and ESSPRI scores (P = 0.028, P = 0.001, P = 0.03, P = 0.021, respectively). UWSF at 60 weeks was higher compared with T0 in the saline group (median: 0.14 vs median: 0.10, P = 0.02) and in the saline/TA group (median: 0.20, vs 0.13, P = 0.035). In the saline/TA group SWSF at 48 weeks was higher compared with T0 (median: 0.74 vs 0.38, P = 0.004). Increase in unstimulated salivary flow was also reflected in improved CODS, XI and ESSPRI scores compared with baseline.CONCLUSION: Irrigation of the major salivary glands in patients with SS increases salivary flow and reduces xerostomia.</p
Heart failure treatment up-titration and outcome and age:an analysis of BIOSTAT-CHF
No full textAims: Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up-titration of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta-blockers on outcome across the age spectrum in HFrEF patients. Methods and results: We analysed HFrEF patients on sub-optimal doses of ACEI/ARB and/or beta-blockers from the BIOSTAT-CHF study stratified by age. Patients underwent a 3-month up-titration period. We used inverse probability weighting to adjust for the likelihood of successful up-titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow-up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta-blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, [ACEI-ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91–0.94, P < 0.001; beta-blocker: HR 0.98, 95% CI 0.95–1.00, P = 0.046], with a significant interaction with age seen for beta-blockers but not ACEI/ARB (P = 0.034 and P = 0.22, respectively). Conclusions: Achieving higher doses of ACEI/ARB was associated with improved outcome regardless of age. However, achieving higher doses of beta-blockers was only associated with improved outcome in younger, but not in older patients.</p
Renal outcomes and all-cause death associated with sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL 3 Korea)
No full textAims To investigate the effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors on the risk of progression to end-stage renal disease (ESRD) and all-cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort.Materials and Methods Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all-cause death.Results There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 +/- 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 +/- 27.4 mL/min/1.73m(2), and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all-cause deaths during follow-up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all-cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m(2) and those with eGFR <60 mL/min/1.73m(2), and a lower risk of all-cause death was associated with SGLT2 inhibitors versus oGLDs in patients with eGFR >= 90 and 60 to 90 mL/min/1.73m(2).Conclusion In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all-cause death.</p
Co-constructive Patient Simulation:A Learner-Centered Method to Enhance Communication and Reflection Skills
No full textINTRODUCTION: In simulation sessions using standardized patients (SPs), it is the instructors, rather than the learners, who traditionally identify learning goals. We describe co-constructive patient simulation (CCPS), an experiential method in which learners address self-identified goals.METHODS: In CCPS, a designated learner creates a case script based on a challenging clinical encounter. The script is then shared with an actor who is experienced working as an SP in medical settings. An instructor with experience in the model is involved in creating, editing, and practicing role play of the case. After co-creation of the case, learners with no prior knowledge of the case (peers or a supervisor) interview the SP. The clinical encounter is followed by a group debriefing session.RESULTS: We conducted 6 CCPS sessions with senior trainees in child and adolescent psychiatry. Topics that are difficult to openly talk about may be especially appropriate for the CCPS model-without overt guidance or solicitation, the scripts developed by learners for this series involved: medical errors and error disclosure; racial tensions, including overt racism; interprofessional conflict; transphobia; patient-on-provider violence; sexual health; and the sharing of vulnerability and personal imperfections in the clinical setting.CONCLUSIONS: Co-constructive patient simulation provides an alternative multistage and multimodal approach to traditional SP simulation sessions that can adapt iteratively and in real time to new clinical vicissitudes and challenges This learner-centered model holds promise to enrich simulation-based education by fostering autonomous, meaningful, and relevant experiences that are in alignment with trainees' self-identified learning goals.</p
Molecular imaging of immunotherapy biodistribution and the tumor immune environment
No full textThe major anticancer effects of cancer immune checkpoint inhibitors changed treatment options for patients with several tumor types. Durable responses and cures have been observed in the metastatic setting. However, not all patients respond to currently available immunotherapies. To optimally exploit the effects of cancer-immunotherapy it is paramount to identify as early as possible the patients that will and will not respond, and to understand why patients respond. Furthermore, developing novel strategies beneficial to patients that previously did not respond is critical to further advance cancer care. A novel approach is the application of bispecific T-cell engager molecules. They, in contrast to other cancer drugs, actively involve and bind immune cells to induce T-cell mediated tumor cell killing. Understanding their biodistribution will provide insight into their application in the clinic. Molecular imaging can be used to non-invasively visualize the tumor immune microenvironment and show how it changes in response to cancer-immunotherapy. In addition, molecular imaging can facilitate drug development by providing information on drug biodistribution and tumor targeting. The research performed in this thesis uses molecular imaging and aims to evaluate the biodistribution of novel immunotherapies, with a focus on bispecific T-cell engager molecules, and to visualize the tumor immune microenvironment
Pre-Transplant Plasma Potassium as a Potential Risk Factor for the Need of Early Hyperkalaemia Treatment after Kidney Transplantation:A Cohort Study
No full textINTRODUCTION: Plasma potassium (K+) abnormalities are common among patients with chronic kidney disease and are associated with higher rates of death, major adverse cardiac events, and hospitalization in this population. Currently, no guidelines exist on how to handle pre-transplant plasma K+ in renal transplant recipients (RTR).OBJECTIVE: The aim of this study is to examine the relation between pre-transplant plasma K+ and interventions to resolve hyperkalaemia within 48 h after kidney transplantation.METHODS: In a single-centre cohort study, we addressed the association between the last available plasma K+ level before transplantation and the post-transplant need for dialysis or use of K+-lowering medication to resolve hyperkalaemia within 48 h after renal transplantation using multivariate logistic regression analysis.RESULTS: 151 RTR were included, of whom 51 (33.8%) patients received one or more K+ interventions within 48 h after transplantation. Multivariate regression analysis revealed that a higher pre-transplant plasma K+ was associated with an increased risk of post-transplant intervention (odds ratio 2.2 [95% CI: 1.1-4.4]), independent of donor type (deceased or living) and use of K+-lowering medication within 24 h prior to transplantation).CONCLUSIONS: This study indicates that a higher pre-transplant plasma K+ is associated with a higher risk of interventions necessary to resolve hyperkalaemia within 48 h after renal transplantation. Further research is recommended to determine a cutoff level for pre-transplant plasma K+ that can be used in practice.</p
Minimax sliding mode control design for linear evolution equations with noisy measurements and uncertain inputs
No full textWe extend a sliding mode control methodology to linear evolution equations with uncertain but bounded inputs and noise in observations. We first describe the reachability set of the state equation in the form of an infinite-dimensional ellipsoid, and then steer the minimax center of this ellipsoid toward a finite-dimensional sliding surface in finite time by using the standard sliding mode output-feedback controller in equivalent form. We demonstrate that the designed controller is the best (in the minimax sense) in the class of all measurable functionals of the output. Our design is illustrated by two numerical examples: output-feedback stabilization of linear delay equations, and control of moments for an advection–diffusion equation in 2D.</p
Grip on recovery after paediatric forearm fractures
No full textPaediatric forearm fractures often do not need to be aligned perfectly, since growing bones can still remodel. Whilst scarce studies advocate less invasive treatments, surgical intervention is becoming an upward trend. This development is worry some, considering the incidence is simultaneously increasing. Functional outcome is rarely examined prospectively, and there is no consensus regarding outcome measures. This thesis focuses on outcome measures of functional recovery. It provides interpersonal and intrapersonal reference values of grip strength. Intrapersonal data is easier to obtain and has a higher accuracy. Compared to other strength measurements, namely key grip and three-jaw chuck, grip strength is more sensitive to change. The extent as well as the duration of strength loss is more prominent the more invasive the treatment underwent. Grip strength is associated with fracture angulation whereas range of motion is not. Loss of mobility of elbow, forearm and wrist can be considered mild with an overall average below 20° for reduced and below 10° for non-reduced fractures 6 weeks post-injury. Measurements of pronation and palmar flexion are significantly impaired up to 3 months post-injury. Similarly to strength, an inverse relation was seen between extent of impairment and invasiveness of treatment. The recovery of pain, reduced sensitivity and hypertrichosis warrants further investigation. Although a trend was observed in relation to treatment invasiveness, the operative group was too small. Future research should focus on the consequences on functional recovery when moving the (arbitrary) lines between successive treatments in favor of the least invasive one