Mediamusic (E-Journal)
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A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores
No full textBackground:Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes.Methods:The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months' treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease.Results:The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) -5 to 12], whereas the observed risk change was -28.8% (95% CI -42.0 to -11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of -12.4% (95% CI -17 to -7), which underestimated the observed risk change -21.8% (95% CI -34 to -6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [-24.0% (95% CI -30 to -17) and -22.6% (95% CI -23 to -16) for ESRD and the composite renal outcome, respectively].Conclusion:A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies.</p
Perioperative optimization using hemodynamically focused echocardiography in high-risk patients-A practice guide
No full textBACKGROUND: The number of high-risk patients undergoing surgery is steadily increasing. In order to maintain and, if necessary, optimize perioperative hemodynamics as well as the oxygen supply to the organs (DO2) in this patient population, a timely assessment of cardiac function and the underlying pathophysiological causes of hemodynamic instability is essential for the anesthesiologist. A variety of hemodynamic monitoring procedures are available for this purpose; however, due to method-immanent limitations they are often not able to directly identify the underlying cause of cardiovascular impairment.OBJECTIVE: To present a stepwise algorithm for a perioperative echocardiography-based hemodynamic optimization in noncardiac surgery high-risk patients. In this context, echocardiography on demand according to international guidelines can be performed under certain conditions (hemodynamic instability, nonresponse to hemodynamic treatment) as well as in the context of a planned intraoperative procedure, mostly as a transesophageal echocardiography.METHODS AND RESULTS: Hemodynamically focused echocardiography as a rapidly available bedside method, enables the timely diagnosis and assessment of cardiac filling obstructions, volume status and volume response, right and left heart function, and the function of the heart valves.CONCLUSION: Integrating all echocardiographic findings in a differentiated assessment of the patient's cardiovascular function enables a (patho)physiologically oriented and individualized hemodynamic treatment.</p
Hemostatic system activation and reperfusion injury in liver machine preservation and transplantation of extended criteria donor livers
No full textFor patients with end-stage liver disease and certain types of hepatic malignancies, liver transplantation is universally accepted as the most effective and only curable treatment available. The success of liver transplantation has ironically however, become one of the greatest challenges faced by transplant health professionals worldwide as a great discrepancy continues to exist between the supply of suitable donor livers for transplantation and the demand. In an effort to tackle the donor organ scarcity, a significant proportion of additional donor organs has resulted from the increased reliance on the use of extended criteria donor (ECD) livers. Such livers include; livers from older donors, livers that exceed the traditionally accepted degree of steatosis (or in lay terms; “fatty livers”) and livers donated after circulatory death (DCD). In fact, in 2018 in the Netherlands, more than 50% of deceased donor liver transplants were derived from DCD donors. Several studies have shown that selective use of ECD livers results in successful transplantation procedures and acceptable survival rates following transplantation. Nevertheless, a higher incidence of post-transplant morbidity such as early allograft dysfunction, (severe) intraoperative bleeding and life threatening biliary complications, have been reported after transplantations with ECD livers. Studies have shown that these are largely attributed to by ischemia-reperfusion injury (IR injury) incurred by these organs during the procurement, preservation and implantation processes. Machine perfusion (MP) is a promising alternative preservation modality that allows for the storage of donor organs under conditions simulating in vivo physiology. Therefore, ischemia, and subsequently, ischemia-reperfusion injury is minimized. In this thesis more insight is provided into (1) the incidence of bleeding and coagulation problems in DCD transplantation, (2) machine perfusion as a method to (better) preserve ECD-DCD donor livers to reduce intra- and postoperative complications and (3) the effect of machine perfusion on the coagulation system and on ischemia-reperfusion damage in ECD-DCD donor livers
Wachten tot het kantelt? Hoe kennis van nieuwe regelgeving de MKB-ondernemer kan ondersteunen bij de overgang naar de businessmodellen van de toekomst
No full textHoe kennis van nieuwe regelgeving de MKB-ondernemer kan ondersteunen bij de overgang naar de businessmodellen van de toekomstSerie van 4 essays behandelt de transformatie naar een nieuwe, gezonde en vol te houden economie
Improving gene function predictions using independent transcriptional components
No full textThe interpretation of high throughput sequencing data is limited by our incomplete functional understanding of coding and non-coding transcripts. Reliably predicting the function of such transcripts can overcome this limitation. Here we report the use of a consensus independent component analysis and guilt-by-association approach to predict over 23,000 functional groups comprised of over 55,000 coding and non-coding transcripts using publicly available transcriptomic profiles. We show that, compared to using Principal Component Analysis, Independent Component Analysis-derived transcriptional components enable more confident functionality predictions, improve predictions when new members are added to the gene sets, and are less affected by gene multi-functionality. Predictions generated using human or mouse transcriptomic data are made available for exploration in a publicly available web portal. Our understanding of the function of many transcripts is still incomplete, limiting the interpretability of transcriptomic data. Here the authors use consensus-independent component analysis, together with a guilt-by-association approach, to improve the prediction of gene function.</p
Sex Proportionality in Pre-clinical and Clinical Trials: An Evaluation of 22 Marketing Authorization Application Dossiers Submitted to the European Medicines Agency
No full textThis study assessed to what extent women were included in all phases of drug development; whether the clinical studies in the marketing authorization application dossiers include information per sex; and explored whether there are differences between women and men in the drugs' efficacy and safety. Data were extracted from dossiers submitted to the European Medicines Agency. Twenty-two dossiers of drugs approved between 2011 and 2015 for the treatment of various diseases were included. Female animals were included in only 9% of the pharmacodynamics studies, but female and male animals were included in all toxicology studies. Although fewer women than men were included in the clinical studies used to evaluate pharmacokinetics (PK) (29 to 40% women), all dossiers contained sex-specific PK parameter estimations. In the phase III trials, inclusion of women was proportional to disease prevalence for depression, epilepsy, thrombosis, and diabetes [participation to prevalence ratio (PPR) range: 0.91–1.04], but women were considered underrepresented for schizophrenia, hepatitis C, hypercholesterolemia, HIV, and heart failure (PPR range: 0.49-0.74). All dossiers contained sex-specific subgroup analyses of efficacy and safety. There seemed to be higher efficacy for women in one dossier and a trend toward lower efficacy in another dossier. More women had adverse events in both treatment (73.0 vs. 70.6%, p < 0.001) and placebo groups (69.5 vs. 65.5%, p < 0.001). In conclusion, women were included throughout all phases of clinical drug research, and sex-specific information was available in the evaluated dossiers. The included number of women was, however, not always proportional to disease prevalence rates
The power of modelling pulsatile profiles
No full textThe quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release (e.g. insulin, growth hormone, luteinizing hormone). Unfortunately, standard non-linear mixed effects population pharmacodynamic models such as turnover and precursor response models (with or without a cosinor component) are unable to quantify these complex secretion profiles over time. In this study, the statistical power of standard statistical methodology such as 6 post-dose measurements or the area under the curve from 0 to 12 h post-dose on simulated dense concentration-time profiles of growth hormone was compared to a deconvolution-analysis-informed modelling approach in different simulated scenarios. The statistical power of the deconvolution-analysis-informed approach was determined with a Monte-Carlo Mapped Power analysis. Due to the high level of intra- and inter-individual variability in growth hormone concentrations over time, regardless of the simulated effect size, only the deconvolution-analysis informed approach reached a statistical power of more than 80% with a sample size of less than 200 subjects per cohort. Furthermore, the use of this deconvolution-analysis-informed modelling approach improved the description of the observations on an individual level and enabled the quantification of a drug effect to be used for subsequent clinical trial simulations.</p
Legislation and current developments in adverse drug reaction reporting in Mongolia:how far are we?
No full textMonitoring adverse drug reactions is a vital issue to ensure drug safety and to protect the general public from medication-related harmful effects. In order to properly monitor drug safety, a regulatory system needs to be in place as well as an infrastructure that allows for analyzing national and international safety data. In Mongolia, adverse drug reaction (ADR) reporting activities have been implemented in the past decade. During this period, the basic structure and legal basis of an adverse drug reaction monitoring system was established. Because of the fragmented but growing healthcare system and the complexity of pharmaceutical issues in Mongolia, a sustainable process for the development of the adverse drug reaction reporting system is a key issue. The aim of this article is to disclose the Mongolian situation for the rest of the world and to share experiences on how an ADR reporting system can be developed towards a higher and more advanced level to contribute to both national and international drug safety issues. In this article, we review the features of the Mongolian health care and pharmaceutical systems, as well as the current development of the adverse drug reaction reporting system.</p
Treatment with psilocybin:applications for patients with psychiatric disorders
No full textAfter a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. PubMed was searched for clinical trials into "psilocybin" between 2000 and 2020, complemented by handsearching. Articles were also screened for explanatory models and working mechanisms. Psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. Results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. Initial results are encouraging, but there are several limitations. More research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.</p
The psychometric validity of the Montgomery–Åsberg Depression Rating Scale (MADRS) in recent onset schizophrenia spectrum disorders
No full textEarlier recognition and accurate assessment of depressive symptoms is important to improving outcomes in individuals with recent-onset schizophrenia spectrum disorders (termed SSD hereafter)—regardless of whether positive psychotic symptoms are present or have resolved. The Montgomery–Åsberg Depression Rating Scale (MADRS) is frequently used to assess depressive symptoms in SSD, but no study has examined the psychometric validity of MADRS scores in individuals exclusively with SSD and sub-grouped by those with and without positive psychotic symptoms. This study involved baseline data from the Psychosis Recent Onset GRoningen Survey (PROGR-S). Measures used were: MADRS, depressive and negative subscales of Positive and Negative Syndrome Scale (PANSSD, PANSSN), and Schedules for Clinical Assessment in Neuropsychiatry (SCAN). The MADRS total score had sufficient concurrent validity with PANSSD (evidence by ρ≥0.70), and insufficient divergent validity with PANSSN (evidenced by ρ ≥0.30), in the full cohort and when sub-grouped by positive psychotic symptoms. In symptom networks, divergent communities comprising either MADRS or PANSSN items were found, except the MADRS item inability to feel overlapped with PANSSN items. The most divergent MADRS items were sadness, pessimism, and suicidal thoughts. The MADRS total score had sufficient predictive validity for determining caseness for MDD based on SCAN, but the optimal cut-off differed in those with and without positive psychotic symptoms (MADRS≥18 versus MADRS≥11). The MADRS has sufficient validity for assessing depressive symptoms in SSD. Since scores might depend upon symptoms of SSD, MADRS≥11 and the presence of sadness, pessimism, or suicidal ideation might be the best indicator of MDD in SSD