In the last two decades, antisense oligonucleotides (AONs) that induce corrective exon skipping have matured as promising therapies aimed at tackling the dystrophin deficiency that underlies the... Show moreIn the last two decades, antisense oligonucleotides (AONs) that induce corrective exon skipping have matured as promising therapies aimed at tackling the dystrophin deficiency that underlies the severe and progressive muscle fiber degeneration in Duchenne muscular dystrophy (DMD) patients. Pioneering first generation exon 51 skipping AONs like drisapersen and eteplirsen have more recently been followed up by AONs for exons 53 and 45, with, to date, a total of four exon skipping AON drugs having reached (conditional) regulatory US Food and Drug Administration (FDA) approval for DMD. Nonetheless, considering the limited efficacy of these drugs, there is room for improvement. The aim of this study was to develop more efficient [2 '-O-methyl-modified phosphorothioate (2 ' OMePS) RNA] AONs for DMD exon 51 skipping by implementing precision chemistry as well as identifying a more potent target binding site. More than a hundred AONs were screened in muscle cell cultures, followed by a selective comparison in the hDMD and hDMDdel52/mdx mouse models. Incorporation of 5-methylcytosine and position-specific locked nucleic acids in AONs targeting the drisapersen/eteplirsen binding site resulted in 15-fold higher exon 51 skipping levels compared to drisapersen in hDMDdel52/mdx mice. However, with similarly modified AONs targeting an alternative site in exon 51, 65-fold higher skipping levels were obtained, restoring dystrophin up to 30% of healthy control. Targeting both sites in exon 51 with a single AON further increased exon skipping (100-fold over drisapersen) and dystrophin (up to 40%) levels. These dystrophin levels allowed for normalization of creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and improved motor function in hDMDdel52/mdx mice. As no major safety observation was obtained, the improved therapeutic index of these next generation AONs is encouraging for further (pre)clinical development. Show less
Objective Patients with severe traumatic brain injury (TBI) are commonly intubated during prehospital treatment despite a lack of evidence that this is beneficial. Accumulating evidence even... Show moreObjective Patients with severe traumatic brain injury (TBI) are commonly intubated during prehospital treatment despite a lack of evidence that this is beneficial. Accumulating evidence even suggests that prehospital intubation may be hazardous, in particular when performed by inexperienced EMS clinicians. To expand the limited knowledge base, we studied the relationship between prehospital intubation and hospital mortality in patients with severe TBI in a large Dutch trauma database. We specifically hypothesized that the relationship differs depending on whether a physician-based emergency medical service (EMS) was involved in the treatment, as opposed to intubation by paramedics. Methods A retrospective analysis was performed using the Dutch Nationwide Trauma Registry that includes all trauma patients in the Netherlands who are admitted to any hospital with an emergency department. All patients treated for severe TBI (Head Abbreviated Injury Scale score >= 4) between January 2015 and December 2019 were selected. Multivariable logistic regression was used to assess the relationship between prehospital intubation and mortality while adjusting for potential confounders. An interaction term between prehospital intubation and the involvement of physician-based EMS was added to the model. Complete case analysis as well as multiple imputation were performed. Results 8946 patients (62% male, median age 63 years) were analyzed. The hospital mortality was 26.4%. Overall, a relationship between prehospital intubation and higher mortality was observed (complete case: OR 1.86, 95% CI 1.35-2.57, p < 0.001; multiple imputation: OR 1.92, 95% CI 1.56-2.36, p < 0.001). Adding the interaction revealed that the relationship of prehospital intubation may depend on whether physician-based EMS is involved in the treatment (complete case: p = 0.044; multiple imputation: p = 0.062). Physician-based EMS involvement attenuated but did not completely remove the detrimental association between prehospital intubation and mortality. Conclusion The data do not support the common practice of prehospital intubation. The effect of prehospital intubation on mortality might depend on EMS clinician experience, and it seems prudent to involve prehospital personnel well proficient in prehospital intubation whenever intubation is potentially required. The decision to perform prehospital intubation should not merely be based on the largely unsupported dogma that it is generally needed in severe TBI, but should rather individually weigh potential benefits and harms. Show less
Horn, E.K.; Verheul, R.; Thunnissen, M.; Delimon, J.; Soons, M.; Meerman, A.M.M.A.; ... ; Busschbach, J.J.V. 2015
Background For patients with cluster B personality disorders there is no consensus regarding the optimal treatment setting The aim of this study was to compare the effectiveness of different... Show moreBackground For patients with cluster B personality disorders there is no consensus regarding the optimal treatment setting The aim of this study was to compare the effectiveness of different psychotherapeutic settings for patients with cluster B personality disorders, i e outpatient, day hospital, and inpatient treatment Methods The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 207 patients with a DSM-IV-TR axis II cluster B diagnosis Patients were assigned to 3 different settings of psychotherapeutic treatment and effectiveness was assessed at 18 months after baseline An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling As the study was non-randomised, the propensity score method was used to control for initial differences Results Patients in all 3 settings improved significantly in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life 18 months after baseline The inpatient group showed the largest improvements The comparison of outpatient and inpatient treatment regarding psychiatric symptoms showed a marginally significant result (p = 0 057) in favour of inpatient treatment Conclusions Patients with cluster B personality disorders improved in all investigated treatment settings, with a trend towards larger improvements of psychiatric symptoms in the inpatient setting compared to the outpatient setting Specialised inpatient treatment should be considered as a valuable treatment option for cluster B personality disorders, both in research and in clinical practice Copyright (C) 2010 S Karger AG Basel Show less
Background: While psychopharmacological studies are common in patients with cluster A personality disorders, the effects of psychotherapy have received little attention. The aim of this study is to... Show moreBackground: While psychopharmacological studies are common in patients with cluster A personality disorders, the effects of psychotherapy have received little attention. The aim of this study is to explore whether psychotherapeutic treatment yields health gains for these patients. Methods: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 57 patients with a DSM-IV-TR axis II cluster A diagnosis. Patients were assigned to 3 settings of psychotherapeutic treatment (outpatient, day hospital, inpatient), and effectiveness was assessed at 18 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45) and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. Results: Patients in the day hospital and inpatient group improved substantially in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life. Patients in the outpatient group showed less improvement. Direct comparison of the improvement of psychiatric symptoms showed significant results in favour of day hospital (p = 0.046) and inpatient (p = 0.01) treatment, as compared to outpatient treatment. However, due to substantial baseline differences, this direct comparison should be judged carefully. Conclusions: Cluster A psychopathology is not a contraindication to benefit from psychotherapy. This is especially true for more intensive forms like inpatient and day hospital treatment. Future research should focus more on psychotherapeutic treatment to gain further insight into effective treatment options for this patient group. Copyright (C) 2010 S. Karger AG, Basel Show less
Manen, J.G. van; Andrea, H.; Eijnden, E. van den; Meerman, A.M.M.A.; Thunnissen, M.M.; Hamers, E.F.M.; ... ; Verheul, R. 2011
BACKGROUND: No previous studies have compared the effectiveness of different modalities of psychotherapeutic treatment, as defined by different settings and durations, for patients with cluster C... Show moreBACKGROUND: No previous studies have compared the effectiveness of different modalities of psychotherapeutic treatment, as defined by different settings and durations, for patients with cluster C personality disorders. The aim of this multicentre study was to compare the effectiveness of 5 treatment modalities for patients with cluster C personality disorders in terms of psychiatric symptoms, psychosocial functioning, and quality of life. The following treatment modalities were compared: long-term outpatient (more than 6 months), short-term day hospital (up to 6 months), long-term day hospital, short-term inpatient, and long-term inpatient psychotherapy. METHODS: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 371 patients with a DSM-IV-TR axis-II cluster C diagnosis. Patients were assigned to 5 different modalities of psychotherapeutic treatment, and effectiveness was assessed at 12 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. RESULTS: Patients in all treatment groups had improved on all outcomes 12 months after baseline. Patients receiving short-term inpatient treatment showed more improvement than patients receiving other treatment modalities. CONCLUSIONS: Psychotherapeutic treatment, especially in the short-term inpatient modality, is an effective treatment for patients with cluster C personality disorders. Show less
