Making safer preoperative arrangements for patients using vitamin K antagonists.

Use of vitamin K antagonists creates a risk for patient health and safety. The Dutch framework "Nationwide Standard Integrated Care of Anticoagulation" propagates a shared plan and responsibility by surgeon and anesthesiologist together in the preoperative setting. In our institution, this framework had not been implemented. Therefore, a quality-improvement project was started at the Anesthesia Department to improve perioperative safety. After exploration of barriers, multiple interventions were carried out to encourage co-workers at the preoperative screening department to take shared responsibility: distribution of prints, adjustments in electronic patient records, introduction of a protocol and education sessions. Efficacy was measured retrospectively performing a before-after study collecting perioperative data of patients using vitamin K antagonists. The primary outcome measure was the percentage of predefined safe preoperative plans. Secondary outcome measures were (1) incidence of postoperative bleeding and thrombo-embolic events within the first 24 hours after intervention and (2) necessity to preoperative correction of anticoagulation. Before intervention 72 (29%) safe, 93 (38%) partially unsafe and 83 (33%) unsafe arrangements were made. After the intervention these numbers were 105 (80%), 23 (17%) en 4 (3%), respectively: a significant 51% increase in safe preoperative plans (P<0.001). We observed no significant difference (P=0.369) regarding bleeding and thrombo-embolic events: pre-intervention 12 (5%) cases of postoperative bleeding were documented, vs. 6 (5%) post intervention and the number of thrombo-embolic events was 5 (2%) vs. 0. Also, no significant differences concerning preoperative correction of anticoagulation were observed: 11 (4%) vs. 8 (6%) (P=0.489). This quality improvement project demonstrates a major improvement in safer preoperative arrangements in our institution regarding vitamin K antagonists, using the described interventions. A significant effect on bleeding or thrombo-embolic events or necessity to correction of anticoagulation could not be demonstrated.

Impaired Spatio-Temporal Predictive Motor Timing Associated with Spinocerebellar Ataxia Type 6.

Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward-model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the 'anticipatory' period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events.

Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates.

The robustness and safety of liver-directed gene therapy can be substantially improved by enhancing expression of the therapeutic transgene in the liver. To achieve this, we developed a new approach of rational in silico vector design. This approach relies on a genome-wide bio-informatics strategy to identify cis-acting regulatory modules (CRMs) containing evolutionary conserved clusters of transcription factor binding site motifs that determine high tissue-specific gene expression. Incorporation of these CRMs into adeno-associated viral (AAV) and non-viral vectors enhanced gene expression in mice liver 10 to 100-fold, depending on the promoter used. Furthermore, these CRMs resulted in robust and sustained liver-specific expression of coagulation factor IX (FIX), validating their immediate therapeutic and translational relevance. Subsequent translational studies indicated that therapeutic FIX expression levels could be attained reaching 20-35% of normal levels after AAV-based liver-directed gene therapy in cynomolgus macaques. This study underscores the potential of rational vector design using computational approaches to improve their robustness and therefore allows for the use of lower and thus safer vector doses for gene therapy, while maximizing therapeutic efficacy.