Pathway Design for Acute Stroke Care in the Era of Endovascular Thrombectomy:A Critical Overview of Optimization Efforts

The efficacy of intravenous thrombolysis and endovascular thrombectomy (EVT) for acute ischemic stroke is highly time dependent. Optimal organization of acute stroke care is therefore important to reduce treatment delays but has become more complex after the introduction of EVT as regular treatment for large vessel occlusions. There is no singular optimal organizational model that can be generalized to different geographic regions worldwide. Current dominant organizational models for EVT include the drip-and-ship- and mothership model. Guidelines recommend routing of suspected patients with stroke to the nearest intravenous thrombolysis capable facility; however, the choice of routing to a certain model should depend on regional stroke service organization and individual patient characteristics. In general, design approaches for organizing stroke care are required, in which 2 key strategies could be considered. The first entails the identification of interventions within existing organizational models for optimizing timely delivery of intravenous thrombolysis and/or EVT. This includes adaptive patient routing toward a comprehensive stroke center, which focuses particularly on prehospital triage tools; bringing intravenous thrombolysis or EVT to the location of the patient; and expediting services and processes along the stroke pathway. The second strategy is to develop analytical or simulation model-based approaches enabling the design and evaluation of organizational models before their implementation. Organizational models for acute stroke care need to take regional and patient characteristics into account and can most efficiently be assessed and optimized through the application of model-based approaches

Role of the police in linking individuals experiencing mental health crises with mental health services

BACKGROUND: The police are considered frontline professionals in managing individuals experiencing mental health crises. This study examines the extent to which these individuals are disconnected from mental health services, and whether the police response has an influence on re-establishing contact. METHODS: Police records were searched for calls regarding individuals with acute mental health needs and police handling of these calls. Mental healthcare contact data were retrieved from a Psychiatric Case Register. RESULTS: The police were called upon for mental health crisis situations 492 times within the study year, involving 336 individuals (i.e. 1.7 per 1000 inhabitants per year). Half of these individuals (N=162) were disengaged from mental health services, lacking regular care contact in the year prior to the crisis (apart from contact for crisis intervention). In the month following the crisis, 21% of those who were previously disengaged from services had regular care contact, and this was more frequent (49%) if the police had contacted the mental health services during the crisis. The influence of police referral to the services was still present the following year. However, for the majority (58%) of disengaged individuals police did not contact the mental health services at the time of crisis. CONCLUSIONS: The police deal with a substantial number of individuals experiencing a mental health crisis, half of whom are out of contact with mental health services, and police play an important role in linking these individuals to services. Training police officers to recognise and handle mental health crises, and implementing practical models of cooperation between the police and mental health services in dealing with such crises may further improve police referral of individuals disengaged from mental health services

Synthesis and evaluation of dopamine D-3 receptor antagonist C-11-GR218231 as PET tracer for P-glycoprotein

While searching for a PET method to determine the density and occupancy of the dopamine D-3 receptor, we found evidence that suggested that the dopamine D-3 antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions. Methods: As a potential PET tracer, GR218231 was labeled with C-11 by reaction of the newly synthesized desmethyl precursor with C-11-methyl triflate. The biodistribution of C-11-GR218231 was determined in rats. To assess specific binding to the dopamine D3 receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of C-11-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of C-11-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages. Results: C-11-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/mu mol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher C-11-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A close-escalation studies showed a dose-dependent sigmoidal increase in C-11-GR218231 uptake in brain and spleen (median effective dose [ED50], 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED50, 36.0 +/- 4.4 mg/kg). Conclusion: Although C-11-GR218231 is unsuited for dopamine D3 receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier

Routine Violence Risk Assessment in Community Forensic Mental Healthcare

We developed a method for periodic monitoring of violence risk, as part of routine community forensic mental healthcare. The feasibility of the method was tested, as well as its predictive validity for violent and risk enhancing behavior in the subsequent months. Participants were 83 clients who received forensic psychiatric home treatment, and six case managers. The method proved feasible and informative. Violent and risk enhancing behavior could be predicted to a reasonable extent (AUC = .77, 95% CI = .70-.85; respectively .76, .70-.82). Dynamic risk factors had an incremental predictive value over static factors in the prediction of violent behavior (OR = 4.30, 1.72-10.73). The professional judgment of the case managers added further predictive power (OR = 2.16, 1.40-3.33), corroborating the structured professional judgment approach. Finally, unmet needs for care of the client were associated with a reduced risk for violent and risk enhancing behavior (OR = .80, 0.69-0.93, and 0.84, 0.72-0.97). This latter finding suggests that in cases with unmet needs the case manager saw opportunities to do something about the risk. Currently we are testing whether using the method actually prevents violence. Copyright (C) 2009 John Wiley & Sons, Ltd

Altered emotional experiences attributed to antipsychotic medications - A potential link with estimated dopamine D-2 receptor occupancy

Altered emotional experiences in response to antipsychotics may increase the burden of disease in patients with schizophrenia. In a large cross-sectional study, patients with schizophrenia completed the Subjects Reaction to Antipsychotics questionnaire (SRA) to assess whether they attributed altered emotional experiences (flattened affect or depressive symptoms) to their antipsychotics. Association with antipsychotic D-2 receptor affinity and occupancy was examined using logistic regression. We compared antipsychotic-attributed emotional experiences between patients using antipsychotic monotherapy and combination therapy. Of the 1298 included patients, 23% attributed flattened affect to their anti psychotics and 16% attributed depressive symptoms to their antipsychotics, based on the SRA. No differences were observed between antipsychotics in patients on monotherapy. We discuss that within these patients' relatively low dose range, altered emotional experiences did not appear to relate to the level of D-2 receptor affinity of antipsychotic monotherapy. Patients using antipsychotic combination therapy (22%) were more likely to attribute depressive symptoms to their antipsychotics than patients using antipsychotic monotherapy (OR [95%CI]=1.443 [1.033-2.015]); possibly due to higher D-2 receptor occupancies as estimated by dose equivalents. (C) 2016 Published by Elsevier Ireland Ltd

Leptin levels in SARS-CoV-2 infection related respiratory failure:A cross-sectional study and a pathophysiological framework on the role of fat tissue

Obesity is a risk factor for SARS-CoV-2 infected patients to develop respiratory failure. Leptin produced in visceral fat might play a role in the deterioration to mechanical ventilation. A cross sectional study was performed. The mean BMI was 31 kg/m2 (range 24.8-48.4) for the 31 SARS-CoV-2 ventilated patients and 26 kg/m2 (range 22.4-33.5) for 8 critically ill non-infected control patients. SARS-CoV-2 infected patients with a similar BMI as control patients appear to have significantly higher levels of serum leptin. The mean leptin level was 21.2 (6.0-85.2) vs 5.6 (2.4-8.2) ug/L for SARS-CoV-2 and controls respectively (p = 0.0007). With these findings we describe a clinical and biological framework that may explain these clinical observations. The ACE2 utilization by the virus leads to local pulmonary inflammation due to ACE2-ATII disbalance. This might be enhanced by an increase in leptin production induced by SARS-CoV-2 infection of visceral fat. Leptin receptors in the lungs are now more activated to enhance local pulmonary inflammation. This adds to the pre-existent chronic inflammation in obese patients. Visceral fat, lung tissue and leptin production play an interconnecting role. This insight can lead the way to further research and treatment

A quasi-static approach to structure formation in black hole universes

JD and TC both acknowledge support from the STFC under grant STFC ST/N504257/1