Articles: cations.
-
Curr Opin Anaesthesiol · Aug 2022
ReviewLong-term cognitive and behavioral outcomes following early exposure to general anesthetics.
Nearly 100 clinical studies have been published evaluating neurodevelopmental outcomes in children following surgery and anesthesia. These studies have reported mixed results, likely attributable at least in part to significant heterogeneity in their study designs, types and numbers of exposures, patient populations evaluated, and most importantly, the outcomes that were assessed. This review aims to summarize the results from clinical studies evaluating behavioral outcomes in children exposed to surgery and anesthesia. ⋯ Nearly all clinical studies of anesthetic neurotoxicity are observational in nature, so the associations between anesthetic exposure and behavioral deficits cannot yet be directly attributed to the anesthetic medication. However, the finding of deficits in some neurodevelopmental domains and not others will help guide the selection of appropriate outcomes in future studies of anesthetic neurotoxicity that can further evaluate whether anesthetic medications have an impact on neurodevelopment in children.
-
Review
Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials.
Deposition of tau aggregates is a pathological hallmark of Alzheimer's disease that is closely linked both spatially and temporally to emergence of neurodegeneration and manifestation of clinical symptoms. There is an urgent need for accurate PET, CSF, and plasma biomarkers of tau pathology to improve the diagnostic process in clinical practice and the selection of participants and monitoring of treatment effects in trials. ⋯ Innovative second-generation tau-PET tracers with high affinity and selectivity to tau pathology in Alzheimer's disease have enabled detection of tau pathology in medial temporal lobe subregions that are affected in the earliest disease stages. Furthermore, novel but common tau spreading subtypes have been discovered using tau-PET, suggesting much greater interindividual differences in the distribution of tau pathology across the brain than previously assumed. In the CSF biomarker field, novel phosphorylated tau (p-tau) assays have been introduced that better reflect tau tangle load than established CSF biomarkers of tau pathology. The advent of cost-effective and accessible blood-based biomarkers for tau pathophysiology (ie, p-tau181, p-tau217, and p-tau231) might transform the Alzheimer's disease field, as these biomarkers correlate with post-mortem Alzheimer's disease pathology, differentiate Alzheimer's disease from other types of dementia, and predict future progression from normal cognition and mild cognitive impairment to Alzheimer's disease. In controlled investigational settings, improvements in tau-PET and biofluid p-tau markers have led to earlier disease detection, more accurate diagnostic methods, and refinement of prognosis. The anti-tau therapy landscape is rapidly evolving, with multiple ongoing phase 1 and 2 trials of post-translational modification of tau, tau immunotherapy, tau aggregation inhibitors, and targeting production of tau and reduction of intracellular tau levels. Neuroimaging and biofluid tau markers hold potential for optimising such clinical trials by augmenting participant selection, providing evidence of target engagement, and monitoring treatment efficacy. WHERE NEXT?: Major challenges to overcome are the high cost of tau-PET, partial sensitivity to detect early-stage Alzheimer's disease pathology, and off-target tracer binding. Prospective validation studies of biofluid p-tau markers are needed, and assay-related preanalytical and analytical factors need further refinement. Future studies should focus on demonstrating the diagnostic and prognostic accuracy of tau biomarkers-blood-based markers in particular-in non-tertiary settings, such as primary care, which is characterised by a diverse population with medical comorbidities. Large-scale head-to-head studies are needed across different stages of Alzheimer's disease to determine which tau biomarker is optimal in various clinical scenarios, such as early diagnosis, differential diagnosis, and prognosis, and for aspects of clinical trial design, such as proving target engagement, optimising participant selection, and refining monitoring of treatment effects.
-
Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. ⋯ Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.
-
Curr Opin Crit Care · Aug 2022
ReviewMechanical circulatory support in the treatment of cardiogenic shock.
Cardiogenic shock is a condition that is characterized by end-organ hypoperfusion secondary to reduced cardiac output, and is associated with substantial mortality. The mainstay of therapy for cardiogenic shock is reversal of the underlying cause, and concomitant supportive care with vasoactive medications (vasopressors and inotropes). Patients who continue to deteriorate despite these measures may require mechanical circulatory support (MCS). Here, we review the devices available for MCS, and their associated benefits and risks. ⋯ Various devices for MCS in cardiogenic shock are available, but routine use is not supported by high-quality randomized evidence. Given the resources required for initiation of MCS, use of these treatments should be limited to centers experienced in advanced cardiac care, and future research should focus on what role (if any) these devices have in clinical practice.
-
The authors estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. The authors also consider the effect of the perceived abuse potential of the medication on these variables. ⋯ The authors' data suggest that the unique attributes of pain medications, such as their abuse potential and intended pathology, can influence the probability of successful development and duration of development.