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Reality of evidence-based practice in palliative care.
There has been a paradigm shift in medicine away from tradition, anecdote and theoretical reasoning from the basic sciences towards evidence-based medicine (EBM). In palliative care however, statistically significant benefits may be marginal and may not be related to clinical meaningfulness. The typical treatment vs. placebo comparison necessitated by 'gold standard' randomised controlled trials (RCTs) is not necessarily applicable. The complex multimorbidity of end of life care involves considerations of the patient's physical, psychological, social and spiritual needs. In addition, the field of palliative care covers a heterogeneous group of chronic and incurable diseases no longer limited to cancer. Adequate sample sizes can be difficult to achieve, reducing the power of studies and high attrition rates can result in inadequate follow up periods. This review uses examples of the management of cancer-related fatigue and death rattle (noisy breathing) to demonstrate the current state of EBM in palliative care. The future of EBM in palliative care needs to be as diverse as the patients who ultimately derive benefit. Non-RCT methodologies of equivalent quality, validity and size conducted by collaborative research networks using a 'mixed methods approach' are likely to pose the correct clinical questions and derive evidence-based yet clinically relevant outcomes.
The role of the endoplasmic reticulum stress response following cerebral ischemia
Background Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability . Methods In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion. In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([4′-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). Results In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2α and ATF4) was observed at 3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro, endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased cell death. Both induction and inhibition of autophagy also increased cell death. Conclusion Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia.
The transient intraluminal filament middle cerebral artery occlusion model as a model of endovascular thrombectomy in stroke
The clinical relevance of the transient intraluminal filament model of middle cerebral artery occlusion (tMCAO) has been questioned due to distinct cerebral blood flow profiles upon reperfusion between tMCAO (abrupt reperfusion) and alteplase treatment (gradual reperfusion), resulting in differing pathophysiologies. Positive results from recent endovascular thrombectomy trials, where the occluding clot is mechanically removed, could revolutionize stroke treatment. The rapid cerebral blood flow restoration in both tMCAO and endovascular thrombectomy provides clinical relevance for this pre-clinical model. Any future clinical trials of neuroprotective agents as adjuncts to endovascular thrombectomy should consider tMCAO as the model of choice to determine pre-clinical efficacy.
A Systematic Review and Meta-analysis of Randomized Controlled Trials of Endovascular Thrombectomy Compared to Best Medical Treatment for Acute Ischemic Stroke
Background Acute ischemic strokes involving occlusion of large vessels usually recanalize poorly following treatment with intravenous thrombolysis. Recent studies have shown higher recanalization and higher good outcome rates with endovascular therapy compared to best medical management alone. A systematic review and meta-analysis investigating the benefits of all randomized controlled trials (RCTs) of endovascular thrombectomy where at least 25% of patients were treated with a thrombectomy device for the treatment of acute ischemic stroke compared to intravenous thrombolysis has yet to be performed. Aims To perform a systematic review and a meta-analysis evaluating the effectiveness of endovascular thrombectomy compared with best medical care for treatment of acute ischemic stroke. Summary of review Our search identified 437 publications, from which 8 studies (totaling 2,423 patients) matched the inclusion criteria. Overall, endovascular thrombectomy was associated with improved functional outcomes (mRS 0-2) (odds ratio (OR) 1.56 (1.32-1.85), p< 0.00001). There was a tendency towards decreased mortality (OR 0.84 (0.67-1.05), p=0.12) and symptomatic intracerebral hemorrhage was not increased (OR 1.03 (0.71-1.49), p=0.88) compared to best medical management alone. The OR for a favorable functional outcome increased to 2.23 (1.77-2.81, p<0.00001) when newer generation thrombectomy devices were used in greater than 50% of the cases in each trial. Conclusions There is clear evidence for improvement in functional independence with endovascular thrombectomy compared to standard medical care suggesting that endovascular thrombectomy should be considered the standard effective treatment alongside thombolysis in eligible patients.
Rapamycin in ischemic stroke: Old drug, new tricks?
The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, hampered by the necessity of rapidly imaging patients. A therapy that could extend this window by protecting neurons may improve outcome. Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit. This review highlights the potential use of rapamycin as a multimodal therapy, acting on the blood–brain barrier, cerebral blood flow and inflammation, as well as directly on neurons. There is significant potential in applying this old drug in new ways to improve functional outcomes for patients after stroke.
Comment on Di Giosaffatte et al. A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report. Genes 2022, 13, 1268.
The recent publication of Di Giosaffatte et al. [...].
Paranoia: A Journey Into Extreme Mistrust and Anxiety
'A TRULY IMPORTANT BOOK’ JOHN HUMPHRYS What is paranoia? What makes us mistrustful? How can this be overcome?
Clinical neuromodulatory effects of deep brain stimulation in disorder of consciousness: A literature review
AbstractBackgroundThe management of patients with disorders of consciousness (DOC) presents substantial challenges in clinical practice. Deep brain stimulation (DBS) has emerged as a potential therapeutic approach, but the lack of standardized regulatory parameters for DBS in DOC hinders definitive conclusions.ObjectiveThis comprehensive review aims to provide a detailed summary of the current issues concerning patient selection, target setting, and modulation parameters in clinical studies investigating the application of DBS for DOC patients.MethodsA meticulous systematic analysis of the literatures was conducted, encompassing articles published from 1968 to April 2023, retrieved from reputable databases (PubMed, Embase, Medline, and Web of Science).ResultsThe systematic analysis of 21 eligible articles, involving 146 patients with DOC resulting from acquired brain injury or other disorders, revealed significant insights. The most frequently targeted regions were the Centromedian‐parafascicular complex (CM‐pf) nuclei and central thalamus (CT), both recognized for their role in regulating consciousness. However, other targets have also been explored in different studies. The stimulation frequency was predominantly set at 25 or 100 Hz, with pulse width of 120 μs, and voltages ranged from 0 to 4 V. These parameters were customized based on individual patient responses and evaluations. The overall clinical efficacy rate in all included studies was 39.7%, indicating a positive effect of DBS in a subset of DOC patients. Nonetheless, the assessment methods, follow‐up durations, and outcome measures varied across studies, potentially contributing to the variability in reported efficacy rates.ConclusionDespite the challenges arising from the lack of standardized parameters, DBS shows promising potential as a therapeutic option for patients with DOC. However, there still remains the need for standardized protocols and assessment methods, which are crucial to deepen the understanding and optimizing the therapeutic potential of DBS in this specific patient population.