24 research outputs found
Keeping Meta-Analyses Hygienic During the COVID-19 Pandemic
Despite the massive distribution of different vaccines globally, the current pandemic has revealed the crucial need for an efficient treatment against COVID-19. Meta-analyses have historically been extremely useful to determine treatment efficacy but recent debates about the use of hydroxychloroquine for COVID-19 patients resulted in contradictory meta-analytical results. Different factors during the COVID-19 pandemic have impacted key features of conducting a good meta-analysis. Some meta-analyses did not evaluate or treat substantial heterogeneity (I2 > 75%); others did not include additional analysis for publication bias; none checked for evidence of p–hacking in the primary studies nor used recent methods (i.e., p-curve or p-uniform) to estimate the average population-size effect. These inconsistencies may contribute to contradictory results in the research evaluating COVID-19 treatments. A prominent example of this is the use of hydroxychloroquine, where some studies reported a large positive effect, whereas others indicated no significant effect or even increased mortality when hydroxychloroquine was used with the antibiotic azithromycin. In this paper, we first recall the benefits and fundamental steps of good quality meta-analysis. Then, we examine various meta-analyses on hydroxychloroquine treatments for COVID-19 patients that led to contradictory results and causes for this discrepancy. We then highlight recent tools that contribute to evaluate publication bias and p-hacking (i.e., p-curve, p-uniform) and conclude by making technical recommendations that meta-analyses should follow even during extreme global events such as a pandemic
Triarylmethanes, a New Class of Cx50 Inhibitors
The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC50s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K+ and Na+ channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes
Mechanism of inhibition of connexin channels by the quinine derivative N-benzylquininium
The anti-malarial drug quinine and its quaternary derivative N-benzylquininium (BQ+) have been shown to inhibit gap junction (GJ) channels with specificity for Cx50 over its closely related homologue Cx46. Here, we examined the mechanism of BQ+ action using undocked Cx46 and Cx50 hemichannels, which are more amenable to analyses at the single-channel level. We found that BQ+ (300 µM–1 mM) robustly inhibited Cx50, but not Cx46, hemichannel currents, indicating that the Cx selectivity of BQ+ is preserved in both hemichannel and GJ channel configurations. BQ+ reduced Cx50 hemichannel open probability (Po) without appreciably altering unitary conductance of the fully open state and was effective when added from either extracellular or cytoplasmic sides. The reductions in Po were dependent on BQ+ concentration with a Hill coefficient of 1.8, suggesting binding of at least two BQ+ molecules. Inhibition by BQ+ was voltage dependent, promoted by hyperpolarization from the extracellular side and conversely by depolarization from the cytoplasmic side. These results are consistent with binding of BQ+ in the pore. Substitution of the N-terminal (NT) domain of Cx46 into Cx50 significantly impaired inhibition by BQ+. The NT domain contributes to the formation of the wide cytoplasmic vestibule of the pore and, thus, may contribute to the binding of BQ+. Single-channel analyses showed that BQ+ induced transitions that did not resemble pore block, but rather transitions indistinguishable from the intrinsic gating events ascribed to loop gating, one of two mechanisms that gate Cx channels. Moreover, BQ+ decreased mean open time and increased mean closed time, indicating that inhibition consists of an increase in hemichannel closing rate as well as a stabilization of the closed state. Collectively, these data suggest a mechanism of action for BQ+ that involves modulation loop gating rather than channel block as a result of binding in the NT domain
Highlights From the Annual Meeting of the American Epilepsy Society 2022
With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia
SARS-CoV-2 infection and seizures: the perfect storm
Seizures have been increasingly identified as a neurologic manifestation of coronavirus disease 2019 (COVID-19) infection. They may be symptomatic due to systemic infections, as a result of direct central nervous system (CNS) invasion, or occur in response to inflammatory reactions to the virus. It is possible that proinflammatory molecules released in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to hyperexcitability and epileptogenesis, similar to infections caused by other neurotrophic viruses. Cerebral spinal fluid (CSF) in patients with COVID-19 and seizures is negative for SARS-CoV-2 (PCR) in the majority of patients, but has been found to be positive for proinflammatory molecules like IL-6, IL-8, and anti-neuronal autoantibodies. Electroencephalogram (EEG) in COVID-19 patients are nonspecific. However, in the encephalopathic and critically ill subpopulation, EEG is essential in detecting nonconvulsive seizures and status epilepticus which is associated with increased overall mortality in COVID-19 patients. Thus, as encephalopathy is often the only CNS symptom evidenced in patients with nonconvulsive seizures, more judicious use of continuous EEG in encephalopathic COVID-19 patients should be considered. This would facilitate earlier detection and treatment of seizures in this population, which would ultimately improve outcomes. Further research into the onset and potential for development of seizures and epilepsy in patients with COVID-19 is needed
Recommended from our members
Status epilepticus-time is brain and treatment considerations
Purpose of review Status epilepticus is a neurological emergency associated with high morbidity and mortality. There is a lack of robust data to guide the management of this neurological emergency beyond the initial treatment. This review examines recent literature on treatment considerations including the choice of continuous anesthetics or adjunctive anticonvulsant, the cause of the status epilepticus, and use of nonpharmacologic therapies. Recent findings Status epilepticus remains undertreated and mortality persists to be unchanged over the past 30 years. New anticonvulsant choices, such as levetiracetam and lacosamide have been explored as alternative emergent therapies. Anecdotal reports on the use of other generation anticonvulsants and nonpharmacologic therapies for the treatment of refractory and super-refractory status epilepticus have been described. Finally, recent evidence has examined etiology-guided management of status epilepticus in certain patient populations, such as immune-mediated, paraneoplastic or infectious encephalitis and anoxic brain injury. Randomized clinical trials are needed to determine the role for newer generation anticonvulsants and nonpharmacologic modalities for the treatment of epilepticus remains and evaluate the long-term outcomes associated with continuous anesthetics
Recommended from our members
Electroencephalogram Monitoring in Critical Care
Seizures are common in critically ill patients. Electroencephalogram (EEG) is a tool that enables clinicians to provide continuous brain monitoring and to guide treatment decisions-brain telemetry. EEG monitoring has particular utility in the intensive care unit as most seizures in this setting are nonconvulsive. Despite the increased use of EEG monitoring in the critical care unit, it remains underutilized. In this review, we summarize the utility of EEG and different EEG modalities to monitor patients in the critical care setting
Recommended from our members
Rates and Trends of Endotracheal Intubation in Patients With Status Epilepticus
Objective:
Among patients with status epilepticus, we sought to determine the rate of endotracheal intubation, identify the physician specialties responsible for endotracheal intubation, and characterize the trend in use of endotracheal intubation over the last 20 years.
Methods:
We performed a cross-sectional study using data from 2 sources. First, we used inpatient claims between 2009 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. Patients with status epilepticus were identified using International Classification of Diseases, 9th Revision, Clinical Modification ( ICD-9-CM) codes, and those who underwent endotracheal intubation were identified based on Current Procedural Terminology codes. Medical specialties of providers performing intubation were identified based on Healthcare Provider Taxonomy Codes. Second, we used claims data from the National Inpatient Sample (NIS) to estimate the annual rates and trends of endotracheal intubation and tracheostomy among patients with status epilepticus from 1995 to 2014.
Results:
Among 1971 Medicare beneficiaries with status epilepticus, 566 (29%) patients underwent endotracheal intubation. 375 (66%) patients were intubated on admission. The most common medical providers performing intubation in patients with status epilepticus were emergency medicine physicians (50.4%), anesthesiologists (16.4%), and pulmonary medicine physicians (10.1%). Neurologists accounted for 1.7% of all intubations. Among individuals with status epilepticus identified in the NIS, 248 681 (41.7%) were intubated. The proportion of patients intubated increased from 29.5% (95% confidence interval [CI]: 27.8%-31.3%, P = .018) in 1995 to 50.8% (95% CI: 49.6%-52%, P = .012) in 2014. The proportion of patients with status epilepticus who underwent tracheostomy increased from 2.2% (95% CI: 1.7%-2.7%, P = .005) in 1995 to 3.4% (95% CI: 3%-3.9%, P = .004) in 2014.
Significance:
Approximately 1 in 3 patients with status epilepticus undergo endotracheal intubation. Over the last 20 years, the proportion of patients with status epilepticus undergoing endotracheal intubation has almost doubled. Neurologists perform a small percentage of these intubations