Delta rhythms as a substrate for holographic processing in sleep and wakefulness

PhD ThesisWe initially considered the theoretical properties and benefits of so-called holographic processing in a specific type of computational problem implied by the theories of synaptic rescaling processes in the biological wake-sleep cycle. This raised two fundamental questions that we attempted to answer by an experimental in vitro electrophysiological approach. We developed a comprehensive experimental paradigm based on a pharmacological model of the wake-sleep-associated delta rhythm measured with a Utah micro-electrode array at the interface between primary and associational areas in the rodent neocortex. We first verified that our in vitro delta rhythm model possessed two key features found in both in vivo rodent and human studies of synaptic rescaling processes in sleep: The first property being that prior local synaptic potentiation in wake leads to increased local delta power in subsequent sleep. The second property is the reactivation in sleep of neural firing patterns observed prior to sleep. By reproducing these findings we confirmed that our model is arguably an adequate medium for further study of the putative sleep-related synaptic rescaling process. In addition we found important differences between neural units that reactivated or deactivated during delta; these were differences in cell types based on unit spike shapes, in prior firing rates and in prior spike-train-to-local-field-potential coherence. Taken together these results suggested a mechanistic chain of explanation of the two observed properties, and set the neurobiological framework for further, more computationally driven analysis. Using the above experimental and theoretical substrate we developed a new method of analysis of micro-electrode array data. The method is a generalization to the electromagnetic case of a well-known technique for processing acoustic microphone array data. This allowed calculation of: The instantaneous spatial energy flow and dissipation in the neocortical areas under the array; The spatial energy source density in analogy to well-known current source density analysis. We then refocused our investigation on the two theoretical questions that we hoped to achieve experimental answers for: Whether the state of the neocortex during a delta rhythm could be described by ergodic statistics, which we determined by analyzing the spectral properties of energy dissipation as a signature of the state of the dynamical system; A more explorative approach prompting an investigation of the spatiotemporal interactions across and along neocortical layers and areas during a delta rhythm, as implied by energy flow patterns. We found that the in vitro rodent neocortex does not conform to ergodic statistics during a pharmacologically driven delta or gamma rhythm. We also found a delta period locked pattern of energy flow across and along layers and areas, which doubled the processing cycle relative to the fundamental delta rhythm, tentatively suggesting a reciprocal, two-stage information processing hierarchy similar to a stochastic Helmholtz machine with a wake-sleep training algorithm. Further, the complex valued energy flow might suggest an improvement to the Helmholtz machine concept by generalizing the complex valued weights of the stochastic network to higher dimensional multi-vectors of a geometric algebra with a metric particularity suited for holographic processes. Finally, preliminary attempts were made to implement and characterize the above network dynamics in silico. We found that a qubit valued network does not allow fully holographic processes, but tentatively suggest that an ebit valued network may display two key properties of general holographic processing

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis:1-Year Results From the All-Comers NOTION Randomized Clinical Trial

AbstractBackgroundTranscatheter aortic valve replacement (TAVR) is an option in certain high-risk surgical patients with severe aortic valve stenosis. It is unknown whether TAVR can be safely introduced to lower-risk patients.ObjectivesThe NOTION (Nordic Aortic Valve Intervention Trial) randomized clinical trial compared TAVR with surgical aortic valve replacement (SAVR) in an all-comers patient cohort.MethodsPatients ≥70 years old with severe aortic valve stenosis and no significant coronary artery disease were randomized 1:1 to TAVR using a self-expanding bioprosthesis versus SAVR. The primary outcome was the composite rate of death from any cause, stroke, or myocardial infarction (MI) at 1 year.ResultsA total of 280 patients were randomized at 3 Nordic centers. Mean age was 79.1 years, and 81.8% were considered low-risk patients. In the intention-to-treat population, no significant difference in the primary endpoint was found (13.1% vs. 16.3%; p = 0.43 for superiority). The result did not change in the as-treated population. No difference in the rate of cardiovascular death or prosthesis reintervention was found. Compared with SAVR-treated patients, TAVR-treated patients had more conduction abnormalities requiring pacemaker implantation, larger improvement in effective orifice area, more total aortic valve regurgitation, and higher New York Heart Association functional class at 1 year. SAVR-treated patients had more major or life-threatening bleeding, cardiogenic shock, acute kidney injury (stage II or III), and new-onset or worsening atrial fibrillation at 30 days than did TAVR-treated patients.ConclusionsIn the NOTION trial, no significant difference between TAVR and SAVR was found for the composite rate of death from any cause, stroke, or MI after 1 year. (Nordic Aortic Valve Intervention Trial [NOTION]; NCT01057173