Evolution of Consciousness.

The natural evolution of consciousness in different animal species mandates that conscious experiences are causally potent in order to confer any advantage in the struggle for survival. Any endeavor to construct a physical theory of consciousness based on emergence within the framework of classical physics, however, leads to causally impotent conscious experiences in direct contradiction to evolutionary theory since epiphenomenal consciousness cannot evolve through natural selection. Here, we review recent theoretical advances in describing sentience and free will as fundamental aspects of reality granted by quantum physical laws. Modern quantum information theory considers quantum states as a physical resource that endows quantum systems with the capacity to perform physical tasks that are classically impossible. Reductive identification of conscious experiences with the quantum information comprised in quantum brain states allows for causally potent consciousness that is capable of performing genuine choices for future courses of physical action. The consequent evolution of brain cortical networks contributes to increased computational power, memory capacity, and cognitive intelligence of the living organisms.

Return to Sports and Patients' Rehabilitation Continuum After Deepening Trochleoplasty and Concomitant Patellar-Stabilizing Procedures: A Case Series of 111 Patients at 2 to 4 Years of Follow-up.

BACKGROUND: There are few reports on the return to sports after complex patellar-stabilizing surgery. PURPOSES: To evaluate patients' ability to return to sports and to investigate the extent to which the preoperative level of sports participation influences sports activity after deepening trochleoplasty (TP) and concomitant patellar-stabilizing procedures. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between April 2015 and April 2019, 144 patellar-stabilizing procedures, including deepening TP and medial patellofemoral ligament reconstruction or medial reefing with and without concomitant realignment procedures, were carried out in 142 patients. The Banff Patellofemoral Instability Instrument 2.0 (BPII 2.0) and the Tegner activity score were used to assess patients' quality of life and sports activity level. In addition, a numerical analog scale was used to evaluate patellofemoral pain intensity during rest and activity and subjective knee joint function. RESULTS: Outcomes were available for 111 patients (112 knees) (male/female, 77/34; mean age, 23.4 ± 7.8 years), yielding a 77.7% follow-up rate at a mean of 39.2 ± 9.9 months (range, 24-48 months). Two-thirds of the patients returned to their preoperative level of activity or higher, but their Tegner scores did not change significantly (4.5 ± 2.4 vs 4.7 ± 1.6; P = .365). Low-level athletes (preoperative Tegner score 0-4) participated at a higher level of sports activity (2.7 ± 1.4 to 4.1 ± 1.2; P < .0001), whereas higher-level athletes (preoperative Tegner score 5-10) participated at a lower level (6.8 ± 1.3 to 5.5 ± 1.7; P < .0001). The likelihood of returning to the preoperative activity level (Tegner score) was significantly higher in the low-level activity group than in the high-level activity group (P = .0001; 95% CI, 4.055-27.05; odds ratio, 10.47). All of the patient-reported outcome measures improved postoperatively, independent of the patients' age, sex, and body mass index. CONCLUSION: Patients undergoing deepening TP and medial soft tissue stabilization with or without concomitant realignment surgery for complex patellar instability can expect good clinical results and a high rate of return to sports participation, with two-thirds of patients returning to their preoperative Tegner-level of activity or higher. However, higher-level athletes should be informed that their likelihood of returning to sports at the preoperative level or full participation at a competitive level is reduced.

Treatment of acquired patella baja by proximalization tibial tubercle osteotomy significantly improved knee joint function but overall patient-reported outcome measures remain diminished after two to four years of follow-up.

INTRODUCTION: Acquired patella baja is often characterized by painful limitation of knee joint range of motion and anterior knee pain (AKP). Only few studies have evaluated the effectiveness of surgical treatment in terms of patient-reported outcome measures (PROM's) and sports activity. Thus, the goal of this study was to assess PROM's and sports activity after proximalization tibial tubercle osteotomy (P-TTO) in patients with symptomatic patella baja. METHODS: Between 2016 and 2018, a case series of 11 patients (male/female 4/7; age 48 ± 12 years) were treated by P-TTO and were retrospectively evaluated after a mean of 33.7 months (range 24-51 months). The Tegner activity score and the Kujala anterior knee pain scale were used in addition to a visual analogue scale (VAS; 0-10) regarding self-reported knee joint function and intensity of AKP. Radiographic assessment included the measure of patellar height using the Caton-Deschamps (CD) and Blackburne-Peel (BP) index. RESULTS: Postoperatively both the CD and the BP index increased to normality (p < 0.0001; p = 0.0012). Knee joint flexion improved from 100 ± 32° preoperatively to 123 ± 14° postoperatively (p = 0.0235). AKP decreased from 6.5 ± 2.1 points preoperatively to 3.7 ± 2.1 points postoperatively (p = 0.0061). This was accompanied by a significant increase in self-reported knee joint function from 1.8 ± 1.2 points preoperatively to 6.8 ± 2.3 points postoperatively (p = 0.0001) and an increase of the Tegner activity score from 1.8 ± 1.6 points preoperatively to 3.9 ± 1.5 points postoperatively (p = 0.0074). Although the Kujala score improved significantly by an average of 31.55 points (p = 0.001) overall score results remained reduced at 65.6 ± 17.9 points at final follow-up. CONCLUSION: P-TTO yielded significant improvements in terms of AKP, subjective knee joint function and sports activity. However, the overall Kujala score results remained reduced, indicating that surgical correction of patellar height is not sufficient to relieve all patients' complaints. In addition, the incidence of postoperative complications was high.

Revision surgery for failed medial patellofemoral ligament reconstruction results in better disease-specific outcome scores when performed for recurrent instability than for patellofemoral pain or limited range of motion.

PURPOSE: Medial patellofemoral ligament reconstruction (MPFL-R) is an important treatment for recurrent patellar instability. Although complications such as redislocation, patellofemoral pain (PFP) and restricted knee range of motion have been reported, few studies have investigated the results of revision surgery for failed MPFL-R. Thus, the aim of this study was to determine the results of the tailored revision surgery after considering the cause of the reconstruction failure. MATERIALS AND METHODS: Between 2015 and 2019, 28 patients (male/female 9/19; age 26.2 ± 6.4 years) underwent revision surgery for failed MPFL-R. The patients were grouped into the "recurrent instability" (SG1) group and "PFP" and/or "restricted range of motion" (SG2) group. Preoperatively, the clinical data, anatomical risk factor profile, and position of the femoral MPFL tunnel were determined for each patient. The Banff Patella Instability Instrument 2.0 (BPII 2.0) and numerical analogue scale (NAS 0-10) were administered preoperatively and at the final follow-up for the subjective assessment of the PFP and knee joint function. RESULTS: Overall, the BPII 2.0 score improved from 28.8 ± 16.6 points preoperatively to 68.0 ± 22.7 points (p < 0.0001) postoperatively. SG1 exhibited an increase in the BPII 2.0 score from 28.9 ± 20.2 points to 75.7 ± 23 points (p < 0.0001). PFP decreased from 6.8 ± 2.4 to 1.6 ± 1.9 (p < 0.0001), while the knee joint function increased from 4.3 ± 2.5 to 8.8 ± 1.6 (p < 0.0001). In SG2, the BPII 2.0 score increased from 28.7 ± 12.6 points preoperatively to 57.7 ± 19.7 points (p = 0.0002) postoperatively and was thus significantly lower than that in SG1 (p = 0.038). The intensity of PFP decreased from 6.6 ± 3.0 preoperatively to 2.1 ± 1.9 postoperatively (p = 0.0006), while the subjective knee joint function improved from 3.2 ± 1.4 preoperatively to 7.6 ± 2.3 postoperatively (p < 0.0001). The differences between the groups were not significant. CONCLUSION: Tailored revision surgery for failed MPFL-R significantly improves the patient-reported disease-specific quality of life. The study results indicate that patients undergoing revision surgery as a consequence of patellar redislocation appear to benefit more from revision surgery than those patients undergoing revision due to postoperative PFP and/or a limited knee joint range of motion. LEVEL OF EVIDENCE: Level IV.

Quantum propensities in the brain cortex and free will.

Capacity of conscious agents to perform genuine choices among future alternatives is a prerequisite for moral responsibility. Determinism that pervades classical physics, however, forbids free will, undermines the foundations of ethics, and precludes meaningful quantification of personal biases. To resolve that impasse, we utilize the characteristic indeterminism of quantum physics and derive a quantitative measure for the amount of free will manifested by the brain cortical network. The interaction between the central nervous system and the surrounding environment is shown to perform a quantum measurement upon the neural constituents, which actualize a single measurement outcome selected from the resulting quantum probability distribution. Inherent biases in the quantum propensities for alternative physical outcomes provide varying amounts of free will, which can be quantified with the expected information gain from learning the actual course of action chosen by the nervous system. For example, neuronal electric spikes evoke deterministic synaptic vesicle release in the synapses of sensory or somatomotor pathways, with no free will manifested. In cortical synapses, however, vesicle release is triggered indeterministically with probability of 0.35 per spike. This grants the brain cortex, with its over 100 trillion synapses, an amount of free will exceeding 96 terabytes per second. Although reliable deterministic transmission of sensory or somatomotor information ensures robust adaptation of animals to their physical environment, unpredictability of behavioral responses initiated by decisions made by the brain cortex is evolutionary advantageous for avoiding predators. Thus, free will may have a survival value and could be optimized through natural selection.

Characterization of the public transit air microbiome and resistome reveals geographical specificity.

BACKGROUND: The public transit is a built environment with high occupant density across the globe, and identifying factors shaping public transit air microbiomes will help design strategies to minimize the transmission of pathogens. However, the majority of microbiome works dedicated to the public transit air are limited to amplicon sequencing, and our knowledge regarding the functional potentials and the repertoire of resistance genes (i.e. resistome) is limited. Furthermore, current air microbiome investigations on public transit systems are focused on single cities, and a multi-city assessment of the public transit air microbiome will allow a greater understanding of whether and how broad environmental, building, and anthropogenic factors shape the public transit air microbiome in an international scale. Therefore, in this study, the public transit air microbiomes and resistomes of six cities across three continents (Denver, Hong Kong, London, New York City, Oslo, Stockholm) were characterized. RESULTS: City was the sole factor associated with public transit air microbiome differences, with diverse taxa identified as drivers for geography-associated functional potentials, concomitant with geographical differences in species- and strain-level inferred growth profiles. Related bacterial strains differed among cities in genes encoding resistance, transposase, and other functions. Sourcetracking estimated that human skin, soil, and wastewater were major presumptive resistome sources of public transit air, and adjacent public transit surfaces may also be considered presumptive sources. Large proportions of detected resistance genes were co-located with mobile genetic elements including plasmids. Biosynthetic gene clusters and city-unique coding sequences were found in the metagenome-assembled genomes. CONCLUSIONS: Overall, geographical specificity transcends multiple aspects of the public transit air microbiome, and future efforts on a global scale are warranted to increase our understanding of factors shaping the microbiome of this unique built environment.

Virtual Reality for Neurorehabilitation and Cognitive Enhancement.

Our access to computer-generated worlds changes the way we feel, how we think, and how we solve problems. In this review, we explore the utility of different types of virtual reality, immersive or non-immersive, for providing controllable, safe environments that enable individual training, neurorehabilitation, or even replacement of lost functions. The neurobiological effects of virtual reality on neuronal plasticity have been shown to result in increased cortical gray matter volumes, higher concentration of electroencephalographic beta-waves, and enhanced cognitive performance. Clinical application of virtual reality is aided by innovative brain-computer interfaces, which allow direct tapping into the electric activity generated by different brain cortical areas for precise voluntary control of connected robotic devices. Virtual reality is also valuable to healthy individuals as a narrative medium for redesigning their individual stories in an integrative process of self-improvement and personal development. Future upgrades of virtual reality-based technologies promise to help humans transcend the limitations of their biological bodies and augment their capacity to mold physical reality to better meet the needs of a globalized world.

Computational capacity of pyramidal neurons in the cerebral cortex.

The electric activities of cortical pyramidal neurons are supported by structurally stable, morphologically complex axo-dendritic trees. Anatomical differences between axons and dendrites in regard to their length or caliber reflect the underlying functional specializations, for input or output of neural information, respectively. For a proper assessment of the computational capacity of pyramidal neurons, we have analyzed an extensive dataset of three-dimensional digital reconstructions from the NeuroMorpho.Org database, and quantified basic dendritic or axonal morphometric measures in different regions and layers of the mouse, rat or human cerebral cortex. Physical estimates of the total number and type of ions involved in neuronal electric spiking based on the obtained morphometric data, combined with energetics of neurotransmitter release and signaling fueled by glucose consumed by the active brain, support highly efficient cerebral computation performed at the thermodynamically allowed Landauer limit for implementation of irreversible logical operations. Individual proton tunneling events in voltage-sensing S4 protein α-helices of Na+, K+ or Ca2+ ion channels are ideally suited to serve as single Landauer elementary logical operations that are then amplified by selective ionic currents traversing the open channel pores. This miniaturization of computational gating allows the execution of over 1.2 zetta logical operations per second in the human cerebral cortex without combusting the brain by the released heat.

Quantum information theoretic approach to the mind-brain problem.

The brain is composed of electrically excitable neuronal networks regulated by the activity of voltage-gated ion channels. Further portraying the molecular composition of the brain, however, will not reveal anything remotely reminiscent of a feeling, a sensation or a conscious experience. In classical physics, addressing the mind-brain problem is a formidable task because no physical mechanism is able to explain how the brain generates the unobservable, inner psychological world of conscious experiences and how in turn those conscious experiences steer the underlying brain processes toward desired behavior. Yet, this setback does not establish that consciousness is non-physical. Modern quantum physics affirms the interplay between two types of physical entities in Hilbert space: unobservable quantum states, which are vectors describing what exists in the physical world, and quantum observables, which are operators describing what can be observed in quantum measurements. Quantum no-go theorems further provide a framework for studying quantum brain dynamics, which has to be governed by a physically admissible Hamiltonian. Comprising consciousness of unobservable quantum information integrated in quantum brain states explains the origin of the inner privacy of conscious experiences and revisits the dynamic timescale of conscious processes to picosecond conformational transitions of neural biomolecules. The observable brain is then an objective construction created from classical bits of information, which are bound by Holevo's theorem, and obtained through the measurement of quantum brain observables. Thus, quantum information theory clarifies the distinction between the unobservable mind and the observable brain, and supports a solid physical foundation for consciousness research.

Inner privacy of conscious experiences and quantum information.

The human mind is constituted by inner, subjective, private, first-person conscious experiences that cannot be measured with physical devices or observed from an external, objective, public, third-person perspective. The qualitative, phenomenal nature of conscious experiences also cannot be communicated to others in the form of a message composed of classical bits of information. Because in a classical world everything physical is observable and communicable, it is a daunting task to explain how an empirically unobservable, incommunicable consciousness could have any physical substrates such as neurons composed of biochemical molecules, water, and electrolytes. The challenges encountered by classical physics are exemplified by a number of thought experiments including the inverted qualia argument, the private language argument, the beetle in the box argument and the knowledge argument. These thought experiments, however, do not imply that our consciousness is nonphysical and our introspective conscious testimonies are untrustworthy. The principles of classical physics have been superseded by modern quantum physics, which contains two fundamentally different kinds of physical objects: unobservable quantum state vectors, which define what physically exists, and quantum operators (observables), which define what can physically be observed. Identifying consciousness with the unobservable quantum information contained by quantum physical brain states allows for application of quantum information theorems to resolve possible paradoxes created by the inner privacy of conscious experiences, and explains how the observable brain is constructed by accessible bits of classical information that are bound by Holevo's theorem and extracted from the physically existing quantum brain upon measurement with physical devices.

Challenges in the value assessment, pricing and funding of targeted combination therapies in oncology.

BACKGROUND: The use of targeted combination therapy (TCT) is becoming the standard of care in oncology as cancers are attacked through multiple inhibition mechanisms. TCTs pose a budget challenge to health systems and an economic return challenge for companies developing them. METHODS: We conducted a systematic literature review to identify challenges specific to TCTs and reviewed publicly available reports by health technology assessment and pricing and reimbursement bodies. We synthesized our findings into a problem map. RESULTS AND DISCUSSION: Challenges and policy solutions linked to TCTs remain almost fully unexplored; we identified few resources that explicitly addressed TCTs. Contributors to the budget challenge are found at different layers; they and include static willingness-to-pay (WTP) for TCTs and inefficiencies in managing prices of backbone therapies. Economic return challenges are related to payer-imposed restrictions, peculiarities of TCT development, and conflicting incentives of pharmaceutical companies that own constituent therapies. Consequences are delayed or restricted patient access to TCTs, disincentives for research and development, and fewer life years gained. CONCLUSIONS: Multiple issues will lead to the unsustainability of funding systems and possible conflict between stakeholders around access to TCTs. To manage these, new value assessment and attribution methodologies, modified trial designs and differentiated WTP thresholds can be considered in ways that are customized to the characteristics of different health systems.

The quantum physics of synaptic communication via the SNARE protein complex.

Twenty five years ago, Sir John Carew Eccles together with Friedrich Beck proposed a quantum mechanical model of neurotransmitter release at synapses in the human cerebral cortex. The model endorsed causal influence of human consciousness upon the functioning of synapses in the brain through quantum tunneling of unidentified quasiparticles that trigger the exocytosis of synaptic vesicles, thereby initiating the transmission of information from the presynaptic towards the postsynaptic neuron. Here, we provide a molecular upgrade of the Beck and Eccles model by identifying the quantum quasiparticles as Davydov solitons that twist the protein α-helices and trigger exocytosis of synaptic vesicles through helical zipping of the SNARE protein complex. We also calculate the observable probabilities for exocytosis based on the mass of this quasiparticle, along with the characteristics of the potential energy barrier through which tunneling is necessary. We further review the current experimental evidence in support of this novel bio-molecular model as presented.

Comparison of NITAG policies and working processes in selected developed countries.

BACKGROUND: Vaccines are specific medicines characterized by two country-specific market access processes: (1) a recommendation by National Immunization Technical Advisory Group (NITAG), and (2) a funding policy decision. OBJECTIVES: The objective of this study was to compare and analyze NITAGs of 13 developed countries by describing vaccination committees' bodies and working processes. METHODS: Information about NITAGs bodies and working processes was searched from official sources from June 2011 to November 2012. Retrieved information was completed from relevant articles identified through a systematic literature review and by information provided by direct contact with NITAGs or parent organizations. An expert panel was also conducted to discuss, validate, and provide additional input on obtained results. RESULTS: While complete information, defined as 100%, was retrieved only for the UK, at least 80% of data was retrieved for 9 countries out of the 13 selected countries. Terms of references were identified in 7 countries, and the main mission for all NITAGs was to provide advice for National immunization programs. However, these terms of references did not fully encompass all the actual missions of the NITAGs. Decision analysis frameworks were identified for 10 out of the 13, and all NITAGs considered at least four criteria for decision-making: disease burden, efficacy/effectiveness, safety and cost-effectiveness. Advices were published by most NITAGs, but few NITAGs published meeting agendas and minutes. Only the United States had open meetings. CONCLUSIONS: This study supports previous findings about the disparities in NITAGs processes which could potentially explain the disparity in access to vaccinations and immunization programs across Europe. With NITAGs recommendations being used by policy decision makers for implementation and funding of vaccine programs, guidances should be well-informed and transparent to ensure National Immunization Programs' (NIP) credibility among the public and health care professionals.

Promotion of neuronal differentiation through activation of N-methyl-D-aspartate receptors transiently expressed by undifferentiated neural progenitor cells in fetal rat neocortex.

Neural progenitor cell is a generic term for undifferentiated cell populations composed of neural stem, neuronal progenitor, and glial progenitor cells with abilities for self-renewal and multipotentiality. In this study, we have attempted to evaluate the possible functional expression of N-methyl-D-aspartate (NMDA) receptors by neural progenitor cells prepared from neocortex of 18-day-old embryonic rats. Cells were cultured in the presence of basic fibroblast growth factor (bFGF) for different periods up to 12 days under floating conditions. Reverse transcription-polymerase chain reaction and fluorescence imaging analyses revealed transient expression of functional NMDA receptors in neurospheres formed by clustered progenitors during the culture with bFGF. A similarly potent increase was seen in the fluorescence intensity after brief exposure to NMDA in cells differentiated after the removal of bFGF under adherent conditions, and an NMDA receptor antagonist invariably prevented these increases by NMDA. Moreover, sustained exposure to NMDA not only inhibited the formation of neurospheres when exposed for 10 days from day 2 to day 12 but also promoted spontaneous and induced differentiation of neurospheres to cells immunoreactive for a neuronal marker protein on immunocytochemistry and Western blotting analyses. These results suggest that functional NMDA receptors may be transiently expressed to play a role in mechanisms underlying the modulation of proliferation along with the determination of subsequent differentiation fate toward a neuronal lineage in neural progenitor cells of developing rat neocortex.

Insensitivity to glutamate neurotoxicity mediated by NMDA receptors in association with delayed mitochondrial membrane potential disruption in cultured rat cortical neurons.

We have attempted to elucidate mechanisms underlying differential vulnerability to glutamate (Glu) using cultured neurons prepared from discrete structures of embryonic rat brains. Brief exposure to Glu led to a significant decrease in the mitochondrial activity in hippocampal neurons cultured for 9 or 12 days at 10 muM to 1 mM with an apoptosis-like profile, without markedly affecting that in cortical neurons. Brief exposure to Glu also increased lactate dehydrogenase release along with a marked decrease in the number of cells immunoreactive for a neuronal marker protein in hippocampal, but not cortical, neurons. Similar insensitivity was seen to the cytotoxicity by NMDA, but not to that by tunicamycin, 2,4-dinitrophenol, hydrogen peroxide or A23187, in cortical neurons. However, NMDA was more efficient in increasing intracellular free Ca2+ levels in cortical neurons than in hippocampal neurons. Antagonists for neuroprotective metabotropic Glu receptors failed to significantly affect the insensitivity to Glu, while NMDA was more effective in disrupting mitochondrial membrane potentials in hippocampal than cortical neurons. These results suggest that cortical neurons would be insensitive to the apoptotic neurotoxicity mediated by NMDA receptors through a mechanism related to mitochondrial membrane potentials, rather than intracellular free Ca2+ levels, in the rat brain.