Hierarchies of description enable understanding of cognitive phenomena in terms of neuron activity.

One objective of neuroscience is to understand a wide range of specific cognitive processes in terms of neuron activity. The huge amount of observational data about the brain makes achieving this objective challenging. Different models on different levels of detail provide some insight, but the relationship between models on different levels is not clear. Complex computing systems with trillions of components like transistors are fully understood in the sense that system features can be precisely related to transistor activity. Such understanding could not involve a designer simultaneously thinking about the ongoing activity of all the components active in the course of carrying out some system feature. Brain modeling approaches like dynamical systems are inadequate to support understanding of computing systems, because their use relies on approximations like treating all components as more or less identical. Understanding computing systems needs a much more sophisticated use of approximation, involving creation of hierarchies of description in which the higher levels are more approximate, with effective translation between different levels in the hierarchy made possible by using the same general types of information processes on every level. These types are instruction and data read/write. There are no direct resemblances between computers and brains, but natural selection pressures have resulted in brain resources being organized into modular hierarchies and in the existence of two general types of information processes called condition definition/detection and behavioral recommendation. As a result, it is possible to create hierarchies of description linking cognitive phenomena to neuron activity, analogous with but qualitatively different from the hierarchies of description used to understand computing systems. An intuitively satisfying understanding of cognitive processes in terms of more detailed brain activity is then possible.

Leveraging conscious and nonconscious learning for efficient AI.

Various interpretations of the literature detailing the neural basis of learning have in part led to disagreements concerning how consciousness arises. Further, artificial learning model design has suffered in replicating intelligence as it occurs in the human brain. Here, we present a novel learning model, which we term the "Recommendation Architecture (RA) Model" from prior theoretical works proposed by Coward, using a dual-learning approach featuring both consequence feedback and non-consequence feedback. The RA model is tested on a categorical learning task where no two inputs are the same throughout training and/or testing. We compare this to three consequence feedback only models based on backpropagation and reinforcement learning. Results indicate that the RA model learns novelty more efficiently and can accurately return to prior learning after new learning with less computational resources expenditure. The final results of the study show that consequence feedback as interpretation, not creation, of cortical activity creates a learning style more similar to human learning in terms of resource efficiency. Stable information meanings underlie conscious experiences. The work provided here attempts to link the neural basis of nonconscious and conscious learning while providing early results for a learning protocol more similar to human brains than is currently available.

Development and operation of the defence COVID-19 lab as a SARS-CoV-2 diagnostic screening capability for UK military personnel.

BACKGROUND: In the face of the COVID-19 pandemic, the Defence Science and Technology Laboratory (Dstl) and Defence Pathology combined to form the Defence Clinical Lab (DCL), an accredited (ISO/IEC 17025:2017) high-throughput SARS-CoV-2 PCR screening capability for military personnel. LABORATORY STRUCTURE AND RESOURCE: The DCL was modular in organisation, with laboratory modules and supporting functions combining to provide the accredited SARS-CoV-2 (envelope (E)-gene) PCR assay. The DCL was resourced by Dstl scientists and military clinicians and biomedical scientists. LABORATORY RESULTS: Over 12 months of operation, the DCL was open on 289 days and tested over 72 000 samples. Six hundred military SARS-CoV-2-positive results were reported with a median E-gene quantitation cycle (Cq) value of 30.44. The lowest Cq value for a positive result observed was 11.20. Only 64 samples (0.09%) were voided due to assay inhibition after processing started. CONCLUSIONS: Through a sustained effort and despite various operational issues, the collaboration between Dstl scientific expertise and Defence Pathology clinical expertise provided the UK military with an accredited high-throughput SARS-CoV-2 PCR test capability at the height of the COVID-19 pandemic. The DCL helped facilitate military training and operational deployments contributing to the maintenance of UK military capability. In offering a bespoke capability, including features such as testing samples in unit batches and oversight by military consultant microbiologists, the DCL provided additional benefits to the UK Ministry of Defence that were potentially not available from other SARS-CoV-2 PCR laboratories. The links between Dstl and Defence Pathology have also been strengthened, benefitting future research activities and operational responses.

Smoking cessation in elective surgical patients offered free nicotine patches at listing: a pilot study.

Free nicotine patches may promote pre-operative smoking cessation. Smokers (≥ 10 cigarettes.day-1 ) awaiting non-urgent surgery were randomly assigned (3:1) to an offer of free nicotine patches or a control group who were not offered free nicotine patches. The suggested regimen lasted 5 weeks, with patch strength decreasing incrementally after 3 and 4 weeks. The primary outcome was smoking abstinence for ≥ 4 weeks, as self-reported by participants on the day of surgery, including, where possible, corroboration using exhaled carbon monoxide testing. Out of 600 included smokers, 447 (74.5%) were randomly assigned to an offer of pre-operative nicotine patches, with 175 (39.1%) of these accepting the offer and 56 (12.5%) using patches for ≥ 3 weeks. Out of 396 participants offered nicotine patches who were included for analysis, 36 (9.1%) quit smoking for ≥ 4 weeks before surgery as compared with 8 (5.9%) controls, OR 1.5 [95%CI 0.7-3.2], p = 0.300. Sixty-three (15.9%) quit smoking for 24 h before surgery as compared with 15 (11.1%) controls, OR 1.4 [95%CI 0.8-2.4], p = 0.200. Participants offered nicotine patches were more likely to engage in a cessation attempt lasting more than 24 h, 46 (11.6%) vs. 5 (3.7%), OR 3.4 [95%CI 1.8-8.8], p = 0.010. Out of 78 participants who quit smoking by the day of surgery and were followed up at 6 months, 46 (59%) had relapsed. Offering free nicotine patches stimulated interest in quitting compared with controls, but our protocol had limited effectiveness.

Using the Change Manager Model for the Hippocampal System to Predict Connectivity and Neurophysiological Parameters in the Perirhinal Cortex.

Theoretical arguments demonstrate that practical considerations, including the needs to limit physiological resources and to learn without interference with prior learning, severely constrain the anatomical architecture of the brain. These arguments identify the hippocampal system as the change manager for the cortex, with the role of selecting the most appropriate locations for cortical receptive field changes at each point in time and driving those changes. This role results in the hippocampal system recording the identities of groups of cortical receptive fields that changed at the same time. These types of records can also be used to reactivate the receptive fields active during individual unique past events, providing mechanisms for episodic memory retrieval. Our theoretical arguments identify the perirhinal cortex as one important focal point both for driving changes and for recording and retrieving episodic memories. The retrieval of episodic memories must not drive unnecessary receptive field changes, and this consideration places strong constraints on neuron properties and connectivity within and between the perirhinal cortex and regular cortex. Hence the model predicts a number of such properties and connectivity. Experimental test of these falsifiable predictions would clarify how change is managed in the cortex and how episodic memories are retrieved.

Locked in and out: a case of emerging basilar artery obstruction secondary to vertebral artery dissection thrombolysed with intravenous rt-PA.

The authors present a case in which intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) potentially saved a young man from locked-in syndrome or life threatening consequences. The patient presented with acute stroke secondary to vertebral artery dissection and was treated with intravenous rt-PA. There were no post thrombolysis complications and the patient left hospital with mild neurological symptoms. Our report suggests that in cases of acute posterior circulation stroke due to arterial dissection, treatment with intravenous thrombolysis is safe, practicable and effective.

The hippocampal system as the cortical resource manager: a model connecting psychology, anatomy and physiology.

A model is described in which the hippocampal system functions as resource manager for the neocortex. This model is developed from an architectural concept for the brain as a whole within which the receptive fields of neocortical columns can gradually expand but with some limited exceptions tend not to contract. The definition process for receptive fields is constrained so that they overlap as little as possible, and change as little as possible, but at least a minimum number of columns detect their fields within every sensory input state. Below this minimum, the receptive fields of some columns are expanded slightly until the minimum level is reached. The columns in which this expansion occurs are selected by a competitive process in the hippocampal system that identifies those in which only a relatively small expansion is required, and sends signals to those columns that trigger the expansion. These expansions in receptive fields are the information record that forms the declarative memory of the input state. Episodic memory activates a set of columns in which receptive fields expanded simultaneously at some point in the past, and the hippocampal system is therefore the appropriate source for information guiding access to such memories. Semantic memory associates columns that are often active (with or without expansions in receptive fields) simultaneously. Initially, the hippocampus can guide access to such memories on the basis of initial information recording, but to avoid corruption of the information needed for ongoing resource management, access control shifts to other parts of the neocortex. The roles of the mammillary bodies, amygdala and anterior thalamic nucleus can be understood as modulating information recording in accordance with various behavioral priorities. During sleep, provisional physical connectivity is created that supports receptive field expansions in the subsequent wake period, but previously created memories are not affected. This model matches a wide range of neuropsychological observation better than alternative hippocampal models. The information mechanisms required by the model are consistent with known brain anatomy and neuron physiology.

Hierarchical approaches to understanding consciousness.

There has been much discussion on what a scientific theory of consciousness would look like, and even whether such a theory is possible. Some common misunderstandings of the nature of theories (e.g., in the physical sciences) have confused the discussion of theories concerning consciousness. Theories in the physical sciences establish hierarchies of descriptions that relate high-level descriptions of macro-level phenomena to detailed-level descriptions at a micro level. Detailed descriptions are usually more accurate but information-dense and therefore often beyond human comprehensibility (unless limited to tiny segments of a macro-level phenomenon). High-level descriptions are usually much less information-dense but more approximate. The ability to map between levels of description, and in particular the understanding of when a shift from a higher-level to a more detailed description is needed to achieve a desired degree of accuracy, is fundamental to an effective theory in any field. The form of such a theory of consciousness is sketched, and the limitations of some alternative approaches described.

Quantitative determination of apogossypol, a pro-apoptotic analog of gossypol, in mouse plasma using LC/MS/MS.

A simple and selective liquid chromatography/tandem mass spectrometry (LC/MS/MS) method based on internal standard quantitation using apigenin as the internal standard has been developed and validated for the analysis of the gossypol analog apogossypol, a pro-apoptotic compound, in mouse plasma. The methodology involves protein precipitation of plasma samples followed by LC/MS/MS analysis. Ascorbic acid was added to the spiking solutions and plasma samples to stabilize the easily oxidized compound. Separation of apogossypol and the internal standard from the plasma matrix was achieved using a C18 column with a gradient elution profile consisting of 5mM ammonium acetate and methanol. The validated range of the method extended from 10 to 2000 ng/mL with accuracies of 85-115% and precision of <15%. The average recovery of apogossypol at three concentrations (50, 200 and 1000 ng/mL) assayed in triplicate using this methodology was determined to be 90.8+/-12.9%. Recovery for the internal standard (apigenin) at a concentration of 500 ng/mL was found to be 99.9+/-6.41%. Apogossypol concentrations of 50 ng/mL and above were found to be stable in extracted plasma for 24h when stored at 25 degrees C. This method has been applied to the determination of apogossypol concentrations in plasma collected from mice given an IV dose of apogossypol.

Cerebral microbleeds are common in ischemic stroke but rare in TIA.

BACKGROUND: In patients with stroke, gradient-echo MRI commonly detects microbleeds, indicating small artery disease with increased risk of macroscopic intracranial bleeding. Antithrombotic treatments are frequently prescribed after TIA and stroke, but there have been no previous studies of microbleeds in TIA. Because microbleeds may predict the hemorrhagic risk of antithrombotic treatments, we studied the prevalence of microbleeds, risk factors, and pathophysiologic mechanisms in patients with ischemic stroke and TIA. METHODS: One hundred twenty-nine consecutive patients with ischemic stroke or TIA were studied with MRI including T2, fluid-attenuated inversion recovery, and gradient-echo MRI sequences. Blinded observers counted microbleeds and graded white matter T2 hyperintensities throughout the brain. TIA patients with previous ischemic stroke were excluded. RESULTS: Sixty-seven percent of patients had ischemic stroke; 33% had TIA. Microbleeds were found in 23% of ischemic stroke patients but only 2% of TIA patients (p < 0.001). There were no significant differences in conventional risk factors or the severity of white matter disease on T2 MRI between stroke and TIA patients. Patients with microbleeds were more often hypertensive (81 vs 59%; p = 0.04) and had more severe MRI white matter disease on T2 MRI (p = 0.003). CONCLUSIONS: Microbleeds are common in ischemic stroke but rare in TIA, an observation not explained by differences in vascular risk factors or severity of white matter disease seen on T2 MRI. This finding has implications for the safety of antithrombotic therapy and clinical trial design in the two groups. Microbleeds may also be a new marker for severe microvascular pathology with increased risk of permanent cerebral infarction.

Percutaneous transluminal angioplasty and stenting for vertebral artery stenosis.

BACKGROUND: Surgery for vertebral artery stenosis is technically difficult, potentially hazardous and is not considered in most centres. There is growing evidence from case series that vertebral artery stenosis may be treated endovascularly by percutaneous transluminal angioplasty and stenting. This may be a feasible alternative to surgery to relieve symptoms caused by significant stenosis. OBJECTIVES: The objective of this review was to assess the safety and efficacy of vertebral artery percutaneous transluminal angioplasty, with or without stenting, combined with medical care, compared to medical care alone, in patients with vertebral artery stenosis. SEARCH STRATEGY: We searched the Cochrane Stroke Group's trials register (last searched 28 July 2004). In addition we searched the following bibliographic databases: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to July 2004), EMBASE (1980 to July 2004), and Science Citation Index (1981 to July 2004). We also contacted researchers in the field, and balloon catheter and stent manufacturers. SELECTION CRITERIA: We selected randomised trials of endovascular treatment of vertebral artery stenosis combined with best medical therapy, compared with best medical therapy alone, in patients with symptomatic or asymptomatic vertebral artery stenosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, extracted data and assessed trial quality. MAIN RESULTS: One completed randomised trial was found. In one subgroup of this trial, 16 patients with symptomatic severe vertebral artery stenosis were randomised to endovascular treatment (n = 8) or medical treatment alone (n = 8). There were no strokes in any arterial territory or deaths from any cause in either group within 30 days of treatment (endovascular group) or 30 days of randomisation (medical group). In the endovascular group, two patients had a posterior circulation TIA at the time of the procedure. In the endovascular group, the mean vessel stenosis at follow up was 47% (range 0% to 80%). Patients were followed up for a mean of 4.5 years in the endovascular group and 4.9 years in the medical group. There were no further vertebrobasilar territory strokes in either group for the duration of follow up. Morbidity and mortality was related to carotid and coronary artery disease in this study. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to assess the effects of percutaneous transluminal angioplasty with or without stenting or primary stenting for vertebral artery stenosis.

Criteria for an effective theory of consciousness and some preliminary attempts.

In the physical sciences a rigorous theory is a hierarchy of descriptions in which causal relationships between many general types of entity at a phenomenological level can be derived from causal relationships between smaller numbers of simpler entities at more detailed levels. The hierarchy of descriptions resembles the modular hierarchy created in electronic systems in order to be able to modify a complex functionality without excessive side effects. Such a hierarchy would make it possible to establish a rigorous scientific theory of consciousness. The causal relationships implicit in definitions of access consciousness and phenomenal consciousness are made explicit, and the corresponding causal relationships at the more detailed levels of perception, memory, and skill learning described. Extension of these causal relationships to physiological and neural levels is discussed. The general capability of a range of current consciousness models to support a modular hierarchy which could generate these causal relationships is reviewed, and the specific capabilities of two models with good general capabilities are compared in some detail.

Percutaneous transluminal angioplasty and stenting for carotid artery stenosis.

BACKGROUND: Carotid artery stenosis may be treated endovascularly by percutaneous transluminal balloon angioplasty with or without stent insertion or by primary stenting. Endovascular treatment may be a useful alternative to carotid endarterectomy (CEA), particularly for lesions not suitable for surgery. OBJECTIVES: The objective of this review was to assess the benefits and risks of endovascular treatments compared with carotid endarterectomy (in patients suitable for surgery) or medical therapy (in patients not suitable for surgery). SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched 1 September 2003). In addition we searched the following bibliographic databases: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to June 2003), EMBASE (1980 to June 2003) and Science Citation Index (1981 to June 2003). We also contacted researchers in the field and balloon catheter and stent manufacturers. SELECTION CRITERIA: We selected randomised trials of carotid endovascular treatment compared with carotid endarterectomy, or endovascular treatment plus best medical therapy compared with best medical therapy alone, in patients with symptomatic or asymptomatic carotid artery stenosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, extracted data and assessed trial quality. MAIN RESULTS: Two completed trials comparing endovascular treatment with carotid endarterectomy involving 608 patients were found. In addition there were two trials which fulfilled the inclusion criteria and which were stopped early (242 patients), and a third trial which has completed randomisation and 30 day follow up of 307 patients. Four trials are ongoing. Meta analysis of the data from the included studies found no significant difference between the odds of death or any stroke at 30 days post procedure (Odds Ratio [OR] endovascular:surgery 1.26, 95% Confidence Interval [CI] 0.82 to 1.94). The odds of death or disabling stroke at 30 days were similar in the endovascular and surgical group (OR 1.22, CI 0.61 to 2.41). At one year following procedure, there was no significant difference between the two groups in preventing any stroke or death (OR 1.36,CI 0.87 to 2.13). Endovascular treatment significantly reduced the risk of cranial neuropathy (OR 0.12, CI 0.06 to 0.25). There was no significant difference between the two groups when the risk of death, any stroke or myocardial infarction was considered (OR 0.99, CI 0.66 to 1.48). There was substantial heterogeneity between the trials for four of the five outcomes. REVIEWERS' CONCLUSIONS: Data from randomised trials comparing endovascular treatment for carotid artery stenosis with carotid endarterectomy suggest that the two treatments have similar early risks of death or stroke and similar long term benefits. However, the substantial heterogeneity renders the overall estimates of effect somewhat unreliable. Furthermore, two trials were stopped early because of safety concerns, so perhaps leading to an over-estimate of the risks of endovascular treatment. On the other hand, endovascular treatment appears to avoid completely the risk of cranial neuropathy. There is also uncertainty about the potential for restenosis to develop and cause recurrent stroke after endovascular treatment. The current evidence does not support a widespread change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis. There is a strong case to continue recruitment in the current randomised trials comparing carotid stenting with endarterectomy.

Brain stem encephalitis caused by primary herpes simplex 2 infection in a young woman.

A 27 year old woman developed a vesicular genital rash and cerebellar dysfunction with progressive neurological deterioration suggesting brain stem encephalitis. Respiratory support was required. Magnetic resonance imaging (MRI) of the brain on day 7 showed signal hyperintensity in the central medulla and ventral pons, typical of acute inflammation. The course was severe and relapse occurred. MRI on day 33 showed a haemorrhagic area in the medulla. Treatment with aciclovir/valaciclovir eventually led to gradual recovery. Herpes simplex virus 2 (HSV-2) DNA was detected in CSF on days 11 and 14. HSV-2 was also detected in vesicle fluid from the genital rash. Serum was initially negative for HSV-1 and HSV-2 antibodies, but convalescent samples showed seroconversion to HSV-2, indicating primary infection. Intrathecal synthesis of oligoclonal IgG bands specific for HSV was identified in the CSF. It is important to differentiate HSV-2 from HSV-1, and primary from initial or reactivated infection, so that prolonged aciclovir treatment followed by prophylaxis is instituted to prevent the high likelihood of symptomatic relapse in primary HSV-2 infection.

Developmental lessons of seasoned marital and family therapists: a qualitative investigation.

Little has been published regarding the development of therapists during their professional careers. This qualitative research study explored the development of seasoned marriage and family therapists (MFTs) in order to identify important events and themes in their personal and professional lives. The main developmental theme that emerged was the integration of their personal and professional selves. Information gained from this study might be useful in understanding the self of the therapist within training and supervision and might partially provide a map of the possible transitions facing MFTs along their developmental journey.

Hydrogen-deuterium exchange as a probe of folding and assembly in viral capsids.

The dynamics of proteins within large cellular assemblies are important in the molecular transformations that are required for macromolecular synthesis, transport, and metabolism. The capsid expansion (maturation) accompanying DNA packaging in the dsDNA bacteriophage P22 represents an experimentally accessible case of such a transformation. A novel method, based on hydrogen-deuterium exchange was devised to investigate the dynamics of capsid expansion. Mass spectrometric detection of deuterium incorporation allows for a sensitive and quantitative determination of hydrogen-deuterium exchange dynamics irrespective of the size of the assembly. Partial digestion of the exchanged protein with pepsin allows for region-specific assignment of the exchange. Procapsids and mature capsids were probed under native and slightly denaturing conditions. These experiments revealed regions that exhibit different degrees of flexibility in the procapsid and in the mature capsid. In addition, exchange and deuterium trapping during the process of expansion itself was observed and allowed for the identification of segments of the protein subunit that become buried or stabilized as a result of expansion. This approach may help to identify residues participating in macromolecular transformations and uncover novel patterns and hierarchies of interactions that determine functional movements within molecular machines.

Assessing phytoestrogen exposure in epidemiologic studies: development of a database (United States).

BACKGROUND AND OBJECTIVE: Phytoestrogens (weak estrogens found in plants or derived from plant precursors by human metabolism) have been hypothesized to reduce the risk of a number of cancers. However, epidemiologic studies addressing this issue are hampered by the lack of a comprehensive phytoestrogen database for quantifying exposure. The purpose of this research was to develop such a database for use with food-frequency questionnaires in large epidemiologic studies. METHODS: The database is based on consumption patterns derived from semistructured interviews with 118 African-American, Latina, and white women residing in California's San Francisco Bay Area. HPLC-mass spectrometry was used to determine the content of seven specific phytoestrogenic compounds (i.e. the isoflavones: genistein, daidzein, biochanin A, and formononetin; the coumestan: coumestrol; and the plant lignans: matairesinol and secoisolariciresinol) in each of 112 food items/groups. RESULTS: Traditional soy-based foods were found to contain high levels of genistein and daidzein, as expected, as well as substantial amounts of coumestrol. A wide variety of "hidden" sources of soy (that is, soy protein isolate, soy concentrate, or soy flour added to foods) was observed. Several other foods (such as various types of sprouts and dried fruits, garbanzo beans, asparagus, garlic, and licorice) were also found to be substantial contributors of one or more of the phytoestrogens analyzed. CONCLUSIONS: Databases, such as the one described here, are important in assessing the relationship between phytoestrogen exposure and cancer risk in epidemiologic studies. Agencies, such as the United States Department of Agriculture (USDA), that routinely provide data on food composition, on which epidemiologic investigations into dietary health effects are based, should consider instituting programs for the analysis of phytochemicals, including the phytoestrogens.

p-Cresol sulfate is the dominant component of urinary myelin basic protein like material.

Multiple sclerosis (MS) is clinically heterogeneous and has an uncertain natural history. A high priority for more effective treatment of MS is an objective and feasible laboratory test for predicting the disease's course and response to treatments. Urinary myelin basic protein (MBP)-like material (MBPLM), so designated because it is immunoreactive as a cryptic epitope in peptide 83-89 of the human MBP molecule of 170 amino acids, is present in normal adults, remains normal in relapsing-remitting, but increases in progressive MS. In the present investigation, MBPLM was purified from urine and characterized. p-Cresol sulfate is the major component of urinary MBPLM. This conclusion is based on the following: (1) MBPLM and p-cresol sulfate both have a mass of 187 on negative scans by electrospray ionization mass spectrometry, the same fragments on tandem mass spectrometry of 80 (SO(-)(3)) and 107 (methylphenol), and similar profiles on multiple reaction monitoring; (2) (1)H and (13)C nuclear magnetic resonance spectroscopy revealed identical spectra for MBPLM and p-cresol sulfate; (3) purified p-cresol sulfate reacted in parallel with MBP peptide 83-89 in the same radioimmunoassay for MBPLM; and (4) p-cresol sulfate has the same behavior on preparative HPLC columns as urinary MBPLM. The unexpected immunochemical degeneracy permitting a cross-reaction between p-cresol sulfate and a peptide of an encephalitogenic myelin protein is postulated to be based on shared conformational features. The mechanisms by which urinary p-cresol sulfate, possibly derived from tyrosine-SO(4), reflects progressive worsening that is disabling in MS are unknown.