Information-Theoretical Analysis of the Cycle of Creation of Knowledge and Meaning in Brains under Multiple Cognitive Modalities.

It is of great interest to develop advanced sensory technologies allowing non-invasive monitoring of neural correlates of cognitive processing in people performing everyday tasks. A lot of progress has been reported in recent years in this research area using scalp EEG arrays, but the high level of noise in the electrode signals poses a lot of challenges. This study presents results of detailed statistical analysis of experimental data on the cycle of creation of knowledge and meaning in human brains under multiple cognitive modalities. We measure brain dynamics using a HydroCel Geodesic Sensor Net, 128-electrode dense-array electroencephalography (EEG). We compute a pragmatic information (PI) index derived from analytic amplitude and phase, by Hilbert transforming the EEG signals of 20 participants in six modalities, which combine various audiovisual stimuli, leading to different mental states, including relaxed and cognitively engaged conditions. We derive several relevant measures to classify different brain states based on the PI indices. We demonstrate significant differences between engaged brain states that require sensory information processing to create meaning and knowledge for intentional action, and relaxed-meditative brain states with less demand on psychophysiological resources. We also point out that different kinds of meanings may lead to different brain dynamics and behavioral responses.

Analysis of D-amino acids secreted from murine islets of Langerhans using Marfey's reagent and reversed phase LC-MS/MS.

D-amino acids (D-AAs) are important signaling molecules due to their ability to bind ionotropic N-methyl-D-aspartate receptors. D-serine (D-Ser), D-alanine (D-Ala), and D-aspartate (D-Asp) have been found individually in the endocrine portion of the pancreas, the islets of Langerhans, and/or their secretions. However, there has been no report of a comprehensive assessment of D-AAs in islet secretions. To evaluate the release of these compounds, the effectiveness of both 1-(9-fluorenyl)-ethyl chloroformate (FLEC reagent) and 1-fluoro-2,4-dinitrophenyl-5-L-alanine amide (Marfey's reagent, MR) in separation of D/L-AA enantiomeric pairs in islet-specific buffers were evaluated. MR-derivatized D/L AAs showed greater than baseline resolution (Rs ≥ 1.5) of 13 enantiomeric pairs when using a non-linear gradient and an acidic mobile phase system, while FLEC-derivatized AAs exhibited limited resolution on both biphenyl and C18 columns. The optimized MR method yielded highly reproducible separations with retention times less than 1% RSD. Excellent linearity between the analyte concentrations and response (R2 > 0.98) were obtained, with less than 15% RSD for all analyte responses. Most analytes had an LOD at or below 100 nM, except for L-Ala (200 nM). The optimized MR method was used to quantify D-AAs in secretions of 150 murine islets after incubation in 3- and 20-mM glucose. In response to both solutions, D-Ser and D-glutamine were tentatively identified via comparison of retention time and quantifier-to-qualifer ion ratios with standards, and from spiking experiments. Both were secreted in low quantities which did not differ significantly in either low (D-Ser: 44 ± 2 fmol islet-1h-1; D-Gln: 300 ± 100 fmol islet-1h-1) or high (D-Ser: 23 ± 1 fmol islet-1h-1; D-Gln: 120 ± 50 fmol islet-1h-1) glucose across 3 biological replicates. The method developed is robust and can be applied to further examine the release of D-AAs and their potential roles in islet physiology.

Simultaneous monitoring of multiple hormones from human islets of Langerhans using solid-phase extraction-mass spectrometry.

Islets of Langerhans release peptide hormones in controlled amounts and patterns to ensure proper maintenance of blood glucose levels. The overall release of the hormones is shaped by external factors and by autocrine and paracrine interactions occurring within the islets. To better understand what controls the secretion of islet-secreted peptides, and how these processes go awry in diabetes, methods to monitor the release of multiple hormones simultaneously are needed. While antibody-based assays are typically used, they are most often applied to quantification of a single hormone. Mass spectrometry (MS), on the other hand, is well suited for quantifying multiple hormones simultaneously but typically requires time-consuming separation steps with biological samples. In this report, response surface methodology was used to identify a set of optimal solid-phase extraction (SPE) conditions for the islet-secreted peptides, insulin, C-peptide, glucagon, and somatostatin. The optimized SPE method was used with multiple reaction monitoring and isotopically labeled standards to quantify secretion levels. Calibrations were linear from 0.5 to 50 nM with < 15% RSD peak area ratios. A microfluidic system was used to perfuse 30 human islets with different glucose conditions, and fractions were collected every 2 min for SPE-MS analysis. Results showed the release dynamics of the individual peptides, as well as patterns, such as positively and negatively correlated release and oscillations. This rapid SPE-MS method is expected to be useful for examining other peptide and small-molecule secretions from islets and could be applied to a number of other biological systems for investigating cellular communication.

Analysis of Meditation vs. Sensory Engaged Brain States Using Shannon Entropy and Pearson's First Skewness Coefficient Extracted from EEG Data.

It has been proposed that meditative states show different brain dynamics than other more engaged states. It is known that when people sit with closed eyes instead of open eyes, they have different brain dynamics, which may be associated with a combination of deprived sensory input and more relaxed inner psychophysiological and cognitive states. Here, we study such states based on a previously established experimental methodology, with the aid of an electro-encephalography (EEG) array with 128 electrodes. We derived the Shannon Entropy (H) and Pearson's 1st Skewness Coefficient (PSk) from the power spectrum for the modalities of meditation and video watching, including 20 participants, 11 meditators and 9 non-meditators. The discriminating performance of the indices H and PSk was evaluated using Student's t-test. The results demonstrate a statistically significant difference between the mean H and PSk values during meditation and video watch modes. We show that the H index is useful to discriminate between Meditator and Non-Meditator participants during meditation over both the prefrontal and occipital areas, while the PSk index is useful to discriminate Meditators from Non-Meditators based on the prefrontal areas for both meditation and video modes. Moreover, we observe episodes of anti-correlation between the prefrontal and occipital areas during meditation, while there is no evidence for such anticorrelation periods during video watching. We outline directions of future studies incorporating further statistical indices for the characterization of brain states.

Automated cellular stimulation with integrated pneumatic valves and fluidic capacitors.

Microfluidic technologies have proven to be a reliable tool in profiling dynamic insulin secretion from islets of Langerhans. Most of these systems rely on external pressure sources to induce flow, leading to difficulties moving to more elaborate systems. To reduce complexity, a microfluidic system was developed that used a single vacuum source at the outlet to drive fluidic transport of immunoassay reagents and stimulation solutions throughout the device. A downside to this approach is the lack of flow control over the reagents delivered to the islet chamber. To address this challenge, 4-layer pneumatic valves were integrated into the perfusion lines to automate and control the delivery of stimulants; however, it was found that as the valves closed, spikes in the flow would lead to abnormal insulin secretion profiles. Fluidic capacitors were then incorporated after the valves and found to remove the spikes. The combination of the valves and capacitors resulted in automated collection of insulin secretion profiles from single murine islets that were similar to those previously reported in the literature. In the future, these integrated fluidic components may enable more complex channel designs to be used with a relatively simple flow control solution.

Comparison of Design Approaches for Low-Cost Sampling Mechanisms in Open-Source Chemical Instrumentation.

Robotic positioning systems are used in a variety of chemical instruments, primarily for liquid handling purposes, such as autosamplers from vials or well plates. Here, two approaches to the design of open-source autosampler positioning systems for use with 96-well plates are described and compared. The first system, a 3-axis design similar to many low-cost 3D printers that are available on the market, is constructed using an aluminum design and stepper motors. The other system relies upon a series of 3D printed parts to achieve movement with a series of linker arms based on Selective Compliance Assembly Robot Arm (SCARA) design principles. Full printer design files, assembly instructions, software, and user directions are included for both samplers. The positioning precision of the 3-axis system is better than the SCARA mechanism due to finer motor control, albeit with a slightly higher cost of materials. Based on the improved precision of this approach, the 3-axis autosampler system was used to demonstrate the generation of a segmented flow droplet stream from adjacent wells within a 96-well plate.

Utility of low-cost, miniaturized peristaltic and Venturi pumps in droplet microfluidics.

Many laboratory applications utilizing droplet microfluidics rely on precision syringe pumps for flow generation. In this study, the use of an open-source peristaltic pump primarily composed of 3D printed parts and a low-cost commercial Venturi pump are explored for their use as an alternative to syringe pumps for droplet microfluidics. Both devices provided stable flow (<2% RSD) over a range of 1-7 µL/min and high reproducibility in signal intensity at a droplet generation rate around 0.25 Hz (<3% RSD), which are comparable in performance to similar measurements on standard syringe pumps. As a novel flow generation source for microfluidic applications, the use of the miniaturized Venturi pump was also applied to droplet signal monitoring studies used to measure changes in concentration over time, with average signal reproducibility <4% RSD for both single-stream fluorometric and reagent addition colorimetric applications. These low-cost flow methods provide stable flow sufficient for common droplet microfluidic approaches and can be implemented in a wide variety of simple, and potentially portable, analytical measurement devices.

Low-cost and open-source strategies for chemical separations.

In recent years, a trend toward utilizing open access resources for laboratory research has begun. Open-source design strategies for scientific hardware rely upon the use of widely available parts, especially those that can be directly printed using additive manufacturing techniques and electronic components that can be connected to low-cost microcontrollers. Open-source software eliminates the need for expensive commercial licenses and provides the opportunity to design programs for specific needs. In this review, the impact of the "open-source movement" within the field of chemical separations is described, primarily through a comprehensive look at research in this area over the past five years. Topics that are covered include general laboratory equipment, sample preparation techniques, separations-based analysis, detection strategies, electronic system control, and software for data processing. Remaining hurdles and possible opportunities for further adoption of open-source approaches in the context of these separations-related topics are also discussed.

Ketogenic Diet for the Treatment and Prevention of Dementia: A Review.

Dementia (major neurocognitive disorder) is an increasingly common syndrome with a significant burden on patients, caregivers, the health-care system, and the society. The prevalence of dementia will certainly continue to grow as the US population ages. Current treatments for dementia, though, are limited. One proposed nonpharmacologic approach for the delay or prevention of dementia is the use of a ketogenic diet. The ketogenic diet was originally employed to treat refractory epilepsy and has shown promise in many neurologic diseases. It has also gained recent popularity for its weight loss effects. Several preclinical studies have confirmed a benefit of ketosis on cognition and systemic inflammation. Given the renewed emphasis on neuroinflammation as a pathogenic contributor to cognitive decline, and the decreased systemic inflammation observed with the ketogenic diet, it is plausible that this diet may delay, ameliorate, or prevent progression of cognitive decline. Several small human studies have shown benefit on cognition in dementia with a ketogenic diet intervention. Future, large controlled studies are needed to confirm this benefit; however, the ketogenic diet has shown promise in regard to delay or mitigation of symptoms of cognitive decline.

Exercise Time and Intensity: How Much Is Too Much?

The growing prevalence and popularity of interval training necessitate additional guidelines in regard to maximal levels of time and intensity. PURPOSE: To correlate salivary hormones and time in varying heart-rate (HR) zones. The hypothesis was that chronic exercise durations >9% of total exercise time in the >90% maximum HR zone would lead to decreased variation in salivary cortisol concentration after exercise in a 2-bout high-intensity protocol compared with less or more time in this zone. METHODS: A total of 35 healthy adults who regularly exercised for an average of 8 hours per week recorded their HR during every training session for 3 weeks. Later, they completed an experimental day composed of two 30-minute high-intensity interval sessions separated by 4 hours of nonactive recovery. The authors collected saliva samples before, immediately following, and 30 minutes after each exercise session to assess changes in cortisol concentrations. RESULTS: There was a correlation between weekly time training at an intensity >90% maximum HR and the variables associated with overtraining. Salivary cortisol concentration fluctuated less in the participants who exercised in this extreme zone for >40 minutes per week (P < .001). CONCLUSION: Based on the current study data, for individuals who regularly exercise, 4% to 9% total training time above 90% maximum HR is the ideal duration to maximize fitness and minimize symptoms related to overreaching.

Incorporation of Quality and Safety Principles in Maintenance of Certification: A Qualitative Analysis of American Board of Medical Specialties Member Boards.

Maintenance of Certification (MOC) is one way physicians demonstrate to the public that they are competent to deliver safe, high-quality medical care. The authors conducted a qualitative content analysis of information from 24 Member Boards of the American Board of Medical Specialties. A constant comparative approach was used to categorize themes of quality and safety and related concepts. All Boards (24/24) had public websites with formal documents and 23/24 had at least 1 representative respond to a survey. Sixty-three percent (15/24) of Boards had a patient safety requirement, and 96% (23/24) of Boards had a quality improvement requirement. Nearly all Boards incorporate quality improvement and most incorporate patient safety, but their assessment methods and level of inclusion on the topic vary. Sharing methods of incorporating quality and safety among certifying Boards will allow Member Boards to cater to the evolution of the MOC landscape and benefit from other Boards' experiences.

Ultrasonography in Undergraduate Medical Education: A Systematic Review.

OBJECTIVES: The purpose of this study was to conduct a systematic review of the evidence of educational outcomes associated with teaching ultrasonography (US) to medical students. METHODS: A review of databases through 2016 was conducted for research studies that reported data on teaching US to medical students. Each title and abstract were reviewed by teams of 2 independent abstractors to determine whether the article would be ordered for full-text review and subsequently by 2 independent authors for inclusion. Data were abstracted with a form developed a priori by the authors. RESULTS: Ninety-five relevant unique articles were included (of 6936 identified in the databases). Survey data showed that students enjoyed the US courses and desired more US training. Of the studies that assessed US-related knowledge and skill, most of the results were either positive (16 of 25 for knowledge and 24 of 58 for skill) or lacked a control (8 of 25 for knowledge and 27 of 58 for skill). The limited evidence (14 of 95 studies) of the effect of US training on non-US knowledge and skill (eg, anatomy knowledge or physical examination skill) was mixed. CONCLUSIONS: There is ample evidence that students can learn US knowledge and skills and that they enjoy and want US training in medical school. The evidence for the effect of US on external outcomes is limited, and there is insufficient evidence to recommend it for this purpose at this time.

What Every Graduating Resident Needs to Know About Quality Improvement and Patient Safety: A Content Analysis of 26 Sets of ACGME Milestones.

PURPOSE: Quality improvement (QI) and patient safety (PS) are broadly relevant to the practice of medicine, but specialty-specific milestones demonstrate variable expectations for trainee competency in QI/PS. The purpose of this study was to develop a unifying portrait of QI/PS expectations for graduating residents irrespective of specialty. METHOD: Milestones from 26 residency programs representing the 24 member boards of the American Board of Medical Specialties were downloaded from the Accreditation Council for Graduate Medical Education (ACGME) Web site in 2015. A codebook was generated by in-depth reading of all milestone sets by two authors. Using a content analytic approach, milestones were then coded by a single author, with a 25% sample double coded by another author. Descriptive statistics were used to characterize frequency counts. RESULTS: Of 612 total milestones, 249 (40.7%) made mention of QI/PS. A median 10 milestones per specialty (interquartile range, 5.25-11.75) mentioned QI/PS. There were 446 individual references to QI, 423 references to PS, and another 1,065 references to QI/PS-related concepts, including patient-centered care, cost-effective practice, documentation, equity, handoffs and care transitions, and teamwork. QI/PS references reflected expectations about both individual-level practice (531/869; 61.1%) and practice within a health care system (338/869; 38.9%). QI and PS references were linked to all six ACGME core competencies. CONCLUSIONS: Although there is variability in the emphasis placed on QI/PS across specialties, overall, QI/PS is reflected in more than 40% of residency milestones. Graduating residents in all specialties are expected to demonstrate competence in QI, PS, and multiple related concepts.

Regular Cycles of Forward and Backward Signal Propagation in Prefrontal Cortex and in Consciousness.

This paper addresses two fundamental questions: (1) Is it possible to develop mathematical neural network models which can explain and replicate the way in which higher-order capabilities like intelligence, consciousness, optimization, and prediction emerge from the process of learning (Werbos, 1994, 2016a; National Science Foundation, 2008)? and (2) How can we use and test such models in a practical way, to track, to analyze and to model high-frequency (≥ 500 hz) many-channel data from recording the brain, just as econometrics sometimes uses models grounded in the theory of efficient markets to track real-world time-series data (Werbos, 1990)? This paper first reviews some of the prior work addressing question (1), and then reports new work performed in MATLAB analyzing spike-sorted and burst-sorted data on the prefrontal cortex from the Buzsaki lab (Fujisawa et al., 2008, 2015) which is consistent with a regular clock cycle of about 153.4 ms and with regular alternation between a forward pass of network calculations and a backwards pass, as in the general form of the backpropagation algorithm which one of us first developed in the period 1968-1974 (Werbos, 1994, 2006; Anderson and Rosenfeld, 1998). In business and finance, it is well known that adjustments for cycles of the year are essential to accurate prediction of time-series data (Box and Jenkins, 1970); in a similar way, methods for identifying and using regular clock cycles offer large new opportunities in neural time-series analysis. This paper demonstrates a few initial footprints on the large "continent" of this type of neural time-series analysis, and discusses a few of the many further possibilities opened up by this new approach to "decoding" the neural code (Heller et al., 1995).

High Single-dose Vancomycin Loading Is Not Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients.

OBJECTIVE: Vancomycin loading doses are recommended; however, the risk of nephrotoxicity with these doses is unknown. The primary objective of this study was to compare nephrotoxicity in emergency department (ED) sepsis patients who received vancomycin at high doses (>20 mg/kg) versus lower doses (≤20 mg/kg). METHODS: A retrospective cohort study was performed in three academic EDs. Inclusion criteria were age ≥ 18 years, intravenous vancomycin order, and hospital admission. Exclusion criteria were no documented weight, hemodialysis-dependent, and inadequate serum creatinine (SCr) values for the measured outcome. Analyses compared the incidence of nephrotoxicity for patients who received vancomycin at high dose (>20 mg/kg) versus low dose (≤20 mg/kg). RESULTS: A total of 2,131 consecutive patients prescribed vancomycin over 6 months were identified. Of these, 1,330 patients had three SCr values assessed for the primary outcome. High-dose initial vancomycin was associated with a significantly lower rate of nephrotoxicity (5.8% vs. 11.1%). After age, sex, and initial SCr were adjusted for, the risk of high-dose vancomycin compared to low-dose was decreased for the development of nephrotoxicity (relative risk = 0.60; 95% confidence interval = 0.44 to 0.82). CONCLUSION: Initial dosing of vancomycin > 20 mg/kg was not associated with an increased rate of nephrotoxicity compared with lower doses. Findings from this study support compliance with initial weight-based vancomycin loading doses.

Addressing the mandate for hand-off education: a focused review and recommendations for anesthesia resident curriculum development and evaluation.

The Accreditation Council for Graduate Medical Education requires that residency programs teach residents about handoffs and ensure their competence in this communication skill. Development of hand-off curricula for anesthesia residency programs is hindered by the paucity of evidence regarding how to conduct, teach, and evaluate handoffs in the various settings where anesthesia practitioners work. This narrative review draws from literature in anesthesia and other disciplines to provide recommendations for anesthesia resident hand-off curriculum development and evaluation.