Reduced-Dimension, Biophysical Neuron Models Constructed From Observed Data.

Using methods from nonlinear dynamics and interpolation techniques from applied mathematics, we show how to use data alone to construct discrete time dynamical rules that forecast observed neuron properties. These data may come from simulations of a Hodgkin-Huxley (HH) neuron model or from laboratory current clamp experiments. In each case, the reduced-dimension, data-driven forecasting (DDF) models are shown to predict accurately for times after the training period. When the available observations for neuron preparations are, for example, membrane voltage V(t) only, we use the technique of time delay embedding from nonlinear dynamics to generate an appropriate space in which the full dynamics can be realized. The DDF constructions are reduced-dimension models relative to HH models as they are built on and forecast only observables such as V(t). They do not require detailed specification of ion channels, their gating variables, and the many parameters that accompany an HH model for laboratory measurements, yet all of this important information is encoded in the DDF model. As the DDF models use and forecast only voltage data, they can be used in building networks with biophysical connections. Both gap junction connections and ligand gated synaptic connections among neurons involve presynaptic voltages and induce postsynaptic voltage response. Biophysically based DDF neuron models can replace other reduced-dimension neuron models, say, of the integrate-and-fire type, in developing and analyzing large networks of neurons. When one does have detailed HH model neurons for network components, a reduced-dimension DDF realization of the HH voltage dynamics may be used in network computations to achieve computational efficiency and the exploration of larger biological networks.

Reducing Imaging Utilization in Primary Care Through Implementation of a Peer Comparison Dashboard.

BACKGROUND: High clinical variation has been linked to decreased quality of care, increased costs, and decreased patient satisfaction. We present the implementation and analysis of a peer comparison intervention to reduce clinical variation within a large primary care network. OBJECTIVE: Evaluate existing variation in radiology ordering within a primary care network and determine whether peer comparison feedback reduces variation or changes practice patterns. DESIGN: Radiology ordering data was analyzed to evaluate baseline variation in imaging rates. A utilization dashboard was shared monthly with providers for a year, and imaging rates pre- and post-intervention were retrospectively analyzed. PARTICIPANTS: Providers within the primary care network spanning 1,358,644 outpatient encounters and 159 providers over a 3-year period. INTERVENTIONS: The inclusion of radiology utilization data as part of a provider's monthly quality and productivity dashboards. This information allows providers to compare their practice patterns with those of their colleagues. MAIN MEASURES: We measured provider imaging rates, stratified by modality, as well as order variation over time. KEY RESULTS: We observed significant variation in imaging rates among providers in the network, with the top decile ordering an average of 4.2 times more than the lowest decile in the two years prior to intervention. Provider experience and training were not significantly associated with imaging utilization. In the first year after sharing utilization data with providers, we saw a 17.3% decrease in median imaging rate (p < 0.001) and a 21.4% reduction in provider variation between top and bottom deciles. Median ordering rate for more costly cross-sectional imaging, including CT, MRI, and nuclear medicine studies, decreased by 30.4% (p < 0.001), 20.2% (p = 0.008), and 41.8% (p = 0.002), respectively. CONCLUSIONS: Peer comparison feedback can shape provider imaging behavior even in the absence of targets or financial incentives. Peer comparison is a low-touch, low-cost intervention for influencing provider ordering and may have applicability in other clinical areas.

Vaping and E-Cigarette Use in Children and Adolescents: Implications on Perioperative Care From the American Society of Anesthesiologists Committee on Pediatric Anesthesia, Society for Pediatric Anesthesia, and American Academy of Pediatrics Section on Anesthesiology and Pain Medicine.

Electronic cigarettes (e-cigarettes) or vaping use in adolescents has emerged as a public health crisis that impacts the perioperative care of this vulnerable population. E-cigarettes have become the most commonly used tobacco products among youth in the United States. Fruit and mint flavors and additives such as marijuana have enticed children and adolescents. E-cigarette, or vaping, product use-associated lung injury (EVALI) is a newly identified lung disease linked to vaping. Clinical presentation of EVALI can be varied, but most commonly includes the respiratory system, gastrointestinal (GI) tract, and constitutional symptoms. Clinical management of EVALI has consisted of vaping cessation and supportive therapy, including supplemental oxygen, noninvasive ventilation, mechanical ventilation, glucocorticoids, and empiric antibiotics, until infectious causes are eliminated, and in the most severe cases, extracorporeal membrane oxygenation (ECMO). Currently, although there is an insufficient evidence to determine the safety and the efficacy of e-cigarettes for perioperative smoking cessation, EVALI clearly places these patients at an increased risk of perioperative morbidity. Given the relatively recent introduction of e-cigarettes, the long-term impact on adolescent health is unknown. As a result, the paucity of postoperative outcomes in this potentially vulnerable population does not support evidence-based recommendations for the management of these patients. Clinicians should identify "at-risk" individuals during preanesthetic evaluations and adjust the risk stratification accordingly. Our societies encourage continued education of the public and health care providers of the risks associated with vaping and nicotine use and encourage regular preoperative screening and postoperative outcome studies of patients with regard to smoking and vaping use.

Robust forecasting using predictive generalized synchronization in reservoir computing.

Reservoir computers (RCs) are a class of recurrent neural networks (RNNs) that can be used for forecasting the future of observed time series data. As with all RNNs, selecting the hyperparameters in the network to yield excellent forecasting presents a challenge when training on new inputs. We analyze a method based on predictive generalized synchronization (PGS) that gives direction in designing and evaluating the architecture and hyperparameters of an RC. To determine the occurrences of PGS, we rely on the auxiliary method to provide a computationally efficient pre-training test that guides hyperparameter selection. We provide a metric for evaluating the RC using the reproduction of the input system's Lyapunov exponents that demonstrates robustness in prediction.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 2 Safety: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, a public-private partnership with the US Food and Drug Administration, convened a second meeting of sedation experts from a variety of clinical specialties and research backgrounds to develop recommendations for procedural sedation research. The previous meeting addressed efficacy and patient- and/or family-centered outcomes. This meeting addressed issues of safety, which was defined as "the avoidance of physical or psychological harm." A literature review identified 133 articles addressing safety measures in procedural sedation clinical trials. After basic reporting of vital signs, the most commonly measured safety parameter was oxygen saturation. Adverse events were inconsistently defined throughout the studies. Only 6 of the 133 studies used a previously validated measure of safety. The meeting identified methodological problems associated with measuring infrequent adverse events. With a consensus discussion, a set of core and supplemental measures were recommended to code for safety in future procedural clinical trials. When adopted, these measures should improve the integration of safety data across studies and facilitate comparisons in systematic reviews and meta-analyses.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.

Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington's disease mice.

Huntington's disease (HD) is a fatal neurological disorder caused by a CAG repeat expansion in the HTT gene, which encodes a mutant huntingtin protein (mHTT). The mutation confers a toxic gain of function on huntingtin, leading to widespread neurodegeneration and inclusion formation in many brain regions. Although the hallmark symptom of HD is hyperkinesia stemming from striatal degeneration, several other brain regions are affected which cause psychiatric, cognitive, and metabolic symptoms. Additionally, mHTT expression in peripheral tissue is associated with skeletal muscle atrophy, cardiac failure, weight loss, and diabetes. We, and others, have demonstrated a prevention of motor symptoms in HD mice following direct striatal injection of adeno-associated viral vector (AAV) serotype 1 encoding an RNA interference (RNAi) construct targeting mutant HTT mRNA (mHTT). Here, we expand these efforts and demonstrate that an intrajugular vein injection of AAV serotype 9 (AAV9) expressing a mutant HTT-specific RNAi construct significantly reduced mHTT expression in multiple brain regions and peripheral tissues affected in HD. Correspondingly, this approach prevented atrophy and inclusion formation in key brain regions as well as the severe weight loss germane to HD transgenic mice. These results demonstrate that systemic delivery of AAV9-RNAi may provide more widespread clinical benefit for patients suffering from HD.

Multiorganizational consensus to define guiding principles for perioperative pain management in patients with chronic pain, preoperative opioid tolerance, or substance use disorder.

Significant knowledge gaps exist in the perioperative pain management of patients with a history of chronic pain, substance use disorder, and/or opioid tolerance as highlighted in the US Health and Human Services Pain Management Best Practices Inter-Agency Task Force 2019 report. The report emphasized the challenges of caring for these populations and the need for multidisciplinary care and a comprehensive approach. Such care requires stakeholder alignment across multiple specialties and care settings. With the intention of codifying this alignment into a reliable and efficient processes, a consortium of 15 professional healthcare societies was convened in a year-long modified Delphi consensus process and summit. This process produced seven guiding principles for the perioperative care of patients with chronic pain, substance use disorder, and/or preoperative opioid tolerance. These principles provide a framework and direction for future improvement in the optimization and care of 'complex' patients as they undergo surgical procedures.

Bleedings, purges, and vomits: Dr. Benjamin Rush's republican medicine, the bilious remitting yellow-fever epidemic of 1793, and the non-origin of the law of informed consent.

To the consternation of many physicians, the modern law of informed consent imposes certain constraints on their actions, not least that they respect patients' decisions to redefine at will the scope of care. The consequences of this transfer of power are often a nuisance and occasionally fatal, but always a reflection of democracy's leveling march: Physicians now take orders rather than give them. However frustrating the modern preference for process over result might be, we should ask ourselves-before condemning the law's evolution-about the consequences for patients' health of a more radically democratic practice of medicine. This paper proposes to examine this question as framed by the life of Dr. Benjamin Rush, who, in addition to signing the Declaration of Independence, crafted a medical practice uniquely suited to the young Republic's presumed moral character: Self-aware sufferers would promptly identify their own maladies and courageously treat themselves. In the end, his enterprise was flawed because his democratic instincts misled not only his scientific inquiries (disease is complex, not simple) but also his practice recommendations (patients are scared, not intrepid). Reflection on Rush's failed project should give pause to those who lament the passing of paternalistic medicine, for the law's requirements, however onerous they might be, tolerably accommodate both patients' need for physicians' expertise and our democratic belief that consent is the fundamental precondition of all rule.

Peptide YY(3-36) inhibits morning, but not evening, food intake and decreases body weight in rhesus macaques.

Peptide YY(3-36) [PYY(3-36)] is a hormone that is released after meal ingestion that is currently being investigated for the treatment of obesity; however, there are conflicting reports of the effects of PYY(3-36) on energy balance in rodent models. To shed light on this controversy, we studied the effect of PYY(3-36) on food intake and body weight in a nonhuman primate. Intravenous PYY(3-36) infusions before a morning meal transiently suppressed the rate of food intake but did not suppress the evening meal or 24-h intake. Twice-daily or continuous intravenous PYY(3-36) infusions to supraphysiological levels (levels that exceeded normal physiological levels) again suppressed the rate of feeding for the morning but not the evening meal. Twice-daily intravenous PYY(3-36) infusions for 2 weeks significantly decreased body weight in all test animals (average weight loss 1.9%) without changing insulin response to glucose infusion. These results show that endogenous PYY(3-36) may alter morning but not evening meal intake, and supraphysiological doses are required for effective suppression of food intake.

Stereotaxic Surgical Targeting of the Nonhuman Primate Caudate and Putamen: Gene Therapy for Huntington's Disease.

Stereotaxic surgery is an invaluable tool to deliver a variety of gene therapy constructs to the nonhuman primate caudate and putamen in preclinical studies for the genetic, neurodegenerative disorder, Huntington's disease (HD). Here we describe in detail how to perform this technique beginning with a pre-surgical magnetic resonance imaging scan to determine surgical coordinates followed by the stereotaxic surgical injection technique. In addition, we include methodology of a full necropsy including brain and peripheral tissue removal and a standard immunohistochemical technique to visualize the injected gene therapy agent.

Elucidating the neurotoxic effects of MDMA and its analogs.

AIMS: There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural congeners/analogs globally. MDMA and MDMA-analogs have been synthesized illegally in furtive dwellings and are abused due to its addictive potential. Furthermore, MDMA and MDMA-analogs have shown to have induced several adverse effects. Hence, understanding the mechanisms mediating this neurotoxic insult of MDMA-analogs is of immense importance for the public health in the world. MAIN METHODS: We synthesized and investigated the neurotoxic effects of MDMA and its analogs [4-methylenedioxyamphetamine (MDA), 2, 6-methylenedioxyamphetamine (MDMA), and N-ethyl-3, 4-methylenedioxyamphetamine (MDEA)]. The stimulatory or the dopaminergic agonist effects of MDMA and MDMA-analogs were elucidated using the established 6-hydroxydopamine lesioned animal model. Additionally, we also investigated the neurotoxic mechanisms of MDMA and MDMA-analogs on mitochondrial complex-I activity and reactive oxygen species generation. KEY FINDINGS: MDMA and MDMA-analogs exhibited stimulatory activity as compared to amphetamines and also induced several behavioral changes in the rodents. MDMA and MDMA-analogs enhanced the reactive oxygen generation and inhibited mitochondrial complex-I activity which can lead to neurodegeneration. Hence the mechanism of neurotoxicity, MDMA and MDMA-analogs can enhance the release of monoamines, alter the monoaminergic neurotransmission, and augment oxidative stress and mitochondrial abnormalities leading to neurotoxicity. SIGNIFICANCE: Thus, our study will help in developing effective pharmacological and therapeutic approaches for the treatment of MDMA and MDMA-analog abuse.

Fish with chips: tracking reef fish movements to evaluate size and connectivity of Caribbean marine protected areas.

Coral reefs and associated fish populations have experienced rapid decline in the Caribbean region and marine protected areas (MPAs) have been widely implemented to address this decline. The performance of no-take MPAs (i.e., marine reserves) for protecting and rebuilding fish populations is influenced by the movement of animals within and across their boundaries. Very little is known about Caribbean reef fish movements creating a critical knowledge gap that can impede effective MPA design, performance and evaluation. Using miniature implanted acoustic transmitters and a fixed acoustic receiver array, we address three key questions: How far can reef fish move? Does connectivity exist between adjacent MPAs? Does existing MPA size match the spatial scale of reef fish movements? We show that many reef fishes are capable of traveling far greater distances and in shorter duration than was previously known. Across the Puerto Rican Shelf, more than half of our 163 tagged fish (18 species of 10 families) moved distances greater than 1 km with three fish moving more than 10 km in a single day and a quarter spending time outside of MPAs. We provide direct evidence of ecological connectivity across a network of MPAs, including estimated movements of more than 40 km connecting a nearshore MPA with a shelf-edge spawning aggregation. Most tagged fish showed high fidelity to MPAs, but also spent time outside MPAs, potentially contributing to spillover. Three-quarters of our fish were capable of traveling distances that would take them beyond the protection offered by at least 40-64% of the existing eastern Caribbean MPAs. We recommend that key species movement patterns be used to inform and evaluate MPA functionality and design, particularly size and shape. A re-scaling of our perception of Caribbean reef fish mobility and habitat use is imperative, with important implications for ecology and management effectiveness.