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The existence of finite amplitude shape distortion caused by parametrically excited surface instabilities for a gas bubble in water driven by a temporally periodic, spatially uniform pressure field in an axisymmetric geometry is investigated. Employing a nonlinear coupled system of equations which includes shape mode interactions to third order, the resultant spherical oscillations, translation, and shape distortion of the bubble are modelled, placing no restriction on the size of the spherical oscillations. The model accounts for viscous and thermal damping with compressibility effects. The existence of synchronous and higher order parametrically induced sustained, finite amplitude, periodic shape deformation is demonstrated. The excitement of an odd shape mode via the synchronous mechanism is shown to give rise to linear bubble self-propulsion. For larger driving amplitudes, it is shown that more than one shape mode can be parametrically excited at the same driving frequency but by different resonance mechanisms, leading to more involved shape deformation and the increased possibility of bubble self-propulsion., (© 2024 Acoustical Society of America.)

Cleavage of bacteriophage DNA by the Type III restriction-modification enzymes requires long-range interaction between DNA sites. This is facilitated by one-dimensional diffusion ('DNA sliding') initiated by ATP hydrolysis catalyzed by a superfamily 2 helicase-like ATPase. Here we combined ultrafast twist measurements based on plasmonic DNA origami nano-rotors with stopped-flow fluorescence and gel-based assays to examine the role(s) of ATP hydrolysis. Our data show that the helicase-like domain has multiple roles. First, this domain stabilizes initial DNA interactions alongside the methyltransferase subunits. Second, it causes environmental changes in the flipped adenine base following hydrolysis of the first ATP. Finally, it remodels nucleoprotein interactions via constrained translocation of a ∼ 5 to 22-bp double stranded DNA loop. Initiation of DNA sliding requires 8-15 bp of DNA downstream of the motor, corresponding to the site of nuclease domain binding. Our data unify previous contradictory communication models for Type III enzymes., (© 2024. The Author(s).)

The self-propulsion (translational instability) of a gas bubble in a liquid undergoing parametrically induced axisymmetric shape distortion due to being forced by a temporally sinusoidal, spatially constant acoustic field is investigated. Employing a model which accounts for the nonlinear coupling between the spherical oscillations, the axial translation and shape deformation of the bubble, the parametric excitement of two neighboring shape modes by the fundamental resonance, at the same driving frequency is studied. It is shown that provided pertinent driving pressure threshold values are exceeded, the respective shape modes are excited on different timescales. The growth of the shape mode on the faster timescale saturates giving rise to sustained constant amplitude oscillations, while the growth of the shape mode on the slower timescale is both modulated and unbounded. During the growth of the second shape mode, growing, oscillatory bubble translation is also observed.

Bacteria have evolved a variety of defence mechanisms to protect against mobile genetic elements, including restriction-modification systems and CRISPR-Cas. In recent years, dozens of previously unknown defence systems (DSs) have been discovered. Notably, diverse DSs often coexist within the same genome, and some co-occur at frequencies significantly higher than would be expected by chance, implying potential synergistic interactions. Recent studies have provided evidence of defence mechanisms that enhance or complement one another. Here, we review the interactions between DSs at the mechanistic, regulatory, ecological and evolutionary levels., Competing Interests: Declaration of Competing Interest AM and EW are inventors on patent GB2303034.9., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: While most studies on burn outcomes have focused on adults, it is unclear if the same socioeconomic and environmental inequalities affect paediatric patients. This study aims to investigate the impact of race and ethnicity on outcomes in paediatric burn patients., Methods: The Kids' Inpatient Database is released by Agency for Healthcare Research and Quality, and is the largest publicly available database for the United States inpatient paediatric population. All paediatric burned patients in 2016 and 2019 were identified. Race and/or ethnicity was the primary exposure variable, and the primary outcome was a composite of several in-hospital morbidities. Secondary outcomes included death, non-routine disposition, and length of stay. Fine-Gray competing risks regression and multivariable logistic regression were used to analyze length of stay and all other outcomes, respectively. Analysis also isolated subgroups related to socioeconomic status and case severity., Results: We included12,582 pediatric burn patients in this study. No difference was found in composite morbidity between White patients and those of other race or ethnicity groups. Hispanic ethnicity was associated with longer lengths of stay and increased odds of routine (i.e. home) discharge. Black patients had increased length of stay compared to White patients only in severe burn cases., Conclusions: Our study implies that race- or ethnicity-associated mechanisms driving outcome disparities in adults does not necessarily apply in paediatric burn patients., Competing Interests: Declaration of Competing Interest The University of California has received funding and product for other research projects from Epimed International (Farmers Branch, TX); Infutronics (Natick, MA); Precision Genetics (Greenville County, SC); and SPR Therapeutics (Cleveland, OH) for the following author: Dr. Gabriel. The University of California San Diego is a consultant for Avanos (Alpharetta, GA), in which Dr. Gabriel represents., (Copyright © 2023 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

A set of focused analogues have been generated around a lead indirect adenosine monophosphate-activated kinase (AMPK) activator to improve the rat clearance of the molecule. Analogues were focused on inhibiting amide hydrolysis by the strategic placement of substituents that increased the steric environment about the secondary amide bond between 4-aminopiperidine and pyridine-5-carboxylic acid. It was found that placing substituents at position 3 of the piperidine ring and position 4 of the pyridine could all improve clearance without significantly impacting on-target potency. Notably, trans -3-fluoropiperidine 32 reduced rat clearance from above liver blood flow to 19 mL/min/kg and improved the hERG profile by attenuating the basicity of the piperidine moiety. Oral dosing of 32 activated AMPK in mouse liver and after 2 weeks of dosing improved glucose handling in a db/db mouse model of Type II diabetes as well as lowering fasted glucose and insulin levels.

Dimethyl fumarate 1 is approved for the treatment of multiple sclerosis but is also associated with off-target activation of the niacin receptor. By using a tetrazolone or triazolone bioisostere approach to the fumarate and vinyl sulfone series of Nrf2 activators, we have optimized the electrophilicity of the double bond to tune the on-target Nrf2 activation with PK properties to achieve efficacy in animal models of multiple sclerosis. The study linked highly potent, highly electrophilic molecules to low plasma stability and, subsequently, limited efficacy. By contrast, a sulfonylvinyltriazolone 17 retains on-target potency but shows much weaker electrophilic potential. As a consequence, in vivo high exposures of 17 are obtained, resulting in efficacy in the EAE model similar to that observed for DMF. 17 (R079) is Ames negative, is not cytotoxic to cells, and shows little inhibition of either the niacin receptor or a panel of off-target receptors., Competing Interests: The authors declare the following competing financial interest(s): All authors were employed by Rigel Pharmaceuticals, Inc at the time of this work., (© 2023 American Chemical Society.)

Health literacy is an important foundation for health promotion and an under-recognized risk factor for immigrant and refugee groups. Yet measuring health literacy among diverse ethnic and linguistic populations presents complex challenges. We describe cultural and translation challenges encountered in measuring health literacy among Russian-speaking immigrants to the USA and offer a mixed-methods approach to understanding them. The Rx-Health Literacy (RxHL) study used cross-sectional quantitative and qualitative data to examine health literacy and medication adherence among five cultural and four language groups (Latinx, Vietnamese, African-American, Russian-speaking immigrant and White American) who are patients at Caring Health Center, a federally qualified health center in Springfield, MA. We translated an existing health literacy scale into Russian and Vietnamese and examined item difficulty across cultural groups. We conducted qualitative cognitive interviews to learn more about Russian speakers' understandings of the scale. Health literacy scores varied by cultural group, and the range of correct responses was much greater among Russian speakers than in other groups. Percentage correct varied by 69.7% for Russian speakers, compared with 25.0-44.0% for other groups. These findings indicate greater variability in health literacy levels among this group compared with others. Cognitive interviews with Russian-speaking participants revealed multiple interpretations of several items, suggesting that the English version of the scale contained embedded meanings associated with an American health care context that were not captured in the translated instrument. Combining qualitative and quantitative research methods allows for greater insight into contextual and translation factors that may shape the results of translated instruments in unanticipated ways., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective. Invasive brain-computer interfaces (BCIs) have shown promise in restoring motor function to those paralyzed by neurological injuries. These systems also have the ability to restore sensation via cortical electrostimulation. Cortical stimulation produces strong artifacts that can obscure neural signals or saturate recording amplifiers. While front-end hardware techniques can alleviate this problem, residual artifacts generally persist and must be suppressed by back-end methods. Approach. We have developed a technique based on pre-whitening and null projection (PWNP) and tested its ability to suppress stimulation artifacts in electroencephalogram (EEG), electrocorticogram (ECoG) and microelectrode array (MEA) signals from five human subjects. Main results. In EEG signals contaminated by narrow-band stimulation artifacts, the PWNP method achieved average artifact suppression between 32 and 34 dB, as measured by an increase in signal-to-interference ratio. In ECoG and MEA signals contaminated by broadband stimulation artifacts, our method suppressed artifacts by 78%-80% and 85%, respectively, as measured by a reduction in interference index. When compared to independent component analysis, which is considered the state-of-the-art technique for artifact suppression, our method achieved superior results, while being significantly easier to implement. Significance. PWNP can potentially act as an efficient method of artifact suppression to enable simultaneous stimulation and recording in bi-directional BCIs to biomimetically restore motor function., (© 2023 IOP Publishing Ltd.)

Introduction: It would be valuable if home-based rehabilitation training technologies could automatically assess arm impairment after stroke. Here, we tested whether a simple measure-the repetition rate (or "rep rate") when performing specific exercises as measured with simple sensors-can be used to estimate Upper Extremity Fugl-Meyer (UEFM) score., Methods: 41 individuals with arm impairment after stroke performed 12 sensor-guided exercises under therapist supervision using a commercial sensor system comprised of two pucks that use force and motion sensing to measure the start and end of each exercise repetition. 14 of these participants then used the system at home for three weeks., Results: Using linear regression, UEFM score was well estimated using the rep rate of one forward-reaching exercise from the set of 12 exercises (r 2  = 0.75); this exercise required participants to alternately tap pucks spaced about 20 cm apart (one proximal, one distal) on a table in front of them. UEFM score was even better predicted using an exponential model and forward-reaching rep rate (Leave One Out Cross Validation (LOOCV) r 2  = 0.83). We also tested the ability of a nonlinear, multivariate model (a regression tree) to predict UEFM, but such a model did not improve prediction (LOOCV r 2  = 0.72). However, the optimal decision tree also used the forward-reaching task along with a pinch grip task to subdivide more and less impaired patients in a way consistent with clinical intuition. At home, rep rate for the forward-reaching exercise well predicted UEFM score using an exponential model (LOOCV r 2  = 0.69), but only after we re-estimated coefficients using the home data., Discussion: These results show how a simple measure-exercise rep rate measured with simple sensors-can be used to infer an arm impairment score and suggest that prediction models should be tuned separately for the clinic and home environments., Competing Interests: DKZ has a financial interest in Hocoma AG and Flint Rehab LLC, companies that develop and sell rehabilitation devices. Flint Rehab produces the FitMi sensor used in this study. The terms of these arrangements have been reviewed and approved by the University of California, Irvine, in accordance with its conflict-of-interest policies. DKZ has a financial interest in Flint Rehab, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Swanson, Johnson, Zondervan, Shaw and Reinkensmeyer.)

Introduction: Bi-directional brain-computer interfaces (BD-BCI) to restore movement and sensation must achieve concurrent operation of recording and decoding of motor commands from the brain and stimulating the brain with somatosensory feedback., Methods: A custom programmable direct cortical stimulator (DCS) capable of eliciting artificial sensorimotor response was integrated into an embedded BCI system to form a safe, independent, wireless, and battery powered testbed to explore BD-BCI concepts at a low cost. The BD-BCI stimulator output was tested in phantom brain tissue by assessing its ability to deliver electrical stimulation equivalent to an FDA-approved commercial electrical cortical stimulator. Subsequently, the stimulator was tested in an epilepsy patient with subcortical electrocorticographic (ECoG) implants covering the sensorimotor cortex to assess its ability to elicit equivalent responses as the FDA-approved counterpart. Additional safety features (impedance monitoring, artifact mitigation, and passive and active charge balancing mechanisms) were also implemeneted and tested in phantom brain tissue. Finally, concurrent operation with interleaved stimulation and BCI decoding was tested in a phantom brain as a proof-of-concept operation of BD-BCI system., Results: The benchtop prototype BD-BCI stimulator's basic output features (current amplitude, pulse frequency, pulse width, train duration) were validated by demonstrating the output-equivalency to an FDA-approved commercial cortical electrical stimulator ( R 2 > 0.99). Charge-neutral stimulation was demonstrated with pulse-width modulation-based correction algorithm preventing steady state voltage deviation. Artifact mitigation achieved a 64.5% peak voltage reduction. Highly accurate impedance monitoring was achieved with R 2 > 0.99 between measured and actual impedance, which in-turn enabled accurate charge density monitoring. An online BCI decoding accuracy of 93.2% between instructional cues and decoded states was achieved while delivering interleaved stimulation. The brain stimulation mapping via ECoG grids in an epilepsy patient showed that the two stimulators elicit equivalent responses., Significance: This study demonstrates clinical validation of a fully-programmable electrical stimulator, integrated into an embedded BCI system. This low-cost BD-BCI system is safe and readily applicable as a testbed for BD-BCI research. In particular, it provides an all-inclusive hardware platform that approximates the limitations in a near-future implantable BD-BCI. This successful benchtop/human validation of the programmable electrical stimulator in a BD-BCI system is a critical milestone toward fully-implantable BD-BCI systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sohn, Lim, Wang, Pu, Malekzadeh-Arasteh, Shaw, Armacost, Gong, Kellis, Andersen, Liu, Heydari, Nenadic and Do.)

Background: Previous research has shown pregnant people are not knowledgeable about preeclampsia, a significant cause of maternal morbidity and mortality. This lack of knowledge may impact their ability to report symptoms, comply with recommendations, and receive appropriate follow-up care. Pregnant people commonly seek information from sources outside their treating clinician, including pregnancy-specific books and online sources. We examined commonly used preeclampsia information sources to evaluate whether pregnant people are receiving up-to-date, guideline-based information., Methods: We conducted a content analysis of preeclampsia-related information in top-ranking websites and bestselling pregnancy books. We used American College of Obstetricians and Gynecologists preeclampsia guidelines to construct a codebook, which we used to examine source content completeness and accuracy. For each source, we analyzed information about preeclampsia diagnosis, patient-reported symptoms, risk factors, prevention, treatment, and complications., Results: Across 19 included sources (13 websites and 6 books), we found substantial variation in completeness and accuracy of preeclampsia information. We found high rates of mentions for preeclampsia symptoms. Risk factors were more commonly included in online sources than book sources. Most sources mentioned treatment options, including blood pressure medication and giving birth; however, one-third of online sources positively mentioned the nonrecommended treatment of bed rest. Prevention methods, including prenatal aspirin for high-risk pregnancies, and long-term complications of preeclampsia were infrequently mentioned., Conclusions: Varying rates of accuracy in patient-facing preeclampsia information mean there is substantial room for improvement in these sources. Ensuring pregnant people receive current guideline-based information is critical for improving outcomes and implementing shared decision-making., (Copyright © 2022 Jacobs Institute of Women's Health, George Washington University. Published by Elsevier Inc. All rights reserved.)

Pediatric burns affect approximately 15-20 patients per 100 000 hospital admissions, but unfortunately there is a lack of evidence to guide optimal strategies for acute pain control. The aim of this study was to evaluate whether caudal analgesia with single injection of local anesthetics reduced pain medication consumption in pediatric patients who required surgical intervention for burn injuries. Retrospective data from patients <7 years old who had burn surgery in the operating rooms at a single regional burn center from 2013 to 2021 was obtained and analyzed. A 1:1 propensity-score matching method using nearest neighbor matching without replacement was utilized to create matched cohorts. Primary outcome was opioid consumption, which is presented as opioid equivalents divided by patient weight in kilograms, at 24 h after surgery. Comparing propensity-score matched groups, there were no statistically significant differences in adjusted morphine equivalents received by the caudal group (0.122 [0.0646;0.186]) and the no caudal group (0.0783 [0.0384;0.153]) at 24 h after surgery ( p  = 0.06). This is the first study to the best of our knowledge of the association of caudal analgesia in pediatric burn patients with postoperative pain control. The data showed an increase in pain medication consumption postoperative at 24 h and intraoperative for patients who received single injection caudal blocks, but when adjusted using propensity-score matching, the difference was no longer statistically significant., (© 2022 The Authors. Paediatric and Neonatal Pain published by John Wiley & Sons Ltd.)

Cortical stimulation via electrocorticography (ECoG) may be an effective method for inducing artificial sensation in bi-directional brain-computer interfaces (BD-BCIs). However, strong electrical artifacts caused by electrostimulation may significantly degrade or obscure neural information. A detailed understanding of stimulation artifact propagation through relevant tissues may improve existing artifact suppression techniques or inspire the development of novel artifact mitigation strategies. Our work thus seeks to comprehensively characterize and model the propagation of artifacts in subdural ECoG stimulation. To this end, we collected and analyzed data from eloquent cortex mapping procedures of four subjects with epilepsy who were implanted with subdural ECoG electrodes. From this data, we observed that artifacts exhibited phase-locking and ratcheting characteristics in the time domain across all subjects. In the frequency domain, stimulation caused broadband power increases, as well as power bursts at the fundamental stimulation frequency and its super-harmonics. The spatial distribution of artifacts followed the potential distribution of an electric dipole with a median goodness-of-fit of R 2 = 0.80 across all subjects and stimulation channels. Artifacts as large as ±1,100 μV appeared anywhere from 4.43 to 38.34 mm from the stimulation channel. These temporal, spectral and spatial characteristics can be utilized to improve existing artifact suppression techniques, inspire new strategies for artifact mitigation, and aid in the development of novel cortical stimulation protocols. Taken together, these findings deepen our understanding of cortical electrostimulation and provide critical design specifications for future BD-BCI systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lim, Wang, Shaw, Gong, Armacost, Liu, Do, Heydari and Nenadic.)

Using an in-cell AMPK activation assay, we have developed structure-activity relationships around a hit pyridine dicarboxamide 5 that resulted in 40 (R419). A particular focus was to retain the on-target potency while also improving microsomal stability and reducing off-target activities, including hERG inhibition. We were able to show that removing a tertiary amino group from the piperazine unit of hit compound 5 improved microsomal stability while hERG inhibition was improved by modifying the substitution of the central core pyridine ring. The SAR resulted in 40, which continues to maintain on-target potency. Compound 40 was able to activate AMPK in vivo after oral administration and showed efficacy in animal models investigating activation of AMPK as a therapy for glucose control (both db/db and DIO mouse models)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Low-income U.S. adults experiencing food insecurity have a disproportionately high prevalence of cigarette smoking, and quantitative studies suggest that food insecurity is a barrier to quitting. To guide effective tobacco control strategies, this study aimed to understand the experiences, perceptions, and context of tobacco use and cessation among low-income populations experiencing food insecurity., Methods: We conducted in-depth, semi-structured interviews with 23 adults who were currently smoking cigarettes and were experiencing food insecurity, mostly living in rural settings. Participants were recruited through food-pantry-based needs assessment surveys and study flyers in community-based organizations. The interview guide explored participants' histories of smoking, the role and function of tobacco in their lives, their interest in and barriers to quitting, as well as lived experiences of food insecurity. We used reflexive thematic analysis to analyze transcribed interviews., Results: Within a broader context of structural challenges related to poverty and financial strain that shaped current smoking behavior and experiences with food insecurity, we identified the following five themes: smoking to ignore hunger or eat less; staying addicted to smoking in the midst of instability; smoking being prioritized in the midst of financial strain; life stressors and the difficulty of quitting smoking and staying quit; and childhood adversity at the intersection of food insecurity and tobacco use., Conclusion: The context of tobacco use among adults with food insecurity was highly complex. To effectively address tobacco-related disparities among those who are socially and economically disadvantaged, tobacco control efforts should consider relevant lived experiences and structural constraints intersecting smoking and food insecurity. Findings are applied to a conceptualization of clustering of conditions contributing to nicotine dependence, food insecurity, and stress.

Aim: We evaluated the efficacy of a novel brain permeable "metformin-like" AMP-activated protein kinase activator, R481, in regulating glucose homeostasis., Materials and Methods: We used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively., Results: In vitro , we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro , R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo ., Conclusions: These data demonstrate that peripheral administration of the brain permeable "metformin-like" AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes., Competing Interests: SJS is an employee and shareholder of Rigel Pharmaceuticals, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cruz, Partridge, Malekizadeh, Vlachaki Walker, Weightman Potter, Pye, Shaw, Ellacott and Beall.)

Growth differentiating factor-15 (GDF15) is an emerging target for the treatment of obesity and metabolic disease partly due to its ability to suppress food intake. GDF15 expression and secretion are thought to be regulated by a cellular integrated stress response, which involves endoplasmic reticulum (ER) stress. AMPK is another cellular stress sensor, but the relationship between AMPK, ER stress, and GDF15 has not been assessed in vivo. Wildtype (WT), AMPK β1 deficient (AMPKβ1 -/- ), and CHOP -/- mice were treated with three distinct AMPK activators; AICAR, which is converted to ZMP mimicking the effects of AMP on the AMPKγ isoform, R419, which indirectly activates AMPK through inhibition of mitochondrial respiration, or A769662, a direct AMPK activator which binds the AMPKβ1 isoform ADaM site causing allosteric activation. Following treatments, liver Gdf15, markers of ER-stress, AMPK activity, adenine nucleotides, circulating GDF15, and food intake were assessed. AICAR and R419 caused ER and energetic stress, increased GDF15 expression and secretion, and suppressed food intake. Direct activation of AMPK β1 containing complexes by A769662 increased hepatic Gdf15 expression, circulating GDF15, and suppressed food intake, independent of ER stress. The effects of AICAR, R419, and A769662 on GDF15 were attenuated in AMPKβ1 -/- mice. AICAR and A769662 increased GDF15 to a similar extent in WT and CHOP -/- mice. Herein, we provide evidence that AMPK plays a role in mediating the induction of GDF15 under conditions of energetic stress in mouse liver in vivo., (© 2020 Federation of American Societies for Experimental Biology.)

Electrocorticography (ECoG)-based bi-directional (BD) brain-computer interfaces (BCIs) are a forthcoming technology promising to help restore function to those with motor and sensory deficits. A major problem with this paradigm is that the cortical stimulation necessary to elicit artificial sensation creates strong electrical artifacts that can disrupt BCI operation by saturating recording amplifiers or obscuring useful neural signal. Even with state-of-the-art hardware artifact suppression methods, robust signal processing techniques are still required to suppress residual artifacts that are present at the digital back-end. Herein we demonstrate the effectiveness of a pre-whitening and null projection artifact suppression method using ECoG data recorded during a clinical neurostimulation procedure. Our method achieved a maximum artifact suppression of 21.49 dB and significantly increased the number of artifact-free frequencies in the frequency domain. This performance surpasses that of a more traditional independent component analysis methodology, while retaining a reduced complexity and increased computational efficiency.

Perioperative risk of morbidity and mortality for neonates is significantly higher than that for older children and adults. At particular risk are neonates born prematurely, neonates with major or severe congenital heart disease, and neonates with pulmonary hypertension. Presently no consensus exists regarding the safest anesthetic regimen for neonates. Regional anesthesia appears to be safe, but does not reduce the overall risk of postoperative apnea. Former preterm infants require postoperative observation for apnea. The anesthesiologist caring for the neonate for major surgery should be knowledgeable of the unique physiology of the neonate and maintain the highest level of vigilance throughout., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study aims to contribute to the development of community-responsive research approaches by describing the research methods used in the RxHL study and the interprofessional and community-based collaboration that produced them. The mixed-method RxHL study was developed in close consultation with staff and providers at our research site, a federally qualified health center in Springfield, MA. We utilized quantitative methods including chart review, manual pill counts and self-report surveys to assess factors associated with medication adherence in a diverse population of low-income patients with chronic disease. We triangulated these results with findings from qualitative methods that included in-depth interviews, home visits and chronic disease diaries. We used the constant comparison method and interdisciplinary, participatory team meetings to integrate quantitative and qualitative findings. A community-responsive approach facilitated the recruitment and retention of a diverse sample of patients. Self-report surveys revealed the widespread scope of barriers to care such as medication costs and transportation, and limited health literacy among diverse groups. Qualitative research methods offered a deeper understanding of the social and environmental contexts in which medication adherence takes place. Prioritizing the needs of community partners and research participants facilitates rigorous data collection in clinical settings with maximum participation from community partners., (� The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: State-of-the-art invasive brain-machine interfaces (BMIs) have shown significant promise, but rely on external electronics and wired connections between the brain and these external components. This configuration presents health risks and limits practical use. These limitations can be addressed by designing a fully implantable BMI similar to existing FDA-approved implantable devices. Here, a prototype BMI system whose size and power consumption are comparable to those of fully implantable medical devices was designed and implemented, and its performance was tested at the benchtop and bedside., Approach: A prototype of a fully implantable BMI system was designed and implemented as a miniaturized embedded system. This benchtop analogue was tested in its ability to acquire signals, train a decoder, perform online decoding, wirelessly control external devices, and operate independently on battery. Furthermore, performance metrics such as power consumption were benchmarked., Main Results: An analogue of a fully implantable BMI was fabricated with a miniaturized form factor. A patient undergoing epilepsy surgery evaluation with an electrocorticogram (ECoG) grid implanted over the primary motor cortex was recruited to operate the system. Seven online runs were performed with an average binary state decoding accuracy of 87.0% (lag optimized, or 85.0% at fixed latency). The system was powered by a wirelessly rechargeable battery, consumed  ∼150 mW, and operated for  >60 h on a single battery cycle., Significance: The BMI analogue achieved immediate and accurate decoding of ECoG signals underlying hand movements. A wirelessly rechargeable battery and other supporting functions allowed the system to function independently. In addition to the small footprint and acceptable power and heat dissipation, these results suggest that fully implantable BMI systems are feasible.

Purpose: To examine whether food insecurity longitudinally affects smoking status., Design: Population-based prospective study., Setting: Data from the 2003 and 2015 Panel Study of Income Dynamics (PSID)., Participants: Four thousand five hundred sixty-three adults who were smokers and nonsmokers, participating in the 2003 (current study baseline) and 2015 (current study follow-up) waves of PSID., Measures: Based on self-reported smoking status at baseline and follow-up, respondents were categorized as continued smoking, stopped smoking, started smoking, and continued nonsmoking. Similarly, respondents were categorized as stayed food secure, stayed food insecure, became food insecure, and became food secure based on responses to the Food Security Survey at baseline and follow-up., Analysis: Two logistic regression analyses to examine (1) among smokers at baseline the odds of stopping versus continuing smoking by follow-up and (2) among nonsmokers at baseline the odds of starting versus continuing nonsmoking by follow-up. In both models, change in food insecurity status was the primary independent variable, controlling for demographics including poverty., Results: Among smokers at baseline, becoming food insecure (vs staying food secure) was independently associated with lower likelihood of stopping smoking by follow-up (odds ratio [OR] = 0.66). Among nonsmokers at baseline, becoming food insecure (vs staying food secure) was independently associated with higher likelihood of starting smoking by follow-up (OR = 3.77)., Conclusions: Food insecurity is a risk factor for smoking, which has significant implications for developing interventions to reduce smoking prevalence, especially among low-income groups.

AMP-activated protein kinase (AMPK) is an attractive therapeutic target for managing metabolic diseases. A class of pharmacological activators, including Merck 991, binds the AMPK ADaM site, which forms the interaction surface between the kinase domain (KD) of the α-subunit and the carbohydrate-binding module (CBM) of the β-subunit. Here, we report the development of two new 991-derivative compounds, R734 and R739, which potently activate AMPK in a variety of cell types, including β 2 -specific skeletal muscle cells. Surprisingly, we found that they have only minor effects on direct kinase activity of the recombinant α 1 β 2 γ 1 isoform yet robustly enhance protection against activation loop dephosphorylation. This mode of activation is reminiscent of that of ADP, which activates AMPK by binding to the nucleotide-binding sites in the γ-subunit, more than 60 Å away from the ADaM site. To understand the mechanisms of full and partial AMPK activation, we determined the crystal structures of fully active phosphorylated AMPK α 1 β 1 γ 1 bound to AMP and R734/R739 as well as partially active nonphosphorylated AMPK bound to R734 and AMP and phosphorylated AMPK bound to R734 in the absence of added nucleotides at <3-Å resolution. These structures and associated analyses identified a novel conformational state of the AMPK autoinhibitory domain associated with partial kinase activity and provide new insights into phosphorylation-dependent activation loop stabilization in AMPK., (© 2019 Yan et al.)

Vascular access for venepuncture and peripheral intravenous cannulation is a common procedure within health care. First-attempt cannula insertion success rate has been found to be lower in some patient groups. Multiple unsuccessful cannulation attempts have negative impacts for both patients and practitioners. This article reports on research investigating the effectiveness of an innovative device called the Vacuderm-a single-use tourniquet with added manual vacuum pump-in increasing vein dimensions, temperature difference between vein and its surrounding and visual clarity through an additional effect of creating a vacuum on top of the tourniquet. A randomised crossover design was used in this study for looking at the vein visibility, dimensions and thermal behaviour using infrared thermography. Dorsal areas of both hands were assessed in a random crossover study of 20 healthy volunteers with and without the application of the Vacuderm. The results show significant increase in venous diameter and venous cross-sectional area with highly significant increase in vein clarity caused by using the Vacuderm, which creates a negative pressure for transient suction in addition to its vein occlusion effect.

While prior noninvasive (e.g., electroencephalographic) studies suggest that the human primary motor cortex (M1) is active during gait processes, the limitations of noninvasive recordings make it impossible to determine whether M1 is involved in high-level motor control (e.g., obstacle avoidance, walking speed), low-level motor control (e.g., coordinated muscle activation), or only nonmotor processes (e.g., integrating/relaying sensory information). This study represents the first invasive electroneurophysiological characterization of the human leg M1 during walking. Two subjects with an electrocorticographic grid over the interhemispheric M1 area were recruited. Both exhibited generalized γ-band (40-200 Hz) synchronization across M1 during treadmill walking, as well as periodic γ-band changes within each stride (across multiple walking speeds). Additionally, these changes appeared to be of motor, rather than sensory, origin. However, M1 activity during walking shared few features with M1 activity during individual leg muscle movements, and was not highly correlated with lower limb trajectories on a single channel basis. These findings suggest that M1 primarily encodes high-level gait motor control (i.e., walking duration and speed) instead of the low-level patterns of leg muscle activation or movement trajectories. Therefore, M1 likely interacts with subcortical/spinal networks, which are responsible for low-level motor control, to produce normal human walking.

Bi-directional brain-computer interfaces (BCIs) require simultaneous stimulation and recording to achieve closed-loop operation. It is therefore important that the interface be able to distinguish between neural signals of interest and stimulation artifacts. Current bi-directional BCIs address this problem by temporally multiplexing stimulation and recording. This approach, however, is suboptimal in many BCI applications. Alternative artifact mitigation methods can be devised by investigating the mechanics of artifact propagation. To characterize stimulation artifact behaviors, we collected and analyzed electrocorticography (ECoG) data from eloquent cortex mapping. Ratcheting and phase-locking of stimulation artifacts were observed, as well as dipole-like properties. Artifacts as large as ±1,100 μV appeared as far as 15-37 mm away from the stimulating channel when stimulating at 10 mA. Analysis also showed that the majority of the artifact power was concentrated at the stimulation pulse train frequency (50 Hz) and its super-harmonics (100, 150, 200 Hz). Lower frequencies (0-32 Hz) experienced minimal artifact contamination. These findings could inform the design of future bi-directional ECoG-based BCIs.

The Massachusetts experience of health care reform before the Affordable Care Act of 2010 reveals a moral economy of care in which expanded access was met by neoliberal demands for accountability and cost control. Publicly-subsidized health insurance programs in the U.S. are deeply concerned with managing and regulating low-income residents' access to and coverage for medications. By focusing our attention on the new forms of social relations invoked by specific techniques of governing, analyses of accountability can help us understand the ways in which subjectivities are shaped through their encounters with overarching social and economic structures. This paper presents qualitative findings from a four-year, prospective study that combined two waves of survey and chart-based data collection with four qualitative methods. Medicaid patients are made accountable to their medication regimens as they must track their supply and obtain refills promptly; regular blood tests carried out by health care providers verify their adherence. Both patients and their physicians are subject to cost savings measures such as changing lists of covered medications. Finally, patients struggle to pay ever-increasing out-of-pocket costs for their medications, expenses which may keep patients from taking their medications as prescribed. The fraught relationship between trust, accountability and verification finds emphatic expression in the moral economy of health care, where the vulnerability of the sick and their hope for a cure confront policies designed to hold down costs.

The mechanism by which the human primary motor cortex (M1) encodes upper extremity movement kinematics is not fully understood. For example, human electrocorticogram (ECoG) signals have been shown to modulate with upper extremity movements; however, this relationship has not been explicitly characterized. To address this issue, we recorded high-density ECoG signals from patients undergoing epilepsy surgery evaluation as they performed elementary upper extremity movements while systematically varying movement speed and duration. Specifically, subjects performed intermittent pincer grasp/release, elbow flexion/extension, and shoulder flexion/extension at slow, moderate, and fast speeds. In all movements, bursts of power in the high-[Formula: see text] band (80-160 Hz) were observed in M1. In addition, the amplitude of these power bursts and the area of M1 with elevated high-[Formula: see text] activity were directly proportional to the movement speed. Likewise, the duration of elevated high-[Formula: see text] activity increased with movement duration. Based on linear regression, M1 high-[Formula: see text] power amplitude and duration covaried with movement speed and duration, respectively, with an average [Formula: see text] of [Formula: see text] and [Formula: see text]. These findings indicate that the encoding of upper extremity movement speed by M1 high-[Formula: see text] activity is primarily linear. Also, the fact that this activity remained elevated throughout a movement suggests that M1 does not merely generate transient instructions for a specific movement duration, but instead is responsible for the entirety of the movement. Finally, the spatial distribution of high-[Formula: see text] activity suggests the presence of a recruitment phenomenon in which higher speeds or increased muscle activity involve activation of larger M1 areas.

Human exonuclease 1 (hEXO1) is a member of the 5'-nuclease superfamily and plays important roles in DNA repair. Along with acting as a 5'-exonuclease on blunt, gapped, nicked, and 3'-overhang DNAs, hEXO1 can also act as an endonuclease removing protruding 5'-single-stranded flaps from duplex ends. How hEXO1 and related 5'-nuclease human flap endonuclease 1 (hFEN1) are specific for discontinuous DNA substrates like 5'-flaps has been controversial. Here we report the first functional data that imply that hEXO1 threads the 5'-flap through a hole in the protein known as the helical arch, thereby excluding reactions of continuous single strands. Conjugation of bulky 5'-streptavidin that would "block" threading through the arch drastically slowed the hEXO1 reaction. In contrast, addition of streptavidin to a preformed hEXO1 5'-biotin flap DNA complex trapped a portion of the substrate in a highly reactive threaded conformation. However, another fraction behaves as if it were "blocked" and decayed very slowly, implying there were both threaded and unthreaded forms of the substrate present. The reaction of an unmodified hEXO1-flap DNA complex did not exhibit marked biphasic kinetics, suggesting a fast re-equilibration occurs that produces more threaded substrate when some decays. The finding that a threading mechanism like that used by hFEN1 is also used by hEXO1 unifies the mode of operation for members of the 5'-nuclease superfamily that act on discontinuous substrates. As with hFEN1, intrinsic disorder of the arch region of the protein may explain how flaps can be threaded without a need for a coupled energy source.

There is a range of risk factors that can lead to peripheral intravenous (IV) cannula failure, and several failed cannulation attempts can result in the patient experiencing increased pain, discomfort and delays in receiving IV therapy. The Vessel Health and Preservation (VHP) framework is a tool that can be used to improve clinical decision-making and the patient experience in relation to vascular access and IV therapy. Use of the VHP framework can ensure the right vein and right vascular access device (VAD) is selected at the right time for each patient. This article describes how healthcare practitioners can use the VHP framework to support and enhance vein assessment and VAD selection. It outlines the various types of VAD available, focusing on short-term peripheral IV cannulae, which are the most commonly used devices. It also explores the potential benefits of implementing the VHP framework in clinical areas.

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.

A structure-activity relationship has been developed around the meridianin scaffold for inhibition of Dyrk1a. The compounds have been focussed on the inhibition of kinase Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle phenotype, which may be an effective treatment for diseases where exercise capacity is compromised. The SAR showed that while strong Dyrk1a binding was possible with the meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT residence time in the nucleus were obtained - properties not observed with the reported Dyrk1a inhibitors. One compound was shown to be effective in an ex vivo muscle fiber assay. The increased biological activity is thought to arise from the added interaction between the azaindole nitrogen and the lysine residue in the back pocket., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Vein location and assessment are essential to improve the success rates for vascular access. However, problems remain with first attempt success rates for peripheral cannulation and locating difficult veins. Practitioners may not be aware of developments in technology and aids to assist in the location and assessment of veins to achieve vascular access. This article provides an overview of two vein location aids that can be used to locate difficult veins: the IV-eye vein imager and the Vacuderm tourniquet. It discusses the patient factors that can increase the difficulty of vein assessment and location, and emphasises the importance of vessel health and preservation, and vein palpation. Practitioners should be experienced and skilled in the assessment of veins, and they are encouraged to revisit how they locate and assess veins.

Rationale and key points This article aims to assist practitioners to undertake the safe and effective insertion of a peripheral cannula. It provides information on best practice related to peripheral cannulation with an open-ported safety cannula. The same principles for practice apply to non-ported open safety cannulae. » Peripheral cannulation enables venous access, the administration of intravenous medication, infusion therapy and total parenteral nutrition. It also enables blood samples to be obtained. » Peripheral cannulation is a common procedure that requires high standards of care and management to optimise patient outcomes. Reflective activity 'How to' articles can help update your practice and ensure it remains evidence-based. Apply this article to your practice. Reflect on and write a short account of: » How you think this article has changed your practice when performing peripheral cannulation. » How you could use this resource to assist with supporting colleagues.

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.

Human flap endonuclease-1 (hFEN1) catalyzes the essential removal of single-stranded flaps arising at DNA junctions during replication and repair processes. hFEN1 biological function must be precisely controlled, and consequently, the protein relies on a combination of protein and substrate conformational changes as a prerequisite for reaction. These include substrate bending at the duplex-duplex junction and transfer of unpaired reacting duplex end into the active site. When present, 5'-flaps are thought to thread under the helical cap, limiting reaction to flaps with free 5'-terminiin vivo Here we monitored DNA bending by FRET and DNA unpairing using 2-aminopurine exciton pair CD to determine the DNA and protein requirements for these substrate conformational changes. Binding of DNA to hFEN1 in a bent conformation occurred independently of 5'-flap accommodation and did not require active site metal ions or the presence of conserved active site residues. More stringent requirements exist for transfer of the substrate to the active site. Placement of the scissile phosphate diester in the active site required the presence of divalent metal ions, a free 5'-flap (if present), a Watson-Crick base pair at the terminus of the reacting duplex, and the intact secondary structure of the enzyme helical cap. Optimal positioning of the scissile phosphate additionally required active site conserved residues Tyr(40), Asp(181), and Arg(100)and a reacting duplex 5'-phosphate. These studies suggest a FEN1 reaction mechanism where junctions are bound and 5'-flaps are threaded (when present), and finally the substrate is transferred onto active site metals initiating cleavage., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Electrocorticography (ECoG)-based brain-computer interface (BCI) is a promising platform for controlling arm prostheses. To restore functional independence, a BCI must be able to control arm prostheses along at least six degrees-of-freedoms (DOFs). Prior studies suggest that standard ECoG grids may be insufficient to decode multi-DOF arm movements. This study compared the ability of standard and high-density (HD) ECoG grids to decode the presence/absence of six elementary arm movements and the type of movement performed., Approach: Three subjects implanted with standard grids (4 mm diameter, 10 mm spacing) and three with HD grids (2 mm diameter, 4 mm spacing) had ECoG signals recorded while performing the following movements: (1) pincer grasp/release, (2) wrist flexion/extension, (3) pronation/supination, (4) elbow flexion/extension, (5) shoulder internal/external rotation, and (6) shoulder forward flexion/extension. Data from the primary motor cortex were used to train a state decoder to detect the presence/absence of movement, and a six-class decoder to distinguish between these movements., Main Results: The average performances of the state decoders trained on HD ECoG data were superior (p = 3.05 × 10(-5)) to those of their standard grid counterparts across all combinations of the μ, β, low-γ, and high-γ frequency bands. The average best decoding error for HD grids was 2.6%, compared to 8.5% of standard grids (chance 50%). The movement decoders trained on HD ECoG data were superior (p = 3.05 × 10(-5)) to those based on standard ECoG across all band combinations. The average best decoding errors of 11.9% and 33.1% were obtained for HD and standard grids, respectively (chance error 83.3%). These improvements can be attributed to higher electrode density and signal quality of HD grids., Significance: Commonly used ECoG grids are inadequate for multi-DOF BCI arm prostheses. The performance gains by HD grids may eventually lead to independence-restoring BCI arm prosthesis.

Structure-activity relationships have been developed around 5-bromo-8-toluylsulfonamidoquinoline 1 a hit compound in an assay for the interaction of the E3 ligase Skp2 with Cks1, part of the SCF ligase complex. Disruption of this protein-protein interaction results in higher levels of CDK inhibitor p27, which can act as a tumor suppressor. The results of the SAR developed highlight the relationship between the sulfonamide and quinoline nitrogen, while also suggesting that an aryl substituent at the 5-position of the quinoline ring contributes to the potency in the interaction assay. Compounds showing potency in the interaction assay result in greater levels of p27 and have been shown to inhibit cell growth of two p27 sensitive tumor cell lines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Patient daily goal sheets have been shown to improve compliance with hospital policies but might not represent the dynamic nature of care delivery in the pediatric ICU (PICU) setting. A study was conducted at Children's National Health System (Washington, DC) to determine the effect of a visible, unitwide, real-time dashboard on timeliness of compliance with quality and safety measures., Methods: An automated electronic health record (EHR)- querying tool was created to assess compliance with a PICU Safety Bundle. Querying of the EHR for compliance and updating of the dashboard automatically occurred every five minutes. A real-time visual display showed data on presence of consent for treatment, restraint orders, presence of urinary catheters, deep venous thrombosis (DVT) prophylaxis, Braden Q score, and medication reconciliation. Baseline compliance and duration of noncompliance was established during three time periods: the first, before activation of the dashboard; the second, at one month following activation of the dashboard; and the third, at three months after activation., Results: A total of 450 patients were included in the analysis. Between the first and third time periods, the median time from PICU admission to obtaining treatment consent decreased by 49%, from 393 to 202 minutes (p=.05). The number of patients with urinary catheters in place>96 hours decreased from 16 (32%) in Period 1 to 11 (19%) for Periods 2 and 3 combined (p=.01). Completion of medication reconciliation improved from 80% in the first time period to 93% and 92%, respectively, in the subsequent two periods (p=.002). There was no difference between the three periods in presence of restraint orders, DVT prophylaxis, or development or worsening of pressure ulcers., Conclusions: A unitwide dashboard can increase awareness for potential interventions, affecting patient safety in the PICU in a dynamic manner.

Brain machine interfaces (BMIs) have the potential to provide intuitive control of neuroprostheses to restore grasp to patients with paralyzed or amputated upper limbs. For these neuroprostheses to function, the ability to accurately control grasp force is critical. Grasp force can be decoded from neuronal spikes in monkeys, and hand kinematics can be decoded using electrocorticogram (ECoG) signals recorded from the surface of the human motor cortex. We hypothesized that kinetic information about grasping could also be extracted from ECoG, and sought to decode continuously-graded grasp force. In this study, we decoded isometric pinch force with high accuracy from ECoG in 10 human subjects. The predicted signals explained from 22% to 88% (60 ± 6%, mean ± SE) of the variance in the actual force generated. We also decoded muscle activity in the finger flexors, with similar accuracy to force decoding. We found that high gamma band and time domain features of the ECoG signal were most informative about kinetics, similar to our previous findings with intracortical LFPs. In addition, we found that peak cortical representations of force applied by the index and little fingers were separated by only about 4mm. Thus, ECoG can be used to decode not only kinematics, but also kinetics of movement. This is an important step toward restoring intuitively-controlled grasp to impaired patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The novel small molecule R118 and the biguanide metformin, a first-line therapy for type 2 diabetes (T2D), both activate the critical cellular energy sensor 5'-AMP-activated protein kinase (AMPK) via modulation of mitochondrial complex I activity. Activation of AMPK results in both acute responses and chronic adaptations, which serve to restore energy homeostasis. Metformin is thought to elicit its beneficial effects on maintenance of glucose homeostasis primarily though impacting glucose and fat metabolism in the liver. Given the commonalities in their mechanisms of action and that R118 also improves glucose homeostasis in a murine model of T2D, the effects of both R118 and metformin on metabolic pathways in vivo were compared in order to determine whether R118 elicits its beneficial effects through similar mechanisms., Results: Global metabolite profiling of tissues and plasma from mice with diet-induced obesity chronically treated with either R118 or metformin revealed tissue-selective effects of each compound. Whereas metformin treatment resulted in stronger reductions in glucose and lipid metabolites in the liver compared to R118, upregulation of skeletal muscle glycolysis and lipolysis was apparent only in skeletal muscle from R118-treated animals. Both compounds increased β-hydroxybutyrate levels, but this effect was lost after compound washout. Metformin, but not R118, increased plasma levels of metabolites involved in purine metabolism., Conclusions: R118 treatment but not metformin resulted in increased glycolysis and lipolysis in skeletal muscle. In contrast, metformin had a greater impact than R118 on glucose and fat metabolism in liver tissue.

Objective: This study aimed to quantitatively and qualitatively examine breast cancer screening practices, including breast self-examination (BSE), and health literacy among patients with chronic disease., Design: A prospective, multi-method study conducted with a targeted purposive sample of 297 patients with diabetes and/or hypertension from four ethnic groups (Latino, Vietnamese, African American, White-American) at an urban community health center., Setting: A federally qualified health center in Western Massachusetts., Methods: In our four-year study, 297 participants completed cancer knowledge, beliefs, attitudes and screening utilization scales and measures of health literacy. In addition to survey data collection, we conducted in-depth interviews, focus groups, home visits, and chronic disease diaries (n=71)., Results: In focus groups, African American, Vietnamese and Latina participants offered interviewers an unprompted demonstration of BSE, reported regular BSE use at particular times of the month, and shared positive feelings about the screening method. In a sample where approximately 93% of women have had a mammogram, many also had performed BSE (85.2%). Women with adequate health literacy were more likely than those with inadequate health literacy to rely on it. Despite being positively inclined toward BSE, Vietnamese women, who had the lowest health literacy scores in our sample, were less likely to perform BSE regularly., Conclusions: BSE seemed to be an appealing self-care practice for many women in our study, but we conclude that proper BSE practices may not be reinforced equally across ethnic groups and among patients with low health literacy.

Intermittent claudication is a form of exercise intolerance characterized by muscle pain during walking in patients with peripheral artery disease (PAD). Endothelial cell and muscle dysfunction are thought to be important contributors to the etiology of this disease, but a lack of preclinical models that incorporate these elements and measure exercise performance as a primary end point has slowed progress in finding new treatment options for these patients. We sought to develop an animal model of peripheral vascular insufficiency in which microvascular dysfunction and exercise intolerance were defining features. We further set out to determine if pharmacological activation of 5'-AMP-activated protein kinase (AMPK) might counteract any of these functional deficits. Mice aged on a high-fat diet demonstrate many functional and molecular characteristics of PAD, including the sequential development of peripheral vascular insufficiency, increased muscle fatigability, and progressive exercise intolerance. These changes occur gradually and are associated with alterations in nitric oxide bioavailability. Treatment of animals with an AMPK activator, R118, increased voluntary wheel running activity, decreased muscle fatigability, and prevented the progressive decrease in treadmill exercise capacity. These functional performance benefits were accompanied by improved mitochondrial function, the normalization of perfusion in exercising muscle, increased nitric oxide bioavailability, and decreased circulating levels of the endogenous endothelial nitric oxide synthase inhibitor asymmetric dimethylarginine. These data suggest that aged, obese mice represent a novel model for studying exercise intolerance associated with peripheral vascular insufficiency, and pharmacological activation of AMPK may be a suitable treatment for intermittent claudication associated with PAD.