Grain shape effects in bed load sediment transport.

Bed load sediment transport, in which wind or water flowing over a bed of sediment causes grains to roll or hop along the bed, is a critically important mechanism in contexts ranging from river restoration1 to planetary exploration2. Despite its widespread occurrence, predictions of bed load sediment flux are notoriously imprecise3,4. Many studies have focused on grain size variability5 as a source of uncertainty, but few have investigated the role of grain shape, even though shape has long been suspected to influence transport rates6. Here we show that grain shape can modify bed load transport rates by an amount comparable to the scatter in many sediment transport datasets4,7,8. We develop a theory that accounts for grain shape effects on fluid drag and granular friction and predicts that the onset and efficiency of transport depend on the coefficients of drag and bulk friction of the transported grains. Laboratory experiments confirm these predictions and reveal that the effect of grain shape on sediment transport can be difficult to intuit from the appearance of grains. We propose a shape-corrected sediment transport law that collapses our experimental measurements. Our results enable greater accuracy in predictions of sediment transport and help reconcile theories developed for spherical particles with the behaviour of natural sediment grains.

Use of once-daily oral semaglutide and associated clinical outcomes among adults with type 2 diabetes in routine clinical practice in Canada: A multicentre, prospective real-world study (PIONEER REAL Canada).

AIM: PIONEER REAL Canada examined real-world clinical outcomes associated with the use of once-daily oral semaglutide in adults with type 2 diabetes. MATERIALS AND METHODS: This was a 34- to 44-week, multicentre, prospective, open-label, non-interventional study in adults who were treatment-naive to injectable glucose-lowering medication and initiated oral semaglutide in routine clinical practice. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to the end of the study (EoS). Secondary endpoints assessed at EoS were change from baseline in body weight (BW); the proportion of participants reaching HbA1c levels <7% and the composite endpoints, HbA1c reduction ≥1% point with BW reduction ≥3% and ≥5%; and treatment satisfaction measured using Diabetes Treatment Satisfaction Questionnaires (DTSQ) status and change. Primary analyses were based on the in-study observation period. RESULTS: In total, 182 participants initiated oral semaglutide (mean age, 58.6 years; HbA1c, 8.0%; BW, 93.7 kg). The estimated changes (95% confidence interval) from baseline to EoS in HbA1c and BW were -1.09% points (-1.24, -0.94; p < .0001) and -7.17% (-8.24, -6.11; p < .0001), respectively. At EoS, 53.7% of participants had HbA1c levels <7%; 39.3% and 31.6% reached HbA1c reduction ≥1% point plus BW reduction ≥3% and ≥5%, respectively. Treatment satisfaction significantly increased (DTSQ status, +4.47 points; DTSQ change, 11.83 points; both p < .0001). At EoS, 75.3% of participants remained on oral semaglutide (55.5% received oral semaglutide 14 mg). No new safety signals were identified for oral semaglutide. CONCLUSIONS: In PIONEER REAL Canada, participants treated with oral semaglutide in routine clinical practice experienced clinically relevant reductions in HbA1c and BW and increased treatment satisfaction.

Evaluating Mineral Biomarkers as Mediators and Moderators of Behavioural Improvements in a Randomized Controlled Trial of Multinutrients for Children with ADHD.

Essential minerals are cofactors for synthesis of neurotransmitters supporting cognition and mood. An 8-week fully-blind RCT of multinutrients for ADHD demonstrated three times as many children (age 6-12) had significantly improved behavior ("treatment responders") on multinutrients (54%) compared to placebo (18%). The aim of this secondary study was to evaluate changes in fasted plasma and urinary mineral concentrations following the intervention, and their role as mediators and moderators of treatment response. Fourteen essential or trace minerals were measured in plasma and/or urine at baseline and week 8 from 86 participants (49 multinutrient, 37 placebo). Two-sample t-tests/Mann-Whitney U-tests compared 8-week change between treatment and placebo groups, which were also evaluated as potential mediators. Baseline levels were evaluated as potential moderators, using logistic regression models with clinical treatment response as the outcome. After 8 weeks, plasma boron, chromium (in females only), lithium, molybdenum, selenium, and vanadium, and urinary iodine, lithium, and selenium increased more with multinutrients than placebo, while plasma phosphorus decreased. These changes did not mediate treatment response. However, baseline urinary lithium trended toward moderation: participants with lower baseline urinary lithium were more likely to respond to multinutrients (p=0.058). Additionally, participants with higher baseline iron were more likely to be treatment responders regardless of treatment group (p=0.036.) These results show that multinutrient treatment response among children with ADHD is independent of their baseline plasma mineral levels, while baseline urinary lithium levels show potential as a non-invasive biomarker of treatment response requiring further study.

Efficacy of herbal treatments for functional dyspepsia: A systematic review and meta-analysis of randomized clinical trials.

Functional dyspepsia (FD) is a very common condition globally. Relevant keywords were searched for in title and abstract of selected databases, that is, Medline/PubMed, Scopus, Embase, Web of knowledge, and Google Scholar. Placebo and active-control trials on herbal remedies amongst adults who were diagnosed with FD were included. Dichotomous outcomes were presented as relative risk (RR) with 95% confidence interval (CI) and continuous outcomes were presented as pooled standardized mean difference (SMD) with 95% CI. Forty-nine randomized controlled trials (RCTs) were entered into meta-analysis (6,987 subjects). Herbal remedies resulted in a higher improvement in FD symptoms in comparison with the placebo (SMD = -0.58 [-0.66- -0.51], p < .00001 and RR = 1.73 [1.62-1.85], p < .00001). No significant difference between herbal remedies and placebo in the incidence of adverse events was observed (12.27 vs. 8.41%, RR = 1.06 [0.91-1.23], p = .45). Also, herbal remedies resulted in a higher improvement in quality of life in comparison with placebo (SMD = -0.64 [-0.73- -0.55], p < .00001). When comparing herbal remedies with conventional medicine through sensitivity analysis, no outcomes were significantly different (p > .05). Herbal remedies might be efficacious and safe in treating FD, and demonstrate comparable effect sizes for efficacy to conventional treatments. Further high-quality studies are warranted to firmly establish the clinical efficacy of the herbal remedies.

Supervisor experiences of extended clinical placements in optometry: a mixed methods study.

BACKGROUND: In Australia, optometry students have traditionally undertaken their clinical training in short-block rotations at University-led teaching clinics in metropolitan locations. Demand for clinical placements is growing as the number of optometry students steadily increases. As such, universities and clinical education providers must look for more diverse methods of student placement. Extended clinical placements in community-based settings are one alternative: a model similar to the longitudinal clerkships in medicine. This study aimed to explore the experience of extended clinical placements from the perspective of the optometrists who supervised students. It also sought to determine whether there were differences in views between metropolitan and rural practitioners. METHODS: This mixed methods study included a survey and interviews with optometrists who had previously supervised Deakin University optometry students on an extended 26-week (2 x 13-weeks) clinical placement. Lines of enquiry focused on; the benefits and challenges associated with extended placements; areas for improvement; duration of the placement; and willingness to supervise further students. Interviews were transcribed verbatim and analysed using Braun and Clarke's 6 step method of thematic analysis with a qualitative descriptive approach. RESULTS: Supervisors felt that hosting a student prompted greater reflective practice and critical appraisal of clinical decisions. The extended nature of the placement was thought to foster greater immersion in the clinical setting and community for the students and establish a stronger relationship between supervisor and student. Supervisors recognised the importance of role-modelling and mentoring the next generation of optometrists however noted that taking on a student was a sizeable commitment. Willingness to host a student was not dependent on the supervisor's location (rural vs metropolitan) p = 0.57. However, interviews uncovered motivations that were unique to supervisors residing in rural locations, such as succession planning. CONCLUSION: Overall, supervisors were positive about the value of student extended clinical placement in optometry and felt that it was a fulfilling and professionally beneficial experience. Lack of time and financial remuneration were the key downsides highlighted. Schools of optometry might carefully consider engaging in discussion about the duration of such placements, but 26 weeks was considered appropriate by supervisors.

Student perspectives of extended clinical placements in optometry: a qualitative study.

BACKGROUND: The number of students enrolled in health courses at Australian universities is rising, increasing demand for clinical placements. Optometry students have historically undertaken clinical training in short-block rotations at university-led teaching clinics in metropolitan locations. This is changing, with some optometry programs adopting extended placements. These placements are conducted in community-based practices, with many incorporating a rural component to the training. This study explored factors which influence placement success and satisfaction from the perspective of optometry students. METHODS: Nine focus groups were undertaken with 42 final year optometry students upon completion of a 26-week placement (of which at least half was undertaken in a non-metropolitan area, or area where a shortage of optometrists has been identified). Focus groups were audio recorded and transcribed verbatim. Thematic analysis was conducted according to Braun and Clarke's 6 step method. RESULTS: Four key themes were identified during analysis. 'Changing identity', related to how the students grew both personally and professionally, with the extended placement being considered the vital component that allowed students to begin thinking of themselves as clinicians. The theme 'Dealing with complex dynamics and circumstances' predominantly described instances where the student-supervisor relationship was strained, resulting in high levels of anxiety made worse by a perceived lack of university support. 'Optometrist under instruction', related to students feeling that the placement was an ideal opportunity to trial the everyday reality of work without the obligation of an ongoing commitment or employment contract. Finally, the theme 'Rural practice is more rewarding', was about a chance to seek different experiences, meet new people and challenge themselves professionally. CONCLUSION: While the majority of students enjoyed their placement and felt that it was the key component of their training that equipped them for future practice, it is clear that universities and placement providers must provide both students and supervisors thorough and explicit guidance covering placement expectations. Furthermore, student support systems should be embedded into placement programs to ensure where issues arise, they are dealt with promptly and successfully. It is vital that ongoing professional development and pedagogical training for supervisors underpins continued accreditation.

The perceived value and impact of virtual simulation-based education on students' learning: a mixed methods study.

BACKGROUND: Virtual simulations are used throughout healthcare training programs to enable development of clinical skills, however the potential for virtual simulation to enhance cognitive and affective skills is less well understood. This study explored pre-clinical optometry students' perceptions of the impact of virtual simulation on the development of core competency skills including patient-centred care, communication, scientific literacy, and evidence-based practice. METHODS: A mixed methods study was conducted using pre-existing anonymized data from an electronic survey distributed to pre-clinical optometry students enrolled in the double degree Bachelor of Vision Science/Master of Optometry at Deakin University, Australia. The data were interpreted using descriptive statistics and qualitative analysis using constant comparison for thematic analysis. RESULTS: A total of 51 responses were analyzed. Students reported that virtual simulation motivated them to become an optometrist (93%) and to learn beyond the course material (77%). Students reported that after participating in the virtual simulation, their core competency skills improved: patient-centered care (100%) evidence-based practice (93%) and clinical reasoning (93%). The themes identified through qualitative analysis were: enablers to cognitive experience in virtual simulation in optometry education, realism of the virtual simulation design, dimensions of fidelity in virtual simulations design replicated the complexity of the optometric environment, virtual simulation as an enabler for learning and assessment in optometry education, a place to develop cognitive and affective skills and application of learning in the virtual simulation developed an appreciation of future roles and professional identity. CONCLUSION: Optometry students perceived virtual simulation in optometric education as a valuable training and assessment strategy enabled by qualities that generate contextual, cognitive, functional, task and psychological fidelity. The data provide insight to inform how optometry educators can incorporate simulation into the curriculum.

PLAAT1 Exhibits Phosphatidylcholine:Monolysocardiolipin Transacylase Activity.

Tissue-specific cardiolipin fatty acyl profiles are achieved by remodeling of de novo synthesized cardiolipin, and four remodeling enzymes have thus far been identified. We studied the enzyme phospholipase A and acyltransferase 1 (PLAAT1), and we report the discovery that it has phosphatidylcholine (PC):monolysocardiolipin (MLCL) transacylase activity. Subcellular localization was analyzed by differential centrifugation and immunoblotting. Total levels of major phospholipids, and the fatty acyl profile of cardiolipin, were analyzed in HEK293 cells expressing murine PLAAT1 using gas chromatography. Apparent enzyme kinetics of affinity-purified PLAAT1 were calculated using radiochemical enzyme assays. This enzyme was found to localize predominantly to the endoplasmic reticulum (ER) but was detected at low levels in the mitochondria-associated ER matrix. Cells expressing PLAAT1 had higher levels of total cardiolipin, but not other phospholipids, and it was primarily enriched in the saturated fatty acids myristate, palmitate, and stearate, with quantitatively smaller increases in the n-3 polyunsaturated fatty acids linolenate, eicosatrienoate, and eicosapentanoate and the monounsaturated fatty acid erucate. Affinity-purified PLAAT1 did not catalyze the transacylation of MLCL using 1-palmitoyl-2-[14C]-linoleoyl-PC as an acyl donor. However, PLAAT1 had an apparent Vmax of 1.61 µmol/min/mg protein and Km of 126 µM using [9,10-3H]-distearoyl-PC as an acyl donor, and 0.61 µmol/min/mg protein and Km of 16 µM using [9,10-3H]-dioleoyl-PC. PLAAT1 is therefore a novel PC:MLCL transacylase.

Predicting Non-Alcoholic Fatty Liver Disease for Adults Using Practical Clinical Measures: Evidence from the Multi-ethnic Study of Atherosclerosis.

BACKGROUND: Many adults have risk factors for non-alcoholic fatty liver disease (NAFLD). Screening all adults with risk factors for NAFLD using imaging is not feasible. OBJECTIVE: To develop a practical scoring tool for predicting NAFLD using participant demographics, medical history, anthropometrics, and lab values. DESIGN: Cross-sectional. PARTICIPANTS: Data came from 6194 white, African American, Hispanic, and Chinese American participants from the Multi-Ethnic Study of Atherosclerosis cohort, ages 45-85 years. MAIN MEASURES: NAFLD was identified by liver computed tomography (≤ 40 Hounsfield units indicating > 30% hepatic steatosis) and data on 14 predictors was assessed for predicting NAFLD. Random forest variable importance was used to identify the minimum subset of variables required to achieve the highest predictive power. This subset was used to derive (n = 4132) and validate (n = 2063) a logistic regression-based score (NAFLD-MESA Index). A second NAFLD-Clinical Index excluding laboratory predictors was also developed. KEY RESULTS: NAFLD prevalence was 6.2%. The model included eight predictors: age, sex, race/ethnicity, type 2 diabetes, smoking history, body mass index, gamma-glutamyltransferase (GGT), and triglycerides (TG). The NAFLD-Clinical Index model excluded GGT and TG. In the NAFLD-MESA model, the derivation set achieved an AUCNAFLD-MESA = 0.83 (95% CI, 0.81 to 0.86), and the validation set an AUCNAFLD-MESA = 0.80 (0.77 to 0.84). The NAFLD-Clinical Index model was AUCClinical = 0.78 [0.75 to 0.81] in the derivation set and AUCClinical = 0.76 [0.72 to 0.80] in the validation set (pBonferroni-adjusted < 0.01). CONCLUSIONS: The two models are simple but highly predictive tools that can aid clinicians to identify individuals at high NAFLD risk who could benefit from imaging.

Lateral distribution of phosphatidylinositol 4,5-bisphosphate in membranes regulates formin- and ARP2/3-mediated actin nucleation.

Spatial and temporal control of actin polymerization is fundamental for many cellular processes, including cell migration, division, vesicle trafficking, and response to agonists. Many actin-regulatory proteins interact with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and are either activated or inactivated by local PI(4,5)P2 concentrations that form transiently at the cytoplasmic face of cell membranes. The molecular mechanisms of these interactions and how the dozens of PI(4,5)P2-sensitive actin-binding proteins are selectively recruited to membrane PI(4,5)P2 pools remains undefined. Using a combination of biochemical, imaging, and cell biologic studies, combined with molecular dynamics and analytical theory, we test the hypothesis that the lateral distribution of PI(4,5)P2 within lipid membranes and native plasma membranes alters the capacity of PI(4,5)P2 to nucleate actin assembly in brain and neutrophil extracts and show that activities of formins and the Arp2/3 complex respond to PI(4,5)P2 lateral distribution. Simulations and analytical theory show that cholesterol promotes the cooperative interaction of formins with multiple PI(4,5)P2 headgroups in the membrane to initiate actin nucleation. Masking PI(4,5)P2 with neomycin or disrupting PI(4,5)P2 domains in the plasma membrane by removing cholesterol decreases the ability of these membranes to nucleate actin assembly in cytoplasmic extracts.

Early evidence of efficacy for orally administered SPM-enriched marine lipid fraction on quality of life and pain in a sample of adults with chronic pain.

BACKGROUND: Marine lipids contain omega-3 fatty acids that can be metabolized into anti-inflammatory and pro-resolving mediators-namely 17-HDHA and 18-HEPE-which can serve as modulators of the pain experience. The purpose of this study was to determine the impact of 4 weeks of oral supplementation with a fractionated marine lipid concentration, standardized to 17-HDHA and 18-HEPE, on health-related quality of life and inflammation in adults with chronic pain. METHODS: This study was a prospective, non-randomized, open-label clinical trial. Forty-four adults with ≥ moderate pain intensity for at least 3 months were recruited. The primary outcome was change in health-related quality of life (QOL) using the Patient Reported Outcomes Measurement Information System-43 Profile (PROMIS-43) and the American Chronic Pain Association (ACPA) QOL scale. Exploratory outcomes assessed safety and tolerability, changes in anxiety and depression, levels of pain intensity and interference, patient satisfaction, and impression of change. Changes in blood biomarkers of inflammation (hs-CRP and ESR) were also explored. RESULTS: Outcome measures were collected at Baseline, Week 2, and Week 4 (primary endpoint). At Week 4, PROMIS-43 QOL subdomains changed with significance from baseline (p < 0.05), with borderline changes in the ACPA Quality of Life scale (p < 0.052). Exploratory analyses revealed significant changes (p < 0.05) in all measures of pain intensity, pain interference, depression, and anxiety. There were no statistically significant changes in either hs-CRP or ESR, which stayed within normal limits. CONCLUSION: We conclude that oral supplementation with a fractionated marine lipid concentration standardized to 17-HDHA and 18-HEPE may improve quality of life, reduce pain intensity and interference, and improve mood within 4 weeks in adults with chronic pain. The consistency and magnitude of these results support the need for placebo-controlled clinical trials of marine lipid concentrations standardized to 17-HDHA and 18-HEPE. Trial registration ClinicalTrials.gov: Influence of an Omega-3 SPM Supplement on Quality of Life, NCT02683850. Registered 17 February 2016-retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02683850 .

A multiscale biophysical model for the recruitment of actin nucleating proteins at the membrane interface.

The dynamics and organization of the actin cytoskeleton are crucial to many cellular events such as motility, polarization, cell shaping, and cell division. The intracellular and extracellular signaling associated with this cytoskeletal network is communicated through cell membranes. Hence the organization of membrane macromolecules and actin filament assembly are highly interdependent. Although the actin-membrane linkage is known to happen through many routes, the major class of interactions is through the direct interaction of actin-binding proteins with the lipid class containing poly-phosphatidylinositols (PPIs). Among the PPIs, phosphatidylinositol bisphosphate (PI(4,5)P2) acts as a significant factor controlling actin polymerization in the proximity of the membrane by binding to actin-associated proteins. The molecular interactions between these actin-binding proteins and the membrane lipids remain elusive. Here, using molecular modeling, analytical theory, and experimental methods, we investigate the binding of three different actin-binding proteins, mDia2, NWASP, and gelsolin, to membranes containing PI(4,5)P2 lipids. We perform molecular dynamics simulations on the protein-bilayer system and analyze the membrane binding in the form of hydrogen bonds and salt bridges at various PI(4,5)P2 and cholesterol concentrations. Our experimental study with PI(4,5)P2-containing large unilamellar vesicles mimics the computational experiments. Using the multivalencies of the proteins obtained in molecular simulations and the cooperative binding mechanisms of the proteins, we also propose a multivalent binding model that predicts the actin filament distributions at various PI(4,5)P2 and protein concentrations.

Flow in bedrock canyons.

Bedrock erosion in rivers sets the pace of landscape evolution, influences the evolution of orogens and determines the size, shape and relief of mountains. A variety of models link fluid flow and sediment transport processes to bedrock incision in canyons. The model components that represent sediment transport processes are increasingly well developed. In contrast, the model components being used to represent fluid flow are largely untested because there are no observations of the flow structure in bedrock canyons. Here we present a 524-kilometre, continuous centreline, acoustic Doppler current profiler survey of the Fraser Canyon in western Canada, which includes 42 individual bedrock canyons. Our observations of three-dimensional flow structure reveal that, as water enters the canyons, a high-velocity core follows the bed surface, causing a velocity inversion (high velocities near the bed and low velocities at the surface). The plunging water then upwells along the canyon walls, resulting in counter-rotating, along-stream coherent flow structures that diverge near the bed. The resulting flow structure promotes deep scour in the bedrock channel floor and undercutting of the canyon walls. This provides a mechanism for channel widening and ensures that the base of the walls is swept clear of the debris that is often deposited there, keeping the walls nearly vertical. These observations reveal that the flow structure in bedrock canyons is more complex than assumed in the models presently used. Fluid flow models that capture the essence of the three-dimensional flow field, using simple phenomenological rules that are computationally tractable, are required to capture the dynamic coupling between flow, bedrock erosion and solid-Earth dynamics.

Thermodynamic analysis of multivalent binding of functionalized nanoparticles to membrane surface reveals the importance of membrane entropy and nanoparticle entropy in adhesion of flexible nanoparticles.

We present a quantitative model for multivalent binding of ligand-coated flexible polymeric nanoparticles (NPs) to a flexible membrane expressing receptors. The model is developed using a multiscale computational framework by coupling a continuum field model for the cell membrane with a coarse-grained model for the polymeric NPs. The NP is modeled as a self-avoiding bead-spring polymer chain, and the cell membrane is modeled as a triangulated surface using the dynamically triangulated Monte Carlo method. The nanoparticle binding affinity to a cell surface is mainly determined by the delicate balance between the enthalpic gain due to the multivalent ligand-receptor binding and the entropic penalties of various components including receptor translation, membrane undulation, and NP conformation. We have developed new methods to compute the free energy of binding, which includes these enthalpy and entropy terms. We show that the multivalent interactions between the flexible NP and the cell surface are subject to entropy-enthalpy compensation. Three different entropy contributions, namely, those due to receptor-ligand translation, NP flexibility, and membrane undulations, are all significant, although the first of these terms is the most dominant. However, both NP flexibility and membrane undulations dictate the receptor-ligand translational entropy making the entropy compensation context-specific, i.e., dependent on whether the NP is rigid or flexible, and on the state of the membrane given by the value of membrane tension or its excess area.

Indications and administration practices amongst medical cannabis healthcare providers: a cross-sectional survey.

BACKGROUND: The medical use of cannabis has been legislatively restricted for decades in the US and abroad. In recent years, changing local and national policies have given rise to a community of healthcare providers who may be recommending the medical use of cannabis without the benefit of formal clinical practice guidelines or sufficient training and education. In addition, a citizen science movement has emerged whereby unlicensed and untrained individuals are acting as healthcare provider proxies, offering cannabis-specific clinical care to "patients". This study sought to characterize the clinical practice characteristics of these provider groups. METHODS: An anonymous, online survey was designed to describe levels of cannabis-specific education, practice characteristics, indications for medical use, dose, administration forms and adverse effects related to cannabis use. The questionnaire was disseminated via professional medical cannabis associations and by word-of-mouth. It was accessed between June 31-December 31, 2018. A self-selecting sample of respondents (n = 171) completed the survey. RESULTS: Formal education or training in the medical use of cannabis was significantly more common among licensed respondents than unlicensed respondents (95.5% vs 76.9% respectively, OR, 6.3, 95% CI, 1.2-32.3, p = 0.03). The vast majority (n = 74, 83.15%) of licensed respondents reported having recommended cannabis as an adjunct to an existing prescription drug. Almost two-thirds (n = 64, 71.9%) reported having recommended it as a substitute. When delta-9-tetrahydrocannabinol (THC) is the principal therapeutic constituent of interest, vaporization is the most common method of administration recommended (n = 94 responses, 71.4% of respondents). In contrast, when cannabidiol (CBD) is the principal therapeutic constituent of interest, oral administration (sublingual or oromucosal absorption) is the most common method (n = 70 responses, 71.4% of respondents). CONCLUSIONS: Individuals who recommend the medical use of cannabis appear to be self-generating a community standard of practice in the absence of formal clinical guidelines on dosing, interactions and other characteristics. Reducing barriers to clinical research on cannabis products is needed, not only to better understand their risks and benefits, but also to augment the evidence-base for informing clinical practice.

Curvature-undulation coupling as a basis for curvature sensing and generation in bilayer membranes.

We present coarse-grained molecular dynamics simulations of the epsin N-terminal homology domain interacting with a lipid bilayer and demonstrate a rigorous theoretical formalism and analysis method for computing the induced curvature field in varying concentrations of the protein in the dilute limit. Our theory is based on the description of the height-height undulation spectrum in the presence of a curvature field. We formulated an objective function to compare the acquired undulation spectrum from the simulations to that of the theory. We recover the curvature field parameters by minimizing the objective function even in the limit where the protein-induced membrane curvature is of the same order as the amplitude due to thermal undulations. The coupling between curvature and undulations leads to significant predictions: (i) Under dilute conditions, the proteins can sense a site of spontaneous curvature at distances much larger than their size; (ii) as the density of proteins increases the coupling focuses and stabilizes the curvature field to the site of the proteins; and (iii) the mapping of the protein localization and the induction of a stable curvature is a cooperative process that can be described through a Hill function.

Effects of a topical botanically-enriched salve on cutaneous oxygenation.

OBJECTIVE: There is a medical need to evaluate new treatments that may improve wound healing. This study aimed to determine if Original Healing Salve (OHS, Puremedy, Inc.) a topical, botanically-enriched salve (BES), changes distal leg tissue oxygenation in people with type 2 diabetes. METHOD: A randomised, controlled, crossover, double-blinded clinical trial comparing changes in cutaneous oxygen delivery (mean TcPO2) on multiple sites of the lower extremity following application of a botanically-enriched topical salve, as compared with application of the salve's base in patients with type 2 diabetes. Subjects were recruited from the general population as a convenience sample. RESULTS: A total of 16 participants were recruited. Analysis of the primary outcome demonstrated no statistically significant difference in TcPO2 at 30 minutes postapplication when comparing the BES to the base salve (BS) on the leg (-0.39±8.54mmHg; p=0.86). Analyses of secondary outcomes at 30 minutes postapplication indicated that mean TcPO2 was significantly higher than preapplication levels among subjects receiving both the BES (3.70±6.62mmHg; p=0.04) and BS on the leg (4.08±5.21mmHg; p=0.007). On the foot, mean TcPO2 at 30 minutes postapplication was higher in the BES compared with the BS, this difference was not significant (0.98±8.59mmHg; p=0.66). Mean TcPO2 was higher than preapplication levels among subjects receiving both the BES (1.21±7.70mmHg; p=0.54) and BS on the foot (2.19±7.27mmHg; p=0.25). These differences were non-significant. CONCLUSION: These findings support consideration of topical treatments containing botanical ingredients to increase cutaneous oxygen delivery in the lower extremity in patients with type 2 diabetes.

Naturopathy as a Model of Prevention-Oriented, Patient-Centered Primary Care: A Disruptive Innovation in Health Care.

Background and Objective: The concept of a "disruptive innovation," recently extended to health care, refers to an emerging technology that represents a new market force combined with a new value system, that eventually displaces some, or all, of the current leading "stakeholders, products and strategic alliances." Naturopathy is a distinct system of traditional and complementary medicine recognized by the World Health Organization (WHO), emerging as a model of primary care. The objective here is to describe Naturopathy in the context of the criteria for a disruptive innovation. Methods: An evidence synthesis was conducted to evaluate Naturopathy as a potentially disruptive technology according to the defining criteria established by leading economists and health technology experts: (1) The innovation must cure disease; (2) must transform the way medicine is practiced; or (3) have an impact that could be disruptive or sustaining, depending on how it is integrated into the current healthcare marketplace. Results: The fact that Naturopathy de-emphasizes prescription drug and surgical interventions in favor of nonpharmacological health promotion and self-care could disrupt the present economic model that fuels health care costs. The patient-centered orientation of Naturopathy, combined with an emphasis on preventive behaviors and popular complementary and integrative health services like natural products, mind and body therapies, and other therapies not widely represented in current primary care models increase the likelihood for disruption. Conclusions: Because of its patient-centered approach and emphasis on prevention, naturopathy may disrupt or remain a durable presence in healthcare delivery depending on policymaker decisions.

The lysophosphatidic acid acyltransferases (acylglycerophosphate acyltransferases) family: one reaction, five enzymes, many roles.

PURPOSE OF REVIEW: Lysophosphatidic acid acyltransferases (LPAATs)/acylglycerophosphate acyltransferases (AGPATs) are a homologous group of enzymes that all catalyze the de novo formation of phosphatidic acid from lysophosphatidic acid (LPA) and a fatty acyl-CoA. This review seeks to resolve the apparent redundancy of LPAATs through examination of recent literature. RECENT FINDINGS: Recent molecular studies suggest that individual LPAAT homologues produce functionally distinct pools of phosphatidic acid, whereas gene ablation studies demonstrate unique roles despite a similar biochemical function. Loss of the individual enzymes not only causes diverse effects on down-stream lipid metabolism, which can vary even for a single enzyme from one tissue to the next, but also results in a wide array of physiological consequences, ranging from cognitive impairment, to lipodystrophy, to embryonic lethality. SUMMARY: LPAATs are critical mediators of cell membrane phospholipid synthesis, regulating the production of specific down-stream glycerophospholipid species through generation of distinct pools of phosphatidic acid that feed into dedicated biosynthetic pathways. Loss of any specific LPAAT can lead to alterations in cellular and organellar membrane phospholipid composition that can vary for a single enzyme in different tissues, with unique pathophysiological implications.