Hysteretic behavior of bladder afferent neurons in response to changes in bladder pressure

Abstract Background Mechanosensitive afferents innervating the bladder increase their firing rate as the bladder fills and pressure rises. However, the relationship between afferent firing rates and intravesical pressure is not a simple linear one. Firing rate responses to pressure can differ depending on prior activity, demonstrating hysteresis in the system. Though this hysteresis has been commented on in published literature, it has not been quantified. Results Sixty-six bladder afferents recorded from sacral dorsal root ganglia in five alpha-chloralose anesthetized felines were identified based on their characteristic responses to pressure (correlation coefficient ≥ 0.2) during saline infusion (2 ml/min). For saline infusion trials, we calculated a maximum hysteresis ratio between the firing rate difference at each pressure and the overall firing rate range (or Hmax) of 0.86 ± 0.09 (mean ± standard deviation) and mean hysteresis ratio (or Hmean) of 0.52 ± 0.13 (n = 46 afferents). For isovolumetric trials in two experiments (n = 33 afferents) Hmax was 0.72 ± 0.14 and Hmean was 0.40 ± 0.14. Conclusions A comprehensive state model that integrates these hysteresis parameters to determine the bladder state may improve upon existing neuroprostheses for bladder control.http://deepblue.lib.umich.edu/bitstream/2027.42/134628/1/12868_2016_Article_292.pd

The Body Dances: Carnival Dance and Organization

Building on the work of Pierre Bourdieu and Maurice Merleau-Ponty we seek to open up traditional categories of thought surrounding the relation `body-organization' and elicit a thought experiment: What happens if we move the body from the periphery to the centre? We pass the interlocking theoretical concepts of object-body/subject-body and habitus through the theoretically constructed empirical case of `carnival dance' in order to re-evaluate such key organizational concepts as knowledge and learning. In doing so, we connect with an emerging body of literature on `sensible knowledge'; knowledge that is produced and preserved within bodily practices. The investigation of habitual appropriation in carnival dance also allows us to make links between repetition and experimentation, and reflect on the mechanism through which the principles of social organization, whilst internalized and experienced as natural, are embodied so that humans are capable of spontaneously generating an infinite array of appropriate actions. This perspective on social and organizational life, where change and permanence are intricately interwoven, contrasts sharply with the dominant view in organization studies which juxtaposes change/ creativity and stability

Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here, we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype, is a cellular adaption to extracellular acidity. LD marker PLIN2 is strongly associated with poor overall survival in breast cancer patients. Acid-induced LD accumulation is triggered by activation of the acid-sensing G-protein-coupled receptor (GPCR) OGR1, which is expressed highly in breast tumors. OGR1 depletion inhibits acid-induced lipid accumulation, while activation by a synthetic agonist triggers LD formation. Inhibition of OGR1 downstream signaling abrogates the lipogenic phenotype, which can be rescued with OGR1 ectopic expression. OGR1-depleted cells show growth inhibition under acidic growth conditions in vitro and tumor formation in vivo. Isotope tracing shows that the source of lipid precursors is primarily autophagy-derived ketogenic amino acids. OGR1-depleted cells are defective in endoplasmic reticulum stress response and autophagy and hence fail to accumulate LDs affecting survival under acidic stress

Super Typhoon Bopha and the Mayo River Debris-Flow Disaster, Mindanao, Philippines, December 2012

Category 5 (C5) Super Typhoon Bopha, the world’s worst storm of 2012, formed abnormally close to the West Pacific Equator, and Bopha’s Mindanao landfall has the record equatorial proximity for C5 storms. Bopha generated a debris flow that buried 500 ha of New Bataan municipality and killed 566 people. New Bataan, established in 1968, had never experienced super typhoons and debris flows. We describe the respective histories of New Bataan and Super Typhoon Bopha; debris flows; and how population growth and unwise settlement practices contribute to Philippine “natural” disasters. The historical record of Mindanao tropical cyclones yields clues regarding how climate change may be exacerbating near-equatorial vulnerability to typhoons. Existing models of future typhoon behavior do not apply well to Mindanao because they evaluate only the tropical cyclones that occur during the main June–October typhoon season, and most Mindanao tropical cyclones occur in the off season. The models also ignore tropical depressions, the most frequent—and commonly lethal—Mindanao cyclones. Including these in annual tallies of Mindanao cyclones up to early 2018 reveals a pronounced and accelerating increase since 1990. Mindanao is susceptible to other natural hazards, including other consequences of climate change and volcanic activity

The Full SPECTRUM: Developing a Tripartite Partnership between Community, Government and Academia for Collaborative Social Policy Research

Problem: In Canadian society, public policies guide the development and administration of social services and systems, including the public education system, the justice system, family services, social housing and income support. However, because social services are often planned and implemented in a ‘siloed’ manner, coordination and collaboration across departments, sectors and organisations is sorely lacking. Data and resource constraints may prevent services being evaluated to ensure they meet the needs of the people for whom they are intended. When the needs of individuals are not addressed, the result is poor outcomes and wasted resources across multiple areas.Our Response: In 2018, we formed the SPECTRUM Partnership in response to a recognised need for collaborative cross-sector approaches to strengthening the policies that shape social services and systems in our country. The tripartite SPECTRUM partnership comprises representatives from community organisations, government and academia, and is an entity designed to conduct social policy research and evaluation, incorporating interdisciplinary perspectives and expertise from its members. Guided by community-driven research questions and building on existing data resources, SPECTRUM seeks to address specific knowledge gaps in social programs, services and systems. New research findings are then translated into viable public policy options, in alignment with government priorities, and presented to policy-makers for consideration.Implications: In this practice-based article, we describe the key steps we took to create the SPECTRUM partnership, build our collective capacity for research and evaluation, and transform our research findings into actionable evidence to support sound public policy. We outline four of SPECTRUM’s achievements to date in the hope that the lessons we learned during the development of the partnership may serve as a guide for others aiming to optimise public policy development in a collaborative evidence-based way

Hazardous base surges of Taal’s 2020 eruption

After 43 years of repose, Taal Volcano erupted on 12 January 2020 forming hazardous base surges. Using field, remote sensing (i.e. UAV and LiDAR), and numerical methods, we gathered primary data to generate well-constrained observed information on dune bedform characteristics, impact dynamic pressures and velocities of base surges. This is to advance our knowledge on this type of hazard to understand and evaluate its consequences and risks. The dilute and wet surges traveled at 50-60 ms−1 near the crater rim and decelerated before making impact on coastal communities with dynamic pressures of at least 1.7 kPa. The base surges killed more than a thousand livestock in the southeast of Taal Volcano Island, and then traveled another ~ 600 m offshore. This work is a rare document of a complete, fresh, and practically undisturbed base surge deposit, important in the study of dune deposits formed by volcanic and other processes on Earth and other planets

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Retrospective evaluation of the use of pembrolizumab in malignant mesothelioma in a real-world Australian population

Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. Results: A total of 98 patients were included with a median age of 70 years (range, 46–91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6–6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6–13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment

Informing evaluation of a smartphone application for people with acquired brain injury: a stakeholder engagement study

Background Brain in Hand is a smartphone application (app) that allows users to create structured diaries with problems and solutions, attach reminders, record task completion and has a symptom monitoring system. Brain in Hand was designed to support people with psychological problems, and encourage behaviour monitoring and change. The aim of this paper is to describe the process of exploring the barriers and enablers for the uptake and use of Brain in Hand in clinical practice, identify potential adaptations of the app for use with people with acquired brain injury (ABI), and determine whether the behaviour change wheel can be used as a model for engagement. Methods We identified stakeholders: ABI survivors and carers, National Health Service and private healthcare professionals, and engaged with them via focus groups, conference presentations, small group discussions, and through questionnaires. The results were evaluated using the behaviour change wheel and descriptive statistics of questionnaire responses. Results We engaged with 20 ABI survivors, 5 carers, 25 professionals, 41 questionnaires were completed by stakeholders. Comments made during group discussions were supported by questionnaire results. Enablers included smartphone competency (capability), personalisation of app (opportunity), and identifying perceived need (motivation). Barriers included a physical and cognitive inability to use smartphone (capability), potential cost and reliability of technology (opportunity), and no desire to use technology or change from existing strategies (motivation). The stakeholders identified potential uses and changes to the app, which were not easily mapped onto the behaviour change wheel, e.g. monitoring fatigue levels, method of logging task completion, and editing the diary on their smartphone. Conclusions The study identified that both ABI survivors and therapists could see a use for Brain in Hand, but wanted users to be able to personalise it themselves to address individual user needs, e.g. monitoring activity levels. The behaviour change wheel is a useful tool when designing and evaluating engagement activities as it addresses most aspects of implementation, however additional categories may be needed to explore the specific features of assistive technology interventions, e.g. technical functions

The Bactofilin Cytoskeleton Protein BacM of Myxococcus xanthus Forms an Extended β-Sheet Structure Likely Mediated by Hydrophobic Interactions

Bactofilins are novel cytoskeleton proteins that are widespread in Gram-negative bacteria. Myxococcus xanthus, an important predatory soil bacterium, possesses four bactofilins of which one, BacM (Mxan_7475) plays an important role in cell shape maintenance. Electron and fluorescence light microscopy, as well as studies using over-expressed, purified BacM, indicate that this protein polymerizes in vivo and in vitro into ~3 nm wide filaments that further associate into higher ordered fibers of about 10 nm. Here we use a multipronged approach combining secondary structure determination, molecular modeling, biochemistry, and genetics to identify and characterize critical molecular elements that enable BacM to polymerize. Our results indicate that the bactofilin-determining domain DUF583 folds into an extended β-sheet structure, and we hypothesize a left-handed β-helix with polymerization into 3 nm filaments primarily via patches of hydrophobic amino acid residues. These patches form the interface allowing head-to-tail polymerization during filament formation. Biochemical analyses of these processes show that folding and polymerization occur across a wide variety of conditions and even in the presence of chaotropic agents such as one molar urea. Together, these data suggest that bactofilins are comprised of a structure unique to cytoskeleton proteins, which enables robust polymerization