Mesenchymal Wnts are required for morphogenetic movements of calvarial osteoblasts during apical expansion.

Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. Time-lapse light-sheet imaging of mouse embryos revealed calvarial progenitors intercalate in 3D in the CM above the eye, and exhibit protrusive and crawling activity more apically. CM cells express non-canonical Wnt/planar cell polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand Wnt5a-/- mutants have less dynamic cell rearrangements and protrusive activity. Loss of CM-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of Osx+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.

Shape-driven confluent rigidity transition in curved biological tissues.

Collective cell motions underlie structure formation during embryonic development. Tissues exhibit emergent multicellular characteristics such as jamming, rigidity transitions, and glassy dynamics, but there remain questions about how those tissue-scale dynamics derive from local cell-level properties. Specifically, there has been little consideration of the interplay between local tissue geometry and cellular properties influencing larger-scale tissue behaviors. Here, we consider a simple two-dimensional computational vertex model for confluent tissue monolayers, which exhibits a rigidity phase transition controlled by the shape index (ratio of perimeter to square root area) of cells, on surfaces of constant curvature. We show that the critical point for the rigidity transition is a function of curvature such that positively curved systems are likely to be in a less rigid, more fluid, phase. Likewise, negatively curved systems (saddles) are likely to be in a more rigid, less fluid, phase. A phase diagram we generate for the curvature and shape index constitutes a testable prediction from the model. The curvature dependence is interesting because it suggests a natural explanation for more dynamic tissue remodeling and facile growth in regions of higher surface curvature. Conversely, we would predict stability at the base of saddle-shaped budding structures without invoking the need for biochemical or other physical differences. This concept has potential ramifications for our understanding of morphogenesis of budding and branching structures.

Polycrystalline Diamond Micro-Hotplates.

Micro-hotplate structures are increasingly being investigated for use in a host of applications ranging from broadband infra-red sources within absorption-based gas sensors to in situ heater stages for ultra-high-resolution imaging. With devices usually fabricated from a conductive electrode placed on top of a freestanding radiator element, coefficient of thermal expansion (CTE) mismatches between layers and electro-migration within the heating element typically lead to failure upon exceeding temperatures of 1600 K. In an attempt to mitigate such issues, a series of hotplates of varying geometry have been fabricated from a single layer of mechanically robust, high thermal conductivity, and low CTE boron-doped polycrystalline diamond. Upon testing under high vacuum conditions and characterization of the emission spectra, the resulting devices are shown to exhibit a grey-body like emission response and reach temperatures vastly in excess of conventional geometries of up to 2731 K at applied powers of ⩽100 mW. Characterization of the thermalization time meanwhile demonstrates rapid millisecond response times, while Raman spectroscopy reveals the performance of the devices is dictated by cumulative graphitization at elevated temperatures. As such, both diamond and sp2 carbon are shown to be promising materials for the fabrication of next-generation micro-hotplates.

Improving bleeding disorder treatment log adherence: An application of the information-motivation-behavioral skills model.

INTRODUCTION: For people with severe bleeding disorders (PwBD) who are prescribed home treatment, treatment logs are an important part of the management of their care. Treatment logs provide a clinical picture of the home treatment regimen and can serve as a communication tool between the medical team and the person with a bleeding disorder. Most importantly, treatment logs allow for the adjustment of the treatment dose and frequency to prevent bleeding episodes. Yet, a large number of PwBD do not complete treatment logs. AIMS: We aimed to develop and implement interventions to increase adherence rates of treatment log completion in PwBD on a home treatment regimen by at least 20% over 2 years. METHODS: We conducted a quality improvement initiative from 2019-2022 involving developing and implementing interventions that were guided by the application of the Information-Motivation-Behavioural Skills Model. Examples of interventions included: the development of educational materials on the different methods of log completion and interactive discussions that involved a patient-driven decision of selecting a treatment log method. Data on the implementation of the theoretically-based interventions as well as outcome data on the success of treatment log completion was reviewed monthly. RESULTS: Following the application of the Information-Motivation-Behavioural Skills Model on the designed and implemented interventions, there was a 20% increase in individuals' adherence with treatment logs completion (N = 68). CONCLUSION: Treatment logs are an important piece of a PwBDs' prescribed home treatment regimen. Quality improvement interventions promoted increased treatment log adherence for PwBDs'prescribed prophylactic home treatment.

Assessment of MRI image distortion based on 6 consecutive years of annual QAs and measurements on 14 MRI scanners used for radiation therapy.

PURPOSE: To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning. METHODS AND MATERIALS: We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered. RESULTS: MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter. CONCLUSION: An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners.

Fractionated pre-operative stereotactic radiotherapy for patients with brain metastases: a multi-institutional analysis.

BACKGROUND: The current standard of care for patients with a large brain metastasis and limited intracranial disease burden is surgical resection and post-operative single fraction stereotactic radiosurgery (SRS). However, post-operative SRS can still lead to substantial rates of local failure (LF), radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated treatments may improve local control by allowing delivery of higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) can minimize rates of LF, RN, and MD. METHODS: A retrospective, multi-institutional analysis was conducted and included patients who had pre-operative FSRT for a large or symptomatic brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. A primary measurement was the rate of a composite endpoint of (1) LF, (2) MD, and/or (3) Grade 2 or higher (symptomatic) RN. RESULTS: 53 patients with 55 lesions were eligible for analysis. FSRT was prescribed to a dose of 24-25 Gy in 3-5 fractions. There were 0 LFs, 3 Grade 2-3 RN events, and 1 MD occurrence, which corresponded to an 8% per-patient composite endpoint event rate. CONCLUSIONS: In this study, the composite endpoint of 8% for pre-operative FSRT was improved compared to previously reported rates with post-operative SRS of 49-60% (N107C, Mahajan etal. JCOG0504) and pre-operative SRS endpoints of 20.6% (PROPS-BM). Pre-operative FSRT appears to be safe, effective, and may decrease the incidence of adverse outcomes. Prospective validation is needed.

Modelling blue carbon farming opportunities at different spatial scales.

There is a growing interest in including blue carbon ecosystems (i.e., mangroves, tidal marshes and seagrasses) in climate mitigation programs in national and sub-national policies, with restoration and conservation of these ecosystems identified as potential activities to increase carbon accumulation through time. However, there is still a gap on the spatial scales needed to produce carbon offsets comparable with terrestrial or agricultural ecosystems. Here, we used the Coastal Blue Carbon InVEST 3.7.0 model to estimate future net carbon sequestration in blue carbon ecosystems along Australia's Great Barrier Reef (hereafter GBR) catchments, considering different management scenarios (i.e., reintroduction of tidal exchange through the removal of barriers, sea level rise, restoring low lying land) at three different spatial scales: whole GBR coastline, regional (14,000-16,300 ha), and local (335-370 ha) scales. The focus of the restoration (i.e., tidal marshes and/or mangroves) was dependent on data availability for each scenario. Furthermore, we also estimated the monetary value of carbon sequestration under each management scenario and spatial scale assessed in the study. We found that large scale restoration of tidal marshes could potentially sequester an additional ∼800,000 tonnes of CO2e by 2045 (potentially generating AU$12 million based on the average Australia carbon price), with greater opportunities when sea level rise is accounted for in the modelling. Also, we found that regional and local projects would generate up to 23 tonnes CO2e ha-1 by the end of the crediting period. Our results can guide future decisions in the blue carbon market and financing schemes, however, the return on investment is dependent on the carbon price and funding scheme available for project implementation.

Using Feedback to Improve Accountability in Global Environmental Health and Engineering.

Engineered environmental health interventions and services in low-income and resource-limited settings-such as water supply and treatment, sanitation, and cleaner household energy services-have had a less than expected record of sustainability and have sometimes not delivered on their potential to improve health. These interventions require both effectively functioning technologies as well as supporting financial, political, and human resource systems, and may depend on user behaviors as well as professionalized service delivery to reduce harmful exposures. In this perspective, we propose that the application of smarter, more actionable monitoring and decision support systems and aligned financial incentives can enhance accountability between donors, implementers, service providers, governments, and the people who are the intended beneficiaries of development programming. Made possible in part by new measurement techniques, including emerging sensor technologies, rapid impact evaluation, citizen science, and performance-based contracting, such systems have the potential to propel the development of solutions that can work over the long-term, allowing the benefits of environmental health improvements to be sustained in settings where they are most critical by improving trust and mutual accountability among stakeholders.

Utility of transesophageal echocardiography to assess real time left atrial pressure changes and dynamic mitral regurgitation following placement of transseptal multistage venous cannula for systemic venous drainage and indirect left ventricular venting in venoarterial extracorporeal membrane oxygenation.

A patient with heart failure due to nonischemic cardiomyopathy presented as a transfer to our institution following peripheral (femoral) venoarterial (VA) extracorporeal membrane oxygenation (ECMO) placement. With peripheral VA ECMO cannulation, the patient continued to have unstable ventricular tachyarrhythmias. Echocardiography demonstrated left ventricular (LV) dilation and severe mitral regurgitation (MR) with clinical and chest X-ray evidence of pulmonary edema. To provide venous drainage and simultaneous decompression of the left atrium (LA) and thereby indirect LV venting, a single multistage venous cannula was placed across the inter-atrial septum (IAS) using the previously described left atrial venoarterial (LA-VA) ECMO cannulation technique. Two- and three-dimensional (3D) transesophageal echocardiography (TEE) demonstrated utility in guiding cannula placement into the appropriate position and providing real time assessment of ventricular decompression and MR severity. There was subsequent improvement in pulmonary edema. This case is thought to be the first demonstration of real time resolution of pulmonary venous flow reversal in a patient undergoing LA-VA ECMO cannulation. This demonstration offers important mechanistic insight into some of the potential benefits of such an approach.

Applications of Alkali Metal Hydroxide Hydrofluxes to the Synthesis of Single-Crystal Ternary Actinide Oxides.

Hydrofluxes are hydrated salts with melting points well below that of the dehydrated salt and boiling points well above that of water, affording a reaction medium, in which mild temperatures and pressures can be accessed for the synthesis of materials. Herein, the use of alkali metal hydroxide hydrofluxes for the synthesis of single crystal α-Na2 NpO4 is described, and the single crystal X-ray structure of α-Na2 NpO4 , along with its X-ray absorption spectra and vibrational spectra, is reported. The ability to synthesize complex oxides of the actinides, in particular, transuranium materials, under mild conditions will serve to advance our ability to explore the structure-property relationships of the f elements.

Measuring Environmental Exposure to Enteric Pathogens in Low-Income Settings: Review and Recommendations of an Interdisciplinary Working Group.

Infections with enteric pathogens impose a heavy disease burden, especially among young children in low-income countries. Recent findings from randomized controlled trials of water, sanitation, and hygiene interventions have raised questions about current methods for assessing environmental exposure to enteric pathogens. Approaches for estimating sources and doses of exposure suffer from a number of shortcomings, including reliance on imperfect indicators of fecal contamination instead of actual pathogens and estimating exposure indirectly from imprecise measurements of pathogens in the environment and human interaction therewith. These shortcomings limit the potential for effective surveillance of exposures, identification of important sources and modes of transmission, and evaluation of the effectiveness of interventions. In this review, we summarize current and emerging approaches used to characterize enteric pathogen hazards in different environmental media as well as human interaction with those media (external measures of exposure), and review methods that measure human infection with enteric pathogens as a proxy for past exposure (internal measures of exposure). We draw from lessons learned in other areas of environmental health to highlight how external and internal measures of exposure can be used to more comprehensively assess exposure. We conclude by recommending strategies for advancing enteric pathogen exposure assessments.

Surface guided imaging during stereotactic radiosurgery with automated delivery.

PURPOSE: To report on the use of surface guided imaging during frameless intracranial stereotactic radiotherapy with automated delivery via HyperArcTM (Varian Medical Systems, Palo Alto, CA). METHODS: All patients received intracranial radiotherapy with HyperArcTM and were monitored for intrafraction motion by the AlignRT® (VisionRT, London, UK) surface imaging (SI) system. Immobilization was with the EncompassTM (Qfix, Avondale, PA) aquaplast mask device. AlignRT® log files were correlated with trajectory log files to correlate treatment parameters with SI reported offsets. SI reported offsets were correlated with gantry angle and analyzed for performance issues at non-zero couch angles and during camera-pod blockage during gantry motion. Demographics in the treatment management system were used to identify race and determine if differences in SI reported offsets are due to skin tone settings. RESULTS: A total of 981 fractions were monitored over 14 months and 819 were analyzed. The median AlignRT® reported motion from beginning to the end of treatment was 0.24 mm. The median offset before beam on at non-zero couch angles was 0.55 mm. During gantry motion when camera pods are blocked, the median magnitude was below 1 mm. Median magnitude of offsets at non-zero couch angles was not found to be significantly different for patients stratified by race. CONCLUSIONS: Surface image guidance is a viable alternative to scheduled mid-treatment imaging for monitoring intrafraction motion during stereotactic radiosurgery with automated delivery.

Effects of a large-scale distribution of water filters and natural draft rocket-style cookstoves on diarrhea and acute respiratory infection: A cluster-randomized controlled trial in Western Province, Rwanda.

BACKGROUND: Unsafe drinking water and household air pollution (HAP) are major causes of morbidity and mortality among children under 5 in low and middle-income countries. Household water filters and higher-efficiency biomass-burning cookstoves have been widely promoted to improve water quality and reduce fuel use, but there is limited evidence of their health effects when delivered programmatically at scale. METHODS AND FINDINGS: In a large-scale program in Western Province, Rwanda, water filters and portable biomass-burning natural draft rocket-style cookstoves were distributed between September and December 2014 and promoted to over 101,000 households in the poorest economic quartile in 72 (of 96) randomly selected sectors in Western Province. To assess the effects of the intervention, between August and December, 2014, we enrolled 1,582 households that included a child under 4 years from 174 randomly selected village-sized clusters, half from intervention sectors and half from nonintervention sectors. At baseline, 76% of households relied primarily on an improved source for drinking water (piped, borehole, protected spring/well, or rainwater) and over 99% cooked primarily on traditional biomass-burning stoves. We conducted follow-up at 3 time-points between February 2015 and March 2016 to assess reported diarrhea and acute respiratory infections (ARIs) among children <5 years in the preceding 7 days (primary outcomes) and patterns of intervention use, drinking water quality, and air quality. The intervention reduced the prevalence of reported child diarrhea by 29% (prevalence ratio [PR] 0.71, 95% confidence interval [CI] 0.59-0.87, p = 0.001) and reported child ARI by 25% (PR 0.75, 95% CI 0.60-0.93, p = 0.009). Overall, more than 62% of households were observed to have water in their filters at follow-up, while 65% reported using the intervention stove every day, and 55% reported using it primarily outdoors. Use of both the intervention filter and intervention stove decreased throughout follow-up, while reported traditional stove use increased. The intervention reduced the prevalence of households with detectable fecal contamination in drinking water samples by 38% (PR 0.62, 95% CI 0.57-0.68, p < 0.0001) but had no significant impact on 48-hour personal exposure to log-transformed fine particulate matter (PM2.5) concentrations among cooks (ß = -0.089, p = 0.486) or children (ß = -0.228, p = 0.127). The main limitations of this trial include the unblinded nature of the intervention, limited PM2.5 exposure measurement, and a reliance on reported intervention use and reported health outcomes. CONCLUSIONS: Our findings indicate that the intervention improved household drinking water quality and reduced caregiver-reported diarrhea among children <5 years. It also reduced caregiver-reported ARI despite no evidence of improved air quality. Further research is necessary to ascertain longer-term intervention use and benefits and to explore the potential synergistic effects between diarrhea and ARI. TRIAL REGISTRATION: Clinical Trials.gov NCT02239250.

Air-clad suspended nanocrystalline diamond ridge waveguides.

A hybrid group IV ridge waveguide platform is demonstrated, with potential application across the optical spectrum from ultraviolet to the far infrared wavelengths. The waveguides are fabricated by partial etching of sub-micron ridges in a nanocrystalline diamond thin film grown on top of a silicon wafer. To create vertical confinement, the diamond film is locally undercut by exposing the chip to an isotropic fluorine plasma etch via etch holes surrounding the waveguides, resulting in a mechanically stable suspended air-clad waveguide platform. Optical characterization of the waveguides at 1550 nm yields an average optical loss of 4.67 ± 0.47 dB/mm. Further improvement to the fabrication process is expected to significantly reduce this waveguide loss.

Effect of slurry composition on the chemical mechanical polishing of thin diamond films.

Nanocrystalline diamond (NCD) thin films grown by chemical vapour deposition have an intrinsic surface roughness, which hinders the development and performance of the films' various applications. Traditional methods of diamond polishing are not effective on NCD thin films. Films either shatter due to the combination of wafer bow and high mechanical pressures or produce uneven surfaces, which has led to the adaptation of the chemical mechanical polishing (CMP) technique for NCD films. This process is poorly understood and in need of optimisation. To compare the effect of slurry composition and pH upon polishing rates, a series of NCD thin films have been polished for three hours using a Logitech Ltd. Tribo CMP System in conjunction with a polyester/polyurethane polishing cloth and six different slurries. The reduction in surface roughness was measured hourly using an atomic force microscope. The final surface chemistry was examined using X-ray photoelectron spectroscopy and a scanning electron microscope. It was found that of all the various properties of the slurries, including pH and composition, the particle size was the determining factor for the polishing rate. The smaller particles polishing at a greater rate than the larger ones.

Behavioral Reactivity Associated With Electronic Monitoring of Environmental Health Interventions--A Cluster Randomized Trial with Water Filters and Cookstoves.

Subject reactivity--when research participants change their behavior in response to being observed--has been documented showing the effect of human observers. Electronics sensors are increasingly used to monitor environmental health interventions, but the effect of sensors on behavior has not been assessed. We conducted a cluster randomized controlled trial in Rwanda among 170 households (70 blinded to the presence of the sensor, 100 open) testing whether awareness of an electronic monitor would result in a difference in weekly use of household water filters and improved cookstoves over a four-week surveillance period. A 63% increase in number of uses of the water filter per week between the groups was observed in week 1, an average of 4.4 times in the open group and 2.83 times in the blind group, declining in week 4 to an insignificant 55% difference of 2.82 uses in the open, and 1.93 in the blind. There were no significant differences in the number of stove uses per week between the two groups. For both filters and stoves, use decreased in both groups over four-week installation periods. This study suggests behavioral monitoring should attempt to account for reactivity to awareness of electronic monitors that persists for weeks or more.

Process evaluation and assessment of use of a large scale water filter and cookstove program in Rwanda.

BACKGROUND: In an effort to reduce the disease burden in rural Rwanda, decrease poverty associated with expenditures for fuel, and minimize the environmental impact on forests and greenhouse gases from inefficient combustion of biomass, the Rwanda Ministry of Health (MOH) partnered with DelAgua Health (DelAgua), a private social enterprise, to distribute and promote the use of improved cookstoves and advanced water filters to the poorest quarter of households (Ubudehe 1 and 2) nationally, beginning in Western Province under a program branded Tubeho Neza ("Live Well"). The project is privately financed and earns revenue from carbon credits under the United Nations Clean Development Mechanism. METHODS: During a 3-month period in late 2014, over 470,000 people living in over 101,000 households were provided free water filters and cookstoves. Following the distribution, community health workers visited nearly 98 % of households to perform household level education and training activities. Over 87 % of households were visited again within 6 months with a basic survey conducted. Detailed adoption surveys were conducted among a sample of households, 1000 in the first round, 187 in the second. RESULTS: Approximately a year after distribution, reported water filter use was above 90 % (+/-4 % CI) and water present in filter was observed in over 76 % (+/-6 % CI) of households, while the reported primary stove was nearly 90 % (+/-4.4 % CI) and of households cooking at the time of the visit, over 83 % (+/-5.3 % CI) were on the improved stove. There was no observed association between household size and stove stacking behavior. CONCLUSIONS: This program suggests that free distribution is not a determinant of low adoption. It is plausible that continued engagement in households, enabled by Ministry of Health support and carbon financed revenue, contributed to high adoption rates. Overall, the program was able to demonstrate a privately financed, public health intervention can achieve high levels of initial adoption and usage of household level water filtration and improved cookstoves at a large scale.

Evaluating Cellular Instrumentation on Rural Handpumps to Improve Service Delivery-A Longitudinal Study in Rural Rwanda.

In rural sub-Saharan Africa, where handpumps are common, 10-67% are nonfunctional at any one time, and many never get repaired. Increased reliability requires improved monitoring and responsiveness of maintenance providers. In 2014, 181 cellular enabled water pump use sensors were installed in three provinces of Rwanda. In three arms, the nominal maintenance model was compared against a "best practice" circuit rider model, and an "ambulance" service model. In only the ambulance model was the sensor data available to the implementer, and used to dispatch technicians. The study ran for seven months in 2014-2015. In the study period, the nominal maintenance group had a median time to successful repair of approximately 152 days, with a mean per-pump functionality of about 68%. In the circuit rider group, the median time to successful repair was nearly 57 days, with a per-pump functionality mean of nearly 73%. In the ambulance service group, the successful repair interval was nearly 21 days with a functionality mean of nearly 91%. An indicative cost analysis suggests that the cost per functional pump per year is approximately similar between the three models. However, the benefits of reliable water service may justify greater focus on servicing models over installation models.

A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract.

Intrinsic sensory neurons (ISNs) of the enteric nervous system respond to stimuli such as muscle tension, muscle length, distortion of the mucosa, and the chemical content in the lumen. ISNs form recurrent networks that probably drive many intestinal motor patterns and reflexes. ISNs express a large number of voltage- and calcium-gated ion channels, some of which are modified by inflammation or repeated physiological stimuli, but how interactions between different ionic currents in ISNs produce both normal and pathological behaviors in the intestine remains unclear. We constructed a model of ISNs including voltage-gated sodium and potassium channels, N-type calcium channels, big conductance calcium-dependent potassium (BK) channels, calcium-dependent nonspecific cation channels (NSCa), intermediate conductance calcium-dependent potassium (IK) channels, hyperpolarization-activated cation (Ih) channels, and internal calcium dynamics. The model was based on data from the literature and our electrophysiological studies. The model reproduced responses to short or long depolarizing current pulses and responses to long hyperpolarizing current pulses. Sensitivity analysis showed that Ih, IK, NSCa, and BK have the largest influence on the number of action potentials observed during prolonged depolarizations. The model also predicts that changes to the voltage of activation for Ih have a large influence on excitability, but changes to the time constant of activation for Ih have a minor effect. Our model identifies how interactions between different iconic currents influence the excitability of ISNs and highlights an important role for Ih in enteric neuroplasticity resulting from disease.

Mathematical modelling of enteric neural motor patterns.

1. The enteric nervous system modulates intestinal behaviours, such as motor patterns and secretion. Although much is known about different types of neurons and simple reflexes in the intestine, it remains unclear how complex behaviours are generated. 2. Mathematical modelling is an important tool for assisting the understanding of how the neurons and reflexes can be pieced together to generate intestinal behaviours. 3. Models have identified a functional role for slow excitatory post-synaptic potentials (EPSPs) by distinguishing between fast and slow EPSPs in the ascending excitation reflex. These models also discovered coordinated firing of similarly located neurons as emergent properties of feed-forward networks of interneurons in the intestine. A model of the recurrent network of intrinsic sensory neurons identified important control mechanisms to prevent uncontrolled firing due to positive feedback and that the interaction between these control mechanisms and slow EPSPs is necessary for the networks to encode ongoing sensory stimuli. This model also showed that such networks may mediate migrating motor complexes. 4. A network model of vasoactive intestinal peptide neurons in the submucosal plexus found this relatively sparse recurrent network could produce uncontrolled firing under conditions that appear to be related to cholera toxin-induced hypersecretion. 5. Abstract modelling of the intestinal fed-state motor patterns has identified how stationary contractions can arise from a polarized network. 6. These models have also helped predict and/or explained pharmacological evidence for two rhythm generators and the requirement of feedback from contractions in the circular muscle.