DOES INCREASING FLOW TO A HIGH FLOW NASAL CANNULA AFFECT MEAN AIRWAY PRESSURE IN AN IN VITRO MODEL? Introduction: High-flow nasal cannulas (HFNC) have become popular with many institutions for administration of oxygen (O2). HFNCs are also being used in pediatric and neonatal populations for administration of continuous positive airway pressure (CPAP) as a treatment for respiratory distress. Adult patients are being treated with HFNCs in a effort to provide a high percentage of O2 and correct hypoxemia and other related conditions. The purpose of this study was to examine the effect of increasing flow via a HFNC to an in vitro model to examine the effect of flow on mean airway pressure (MPAW). Method: An in vitro model to simulate non-labored and labored spontaneous breathing was developed using a Michigan Instrument Laboratory Test and Training Lung (MIL TTL) driven by a Hamilton Galileo ventilator to produce a negatively based, inspired tidal volume. Flow was introduced to the MIL TTL via a 41 French double lumen endotracheal tube. Airway pressure measurements were observed via a pressure monitoring port placed between the MIL TTL and the endotracheal tube and connected to the auxiliary pressure monitoring port located on the front of the Galileo ventilator. A Vapotherm 2000i with adult transfer chamber and adult cannula, a Fisher Paykel Optiflow, and a generic HFNC consisting of a concha column and a Salter labs high-flow cannula were tested at 20, 30, and 40LPM flowrates. Data was recorded using two respiratory rates (12 and 24) and two peak flowrates (35 and 65LPM) to simulate non-labored and labored breathing. All other parameters were unchanged and the I:E ratio was consistent. Data Analysis: SPSS 16.0 for Windows was used to analyze all data for this study. Descriptive statistics, one-way analysis of variance (ANOVA), and post hoc Bonferroni was used for this study. A p value less than 0.05 were considered significant. Results: Average MPAW for all devices were increased at all three flowrates. MPAW was highest at 40LPM flow producing 3.1cmH2O averaged for all HFNCs and both respiratory patterns. The difference in MPAW produced by the three HFNCs were also significant with at p=0.000 at all flow rates. Post hoc Bonferroni adjusted probabilities further showed all device comparisons significant except for Vapotherm-Vapotherm Labored at 30 and 40 LPM flow rates and Vapotherm-Generic Labored at 20 LPM at p<0.05. These three comparisons were at p>0.05 and were statistically equal. The generic HFNC produced the highest MPAW (3.5cmH2O). Conclusion: Increased flow via a HFNC does increase MPAW. The Vapotherm, Optiflow, and generic HFNC did not produce the same level of MPAW in this study.

Background: HFNC system is a novel device used with aerosol therapy and seems to be rapidly accepted. Although there are some studies conducted on HFNC and vibrating mesh nebulizer, the effect of HFNC on aerosol delivery using jet nebulizer or pressurized metered-dose inhaler (pMDI) has not been reported. In an effort to examine the effect of HFNC on aerosol deposition, this study was conducted to quantify aerosol drug delivery with or without a HFNC using either pMDI or jet nebulizer. Methodology: The SAINT model, attached to an absolute filter (Respirgard II, Vital Signs Colorado Inc., Englewood, CO, USA) for aerosol collection, was connected to a pediatric breathing simulator (Harvard Apparatus, Model 613, South Natick, MA, USA). To keep the filter and the SAINT model in upright position to collect aerosolized drug, an elbow adapter was connected between the absolute filter and the breathing simulator. An infant HFNC (Optiflow, Fisher & Paykel Healthcare LTD., Auckland, New Zealand) ran at 3 l/min O2 was attached to the nares of the SAINT model. Breathing parameters used in this study were Vt of 100 mL, RR of 30 breaths/min, and I:E ratio of 1: 1.4. Aerosol drug was administered using: 1) Misty-neb jet nebulizer (Allegiance Healthcare, McGaw Park, Illinois, USA) powered by air at 8 l/min using pediatric aerosol facemask (B&F Medical, Allied Healthcare Products, Saint Louis, MO, USA) to deliver albuterol sulfate (2.5 mg/3 mL NS), and 2) Four actuations of Ventolin HFA pMDI (90 μg/puff) (GlaxoSmithKline, Research Triangle Park, NC, USA) combined with VHC (AeroChamber plus with Flow-Vu, Monaghan Medical, Plattsburgh, NY, USA). Aerosol was administered to the model with and without the HFNC and another without (n=3). Drug was collected on an absolute filter, eluted and measured using spectrophotometry. Independent t tests were performed for data analysis. Statistical significance was determined with a p value of <0.05. Results: The mean inhaled mass percent was greatest for pMDI with (p = 0.0001) or without HFNC (p = 0.003). Removing HFNC from the nares before aerosol treatment trended to increase drug delivery with the jet nebulizer (p = 0.024), and increased drug delivery by 6 fold with pMDI (p = 0.003). Conclusions: Aerosol drug may be administered in pediatrics receiving HFNC therapy using either jet nebulizer or pMDI. However, using pMDI, either with or without HFNC, is the best option. When delivering medical aerosol by mask, whether by jet nebulizer or pMDI, removing HFNC led to an increase in inhaled mass percent. However, the benefit of increased aerosol delivery must be weighed against the risk of lung derecruitment when nasal prongs are removed.

Previous studies on the effects of land cover influence on stream nitrogen have focused on base flow conditions or were conducted specifically within urbanized or primarily agricultural watersheds. While these studies have shown relationships between land cover and nitrogen, this relationship and the scale of influence could change during storms. The purpose of my study was to understand how land cover influences nitrogen in streams during storms. This was address using nine watersheds within the Little Tennessee Basin in North Carolina. While this basin is primarily forested, the nine watersheds have mixed agricultural, built, and forest land cover. Land cover influences were addressed through nitrogen concentration/discharge patterns, nitrogen concentration relationship to land cover, and comparison of storm and base flow nitrogen concentrations over time. Weekly base flow samples and samples from six storm were collected in 2010-2011. Total dissolved nitrogen (TDN), nitrate (NO??), dissolved organic nitrogen (DON), and ammonium (NH?⁺) concentrations were compared among sites. During most storms, DON peaked before the peak of the discharge while NO?? peaked after the peak of the storm. This suggest that DON could be coming from a near stream source or surface runoff while NO?? could be from longer pathways such as subsurface flow or from sources further away on the watershed. NO?? concentration varied among sites, while DON concentration varied more between base flow and storm samples. Examining the different landscape scales from 200-m local corridor, 200-m stream corridor, and entire watershed, watershed land cover was the best predictor for all the nitrogen concentrations. Agricultural and built combined best predicted TDN and NO??, while agricultural land cover was a better predictor of DON. For storms, nitrogen concentrations did not show seasonal patterns but was more related to discharge. Nitrogen concentration increased with discharge during storms and the more intense and longer storms had higher TDN and NO?? concentrations. However, conflicting seasonal trends were seen in monthly base flow. The more forested watersheds had high NO?? during the summer and low NO?? in the winter. For sites with higher NO??, the seasonality was reversed, with higher winter NO?? concentration. The least forested site had relatively constant nitrogen through the year at base flow and concentration decreased for most storms. Further studies on storms and nitrogen transport are needed to understand better the seasonal patterns of nitrogen input during storms. / Master of Science

Recent studies have focused on dissolved organic matter (DOM) cycling throughout river corridors or in reservoirs, but few have explored DOM cycling in commonplace but understudied run-of-river (ROR) reservoir systems. Impoundments disrupt river flow patterns, as they increase hydraulic residence time and alter the flow of DOM downstream. During storms when the majority of DOM loading occurs, impoundments become less likely to hold DOM and will increase export of DOM downstream. In this study, we quantified DOM bioavailability and composition, carbon flux, and carbon dioxide (CO2) gas evasion in a ROR reservoir system at baseflow conditions and during a 1.5-year storm event. This study used a combination of high frequency spatial sensor data geotagged to GPS coordinates along the river to reservoir transition, and grab samples of surface water taken at two U.S. Geological Survey stream gauges and three additional sites. The landscape and shallow flow paths to ROR reservoir systems resulted in the export of both aromatic carbon and labile organic matter present within these waters, as water was mixed and exported downstream. Additionally, the reservoir was a net sink of DOC and BDOC flux, while also a source of DIC flux. Finally, CO2 evasion was magnified by high flow, with the reservoir changing from a sink to a source of CO2 to the atmosphere. ROR reservoirs may undergo "short-circuiting" during high flow, which alters DOM transformations and transport of carbon downstream. Our results provide critical insight on carbon dynamics in ROR reservoir systems and highlight the need to incorporate riverine DOM into carbon budgets, especially under variable flow conditions. / Master of Science / Recent studies have focused on dissolved organic matter (DOM) cycling through river corridors, as DOM provides energy to aquatic food webs and can be converted to carbon dioxide (CO₂) through microbial respiration. Few studies have explored DOM cycling in commonplace but understudied run-of-river (ROR) reservoir systems. ROR reservoirs are created by the implementation of a dam across a river channel and use the flow of the river to generate hydroelectric power. During storms, when the majority of DOM loading occurs, impoundments become less likely to hold DOM and will increase export of DOM downstream. In this study, we quantified DOM quality and composition, DOM transport, and carbon dioxide (CO₂) gas evasion in a ROR reservoir system at baseflow conditions and across a 1.5 year storm event. This study used a combination of high frequency spatial sensor data combined with GPS coordinates along the river to reservoir transition, and grab samples of surface water taken at two U.S. Geological Survey stream gauges and three additional sites. Results show that the landscape and shallow flow paths to ROR reservoir systems resulted in the export of both high and low quality carbon present within these waters, as water was mixed and exported downstream. Additionally, the reservoir was a net sink of DOM flux, retaining 40.7% of the total DOM loading for the storm event. Finally, CO₂ evasion was magnified by the storm event, with the reservoir changing from a sink to a source of CO₂ to the atmosphere. Our results provide critical insight on carbon dynamics in ROR reservoir systems and highlight the need to incorporate riverine DOM into carbon budgets, especially under variable flow conditions.

A constructed wetland (0.08 ha) receiving drainage water from a small agricultural catchment (22 ha) with clay soil, was investigated with respect to phosphorus dynamics and retention. The aim was to evaluate the function of the wetland with respect to phosphorus retention, and relate that to gross sedimentation as measured with sediment traps. Hydraulic load and phosphorus retention were estimated for 2003-2010 based on monitoring data. Furthermore, water quality dynamics was studied during three intensive sampling periods of 3-5 days during 2010. For each period, phosphorus retention was calculated and the relationship between flow and phosphorus concentrations analysed. Additionally, the gross sedimentation rate was estimated using sediment traps, and the phosphorus, carbon and nitrogen content analysed. The results suggested that there was no net retention of phosphorus during 2003-2010, except for 04/05. During the intensive sampling periods, release of phosphorus from the wetland mainly occurred during high flow. Sediment analyses showed that settling of inflow particles mostly occurred in the inlet pond, while the sediment found in a shallow vegetated area and outlet pond likely originated from internal processes rather than from the catchment. In fact, the gross sedimentation of phosphorus during April-July and July-August, respectively, exceeded the measured phosphorus inflow. The results showed that short periods with rapid flow increases were crucial for the wetlands function and thus high frequency sampling must be done during these periods. Furthermore, it seems that the particles lost from the catchment during high flows are too small to settle in the wetland.

In many irrigation systems and networks, there are multiple water users and shareholders who take their water from different locations along a single canal or pipeline. Often, irrigation splitter boxes are used to divert water to multiple shareholders from a single location. The splitter boxes, which can be small and compact, are generally installed at different locations along a piped irrigation supply line. The purpose of a splitter box is to split a specific amount of water so that each user receives their allotted portion, regardless of the flow rate in the system. Each splitter box usually includes two compartments, separated by a wall that acts as a weir for the water to flow over. The water in the supply pipe enters the box and fills the upstream compartment until it spills over the weir. As water flows over the weir, it is separated by vertical dividers. Each divider is positioned to split a certain percentage of the total flow to one of the outlet pipes, which carry the water to various destinations. In general, splitter boxes perform very well at lower flow rates. However, if high flow rates are present in the box, due to under-design of the box or for any reason, the water surface becomes turbulent and the flow profile over the weir becomes disturbed and nonuniform. Because of these conditions, the flow becomes unevenly distributed and an accurate flow split cannot be achieved. This study focuses on developing a solution that can be installed in flow splitter boxes to effectively dissipate energy and uniformly distribute the flow across the length of the weir during times of high flow rates.

Nasal high flow (NHF) therapy is a recent form of non-invasive respiratory support for patients suffering from respiratory distress that supplies high flows of heated and humidified air, oxygen or a mix via a nasal cannula. A number of in vivo studies have proven its effectiveness at improving blood oxygenation; however, its mechanisms of action remain widely unproven. Two proposed mechanisms of action, the CO2 washout of anatomic dead space and the production of positive airway pressure, are investigated in this thesis for the use of the Fisher & Paykel Healthcare Ltd (FPH) Optiflow™ adult nasal cannula through a range of experiments. Five anatomically correct upper airway models produced from computed tomography (CT) scan data via 3D printing were employed during in vitro experiments and two live subjects participated in in vivo measurements. The human respiratory system was faithfully replicated for CO2 washout experiments with physiological CO2 diffusion into the lung replicated by a constant flow of CO2 into the lung pump. In vivo measurement of a natural breathing flow pattern was scaled to an average population tidal volume and respiratory rate for in vitro use. In vitro measurements of static pressure during natural breathing found similar flow resistances across the nasal passage for inspiratory and expiratory flow directions; however, across the entire upper airway greater resistance was seen for inspiration. Introduction of NHF therapy produced significant increases in all mean and peak airway pressures within the upper airway with a flow rate of 30 LPM fulfilling the inspiratory work requirements presented by the upper airway resistance. In vivo and in vitro hot wire anemometry measurements at the exterior nares indicated low velocity and turbulence intensity flows at peak inspiration and a high velocity jet with high turbulence during peak expiration. At natural breathing an in vitro anterior-posterior velopharynx traverse captured low turbulence intensities during peak inspiration and high turbulence intensities during peak expiration. Introduction of NHF therapy had little influence on the turbulence intensity profile of peak expiration yet did cause significant increases in the turbulence intensities during peak inspiration. Measurements of the CO2 concentration near the lung volume over many breath cycles were used to find time-averaged CO2 concentrations. For the standard airway model an average CO2 concentration of 4.88 ± 0.07 %V/V was determined during natural breathing. Implementation of increasing levels of NHF therapy generated significant washout of CO2 reducing this average concentration to a minimum of 3.81 ± 0.11 %V/V at a flow rate of 80 LPM. It was determined that airway geometry significantly affected the efficacy of the NHF therapy though CO2 washout was observed in all five airway models.

Malgré une amélioration de la prise en charge thérapeutique au cours des dernières années, les leucémies aiguës myéloïdes (LAM) pédiatriques sont des hémopathies graves, avec des taux de rechute pouvant atteindre 30% et des taux de survie inférieurs à 75%. Une meilleure description des anomalies moléculaires chez les enfants atteints de LAM est nécessaire pour affiner le pronostic de ces patients. En utilisant le séquençage haut débit ciblé sur 36 gènes et la technique de LD (ligation-dependent) RT-PCR, ce travail décrit le profil moléculaire ainsi que sa signification pronostique chez 385 enfants atteints de LAM de novo inclus dans l’essai clinique prospectif ELAM02. 76 % des patients présentent au moins une mutation parmi les gènes étudiés. Les mutations les plus fréquentes concernent les gènes contrôlant les voies de signalisation des tyrosine kinases (61 %), suivis par les facteurs de transcription (16 %), les suppresseurs de tumeurs (14 %), les modificateurs de la chromatine (9 %), la méthylation de l'ADN (8 %), la cohésine (5 %) et le spliceosome (3 %). De plus, un transcrit de fusion est détecté dans près de la moitié des cas. Au final, les réarrangements impliquant le CBF, les mutations de NPM1 et double-mutations de CEBPA (CEBPA-dm) représentent 37% de la cohorte et définissent un sous-groupe moléculaire au pronostic favorable (survie globale à 3 ans: 92,1%) alors que les fusions impliquant NUP98, les mutations WT1, RUNX1 et PHF6 (15% de la cohorte) constituent un sous-groupe moléculaire au pronostic péjoratif (survie globale à 3 ans: 46,1%). Les réarrangements de KMT2A (21 % de la cohorte) sont associés à un risque intermédiaire. Malgré quelques similitudes, le profil moléculaire et sa signification pronostique diffèrent entre les LAM de l’enfant et de l’adulte. Ces résultats contribuent à affiner la stratification du risque pronostique des LAM pédiatriques et ainsi améliorer leur prise en charge thérapeutique. Cette classification moléculaire reste à valider dans d’autres cohortes pédiatriques indépendantes. / Despite major treatment improvements over the past decades, pediatric acute myeloid leukemia (AML) is still a life-threatening malignancy with relapse rates up to 30% and survival rates below 75%. A better description of the pattern of molecular aberrations in childhood AML is needed to refine prognostication in such patients. We report here the comprehensive molecular landscape using both high-throughput sequencing focused on 36 genes and ligation-dependent RT-PCR in 385 children with de novo AML enrolled in the prospective ELAM02 trial and we evaluated their prognostic significance. 76% of patients had at least one mutation among the genes we screened. The most common class of mutations involved genes that control kinase signaling (61%) followed by transcription factors (16%), tumor suppressors (14%), chromatin modifiers (9%), DNA methylation controllers (8%), cohesin genes (5%) and spliceosome (3%). Moreover, a recurrent transcript fusion was detected in about a half of pediatric patients. Overall, CBF rearrangements, NPM1 and double CEBPA mutations represented 37% of the cohort and defined a favorable molecular subgroup (3-years overall survival: 92.1%) while NUP98 fusions, WT1, RUNX1 and PHF6 mutations (15% of the cohort) segregated into a poor molecular subgroup (3-years overall survival: 46.1%). KMT2A-rearrangements (21% of the cohort) were associated with an intermediate risk. Despite some overlaps, the spectrum of molecular aberrations and their prognostic significance differ between childhood and adult AML. These data have important implications to contribute in refining risk stratification of pediatric AML and show the need for further validations in independent pediatric cohorts.

L’aérosolthérapie est une modalité thérapeutique complexe souvent prescrite dans les services de réanimation et de surveillance continue, les services d’urgences et les unités de soins intensifs, notamment chez les patients obstructifs, ce qui fait des bronchodilatateurs la classe médicamenteuse la plus prescrite par voie aérosolisée. Les patients de ces unités de soins aiguë nécessitent aussi fréquemment un support ventilatoire parmi lesquels le haut débit nasal humidifié se montre être une modalité prometteuse en raison de ses effets physiologiques, y compris chez les patients obstructifs. La question de l’administration d’aérosols de médicaments et notamment de bronchodilatateurs chez des patients soumis au haut débit nasal est donc posée. L’administration d’aérosols médicamenteux au cours du haut débit nasal directement dans le circuit de ce support ventilatoire pourrait être une méthode simple, efficace, voire même bénéfique. / Aerosol therapy is a complex method of drug delivery frequently used in intensive care units, step down units and emergency departments, especially in obstructive patients which makes bronchodilators the most prescribed drug class in critical care. Critically ill patients often require ventilatory support, including nasal high flow therapy which showed promising clinical benefits. Given the physiologic effects of nasal high flow therapy, its implementation may be beneficial for obstructive patients. Consequently, the question of aerosol administration, especially bronchodilators, in patients undergoing nasal high flow arises. Aerosol administration during nasal high flow therapy directly in the high flow circuit could be a simple, efficient and possibly beneficial method. However, technical and physiological issues may jeopardize efficacy of this combined administration.

Two types of rotary gate microvalves are developed for flow modulation in a microfluidic system that operates at high flow rate and/or uses particulate flow. This research work encompasses design, microfabrication, and experimental evaluation of these microvalves in three distinct areas compliant micromechanism, microfluidics, and electromagnetic actuation. The microvalve consists of a suspended gate that rotates in the plane of the chip to regulate flow through the orifices. The gate is suspended by a novel fully-compliant in-plane rotary bistable micromechanism (IPRBM) that advantageously constraints the gate in all other degrees of freedom. Multiple inlet/outlet orifices provide flexibility of operating the microvalve in three different flow/port configurations. The suspended gate is made of a soft magnetic material and is electromagnetically actuated like a rotor in a variable-reluctance stepper motor. Therefore, an external electromagnetic (EM) actuation at the integrated set of posts (stator) causes the gate mass to switch from its default angular position to a second angular position. The microvalve chip is fabricated by electroplating a soft magnetic material, Permalloy (Ni80Fe20) in a sacrificial photoresist mold on a Silicon substrate. The inlet/outlet orifices are then etched into the Silicon substrate from the back-side using deep-reactive ion etch process. Finally, the gate structure is released by stripping the PR and seed layers. This research work presents the realization of a new microvalve design that is distinct from traditional diaphragm-type microvalves. The test results are encouraging and show the potential of these microvalves in effectively modulating flow in microfluidic systems that may not require a tight seal. The microvalve uses a novel in-plane rotary bistable micromechanism that may have other applications such as optical shutters, micro-locks, and passive check valves.