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The reproductive choices women make affect their health outcomes; however, the relevance of reproductive history on post-reproductive mortality varies according to the population under study. We examine whether the number of children a woman gives birth to, short birth intervals, late childbearing, having twins, and having children who die young have an influence on maternal mortality among the Amish. We use information from Amish directories to examine reproductive patterns of 228 women in this high fertility group. Our results indicate the patterns typically found for maternal mortality in the general population do not hold in our sample of Amish women. We suggest the mediating role of family and community is integral to understanding the maternal health patterns within the Amish community.

Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 and induces pyroptosis (lytic cell death). These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis. The potential clinical utility of NLRP3 inhibitors is substantiated by an expanding list of indications in which NLRP3 activation has been shown to play a detrimental role. Studies of pharmacological inhibition of NLRP3 in nonclinical models of disease using MCC950 in combination with human genetics, epigenetics, and analyses of the efficacy of biologic inhibitors of IL-1β, such as anakinra and canakinumab, can help to prioritize clinical trials of NLRP3-directed therapeutics. Although MCC950 shows excellent (nanomolar) potency and high target selectivity, its pharmacokinetic and toxicokinetic properties limited its therapeutic development in the clinic. Several improved, next-generation inhibitors are now in clinical trials. Hence the body of research in a plethora of conditions reviewed herein may inform analysis of the potential translational value of NLRP3 inhibition in diseases with significant unmet medical need. SIGNIFICANCE STATEMENT: The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is one of the most widely studied and best validated biological targets in innate immunity. Activation of NLRP3 can be inhibited with MCC950, resulting in efficacy in more than 100 nonclinical models of inflammatory diseases. As several next-generation NLRP3 inhibitors are entering proof-of-concept clinical trials in 2020, a review of the pharmacology of MCC950 is timely and significant.

Carrier gases provide the medium for delivery of inhaled aerosol therapies. The physical properties of these gases substantially affect both fluid and aerosol mechanics in the lung. Gas density affects both the pressure/flow relationship in the airways and the extent of turbulence within the flow. These physical properties also affect the operation of some components of respiratory and aerosol drug delivery equipment. The lower resistance associated with breathing low density gases has prompted many studies of therapeutic applications. This includes the respiration of helium-oxygen gas mixtures to improve oxygenation and carbon dioxide removal, and the use of these gases to improve the delivery of inhaled medications. Results of these studies have been mixed but meta-analyses indicate a benefit of helium-oxygen respiration for croup and bronchiolitis and for bronchodilator delivery in obstructive disease. Some of the variability demonstrated in these studies is likely associated with specific technical aspects of how the gases are delivered. The utility of alternate carrier gases for aerosol delivery would be facilitated by simultaneous assessment of both aerosol deposition and clinical effect during studies. Previous successful applications may offer a basis for improved delivery system designs that fully realize the effects that might be available with these gases.

Objectives: Define aerosol and droplet risks associated with routine otolaryngology clinic procedures during the COVID-19 era. Methods: Clinical procedures were simulated in cadaveric heads whose oral and nasal cavities were coated with fluorescent tracer (vitamin B2) and breathing was manually simulated through retrograde intubation. A cascade impactor placed adjacent to the nares collected generated particles with aerodynamic diameters ≤14.1 µm. The 3D printed models and syringes were used to simulate middle and external ear suctioning as well as open suctioning, respectively. Provider’s personal protective equipment (PPE) and procedural field contamination were also recorded for all trials using vitamin B2 fluorescent tracer. Results: The positive controls of nebulized vitamin B2 produced aerosol particles ≤3.30 µm and endonasal drilling of a 3D model generated particles ≤14.1 µm. As compared with positive controls, aerosols and small droplets with aerodynamic diameter ≤14.1 µm were not detected during rigid nasal endoscopy, flexible fiberoptic laryngoscopy, and rigid nasal suction of cadavers with simulated breathing. There was minimal to no field contamination in all 3 scenarios. Middle and external ear suctioning and open container suctioning did not result in any detectable droplet contamination. The clinic suction unit contained all fluorescent material without surrounding environmental contamination. Conclusion: While patients’ coughing and sneezing may create a baseline risk for providers, this study demonstrates that nasal endoscopy, flexible laryngoscopy, and suctioning inherently do not pose an additional risk in terms of aerosol and small droplet generation. An overarching generalization cannot be made about endoscopy or suctioning being an aerosol generating procedure. Level of Evidence: 3

Introduction For some individuals infection with SARS-CoV-2 leading to COVID-19 can result in a life-threatening multi-system disease. Multiple potential pathophysiological mechanisms for the development of cardiovascular complications have been postulated [1]. Early reports suggested that more than a third of hospitalised patients undergoing TTE had evidence of LV impairment [2]. Purpose To ascertain the incidence of ventricular impairment among critically ill adults with COVID-19 admitted to the intensive care unit (ICU). Methods Retrospective analysis of transthoracic echocardiograms (TTE) performed on patients admitted to ICU with COVID-19 between 10th March and 10th May 2020. Archived studies were reviewed by accredited professionals. Studies were performed according to a modified British Society of Echocardiography (BSE) Level 1 protocol [3], with the addition of right ventricle (RV) focused apical 4 chamber, as well as apical 2 and 3 chamber views, and without ECG synchronisation as per infection control protocols. In the majority of patients the left ventricular ejection fraction (LVEF) was estimated from biplane Simpson's method. The RV function was assessed using the TAPSE in most patients. In the remaining patients the LV or RV function was visually assessed. Results Of 179 patients admitted to ICU, 85 (47.5%) had at least one TTE of diagnostic quality. Studies were performed a median of 7 days after ICU admission (IQR 3–17 days). Baseline and clinical characteristics and key echocardiographic measurements are summarised in table 1. The majority of patients were undergoing mechanical ventilation at the time of the scan (94.1%). One hundred and fifty-nine patients (89%) had elevated Troponin T (≥14ng/L) on the day of the study. LV systolic impairment (LVSD) was present in 5 patients (6.0%). This was known to be chronic in 3 patients (1 with coronary artery disease, 1 with chemotherapy induced cardiomyopathy and 1 with dilated cardiomyopathy of unknown aetiology), whilst pre-morbid cardiac function was unknown in the other 2 patients. No patient had severe LVSD (LVEF ≤35%). RV systolic dysfunction (RVSD) was found in 25 patients (31.3%). Amongst patients receiving mechanical ventilation there was no significant difference in Positive End Expiratory Pressure (PEEP) between patients with and without RVSD (9.4cmH2O vs. 9.8cmH2O, p=0.64), however there was a non-significant trend towards lower PaO2/FiO2 (P/F ratio) amongst patients with RVSD (18.9kPa vs 25.7kPa, p=0.07). Conclusions In contrast to other studies which have reported high frequency of LV impairment amongst hospitalised patients with COVID-19 [3], de novo LVSD was rarely found in this study, occurring in just 2 patients (2.4%), and being severe in neither. RV dilatation and systolic impairment were commonly found. A trend towards lower P/F ratios in patients with RVSD suggests severity of lung injury may be a factor in developing RV impairment. Funding Acknowledgement Type of funding sources: None.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from the dysregulation of signaling pathways that control intrathymic T-cell development. Relapse rates are still significant, and prognosis is particularly bleak for relapsed patients. Therefore, development of novel therapies specifically targeting pathways controlling leukemia-initiating cell (LIC) activity is mandatory for fighting refractory T-ALL. The interleukin-7 receptor (IL-7R) is a crucial T-cell developmental pathway that is commonly expressed in T-ALL and has been implicated in leukemia progression; however, the significance of IL-7R/IL-7 signaling in T-ALL pathogenesis and its contribution to disease relapse remain unknown. To directly explore whether IL-7R targeting may be therapeutically efficient against T-ALL relapse, we focused on a known Notch1-induced T-ALL model, because a majority of T-ALL patients harbor activating mutations in NOTCH1, which is a transcriptional regulator of IL-7R expression. Using loss-of-function approaches, we show that Il7r-deficient, but not wild-type, mouse hematopoietic progenitors transduced with constitutively active Notch1 failed to generate leukemia upon transplantation into immunodeficient mice, thus providing formal evidence that IL-7R function is essential for Notch1-induced T-cell leukemogenesis. Moreover, we demonstrate that IL-7R expression is an early functional biomarker of T-ALL cells with LIC potential and report that impaired IL-7R signaling hampers engraftment and progression of patient-derived T-ALL xenografts. Notably, we show that IL-7R–dependent LIC activity and leukemia progression can be extended to human B-cell acute lymphoblastic leukemia (B-ALL). These results have important therapeutic implications, highlighting the relevance that targeting normal IL-7R signaling may have in future therapeutic interventions, particularly for preventing T-ALL (and B-ALL) relapse.

CFTR function is required for normal mucociliary clearance (MCC) and cough-assisted clearance (CC). Lumacaftor-ivacaftor is approved for use in people with cystic fibrosis (CF) carrying two copies of F508del-CFTR. In this observational study performed at four study sites, we characterized the effect of lumacaftor-ivacaftor on mucociliary and cough clearance and related this to other clinical and research endpoints after one month of treatment. Twenty-five adolescents and adults were enrolled. No effect on whole lung MCC was observed, but CC was significantly increased. Sweat chloride improved by 18 mEq/L in this group, indicating a modest restoration of CFTR activity, but no demonstrable change in FEV1 or lung clearance index was observed. We speculate that the modest effect of lumacaftor-ivacaftor on CFTR function was insufficient to yield an improvement in MCC.

Background: Infants undergoing congenital cardiac surgery with cardiopulmonary bypass are at high risk for respiratory complications. As impaired airway mucociliary clearance (MCC) can potentially contribute to pulmonary morbidity, our study objective was to measure airway clearance in infants undergoing congenital cardiac surgery and examine correlation with clinical covariables that may impair airway clearance function.Materials and Methods: Airway clearance in infants was measured over 30 min using inhaled nebulized Technetium 99m sulfur colloid administered either via a nasal cannula or the endotracheal tube in intubated infants. This was conducted bedside with a portable gamma camera. No difficulty was encountered in positioning the gamma camera over the patient, and neither the camera nor the MCC scan interfered with routine medical care or caused any adverse events. Patient and perioperative variables were examined relative to the MCC measurements.Results: We prospectively enrolled 57 infants undergoing congenital cardiac surgery and conducted a single MCC scan per patient. MCC data from 42 patients were analyzable, including five pre-operative, 15 (40.5%) in the immediate post-operative period (days 1–2), and 22 (59.5%) were later post-operative (≥3 days). Pre-operative MCC was inversely proportional to days requiring post-operative mechanical ventilation (p = 0.006) and non-invasive positive pressure ventilation (p = 0.017). MCC was higher at later post-operative days (p = 0.002) with immediate post-operative MCC being lower (3%; 0–13%) than either pre-operative (21%; 4–25%) (p = 0.091) or later post-operative MCC (18%; 0–29%) (p = 0.054). Among the infants with low post-operative MCC, significantly more were pre-mature [5/19 (26%) vs. 0/18 (0%); p = 0.046], were intubated [14/19 (75%) vs. only 7/18 (39%); p = 0.033] and were receiving higher FiO2 (40%, 27–47% vs. 26%, 21–37%; p = 0.015).Conclusions: This is the first study to show that infants undergoing congenital cardiac surgery have impaired MCC. MCC appeared lowest in the immediate post-operative period. Worse MCC was associated with pre-maturity, mechanical ventilation, or receiving higher FiO2. These findings suggest MCC scans should be further explored for informing clinical decision making to improve post-surgical respiratory outcomes. The possible therapeutic benefit of airway clearance maneuvers for infants with poor MCC function should also be investigated.

HYPOTHESIS: Aerosols are generated during mastoidectomy and mitigation strategies may effectively reduce aerosol spread. BACKGROUND: An objective understanding of aerosol generation and the effectiveness of mitigation strategies can inform interventions to reduce aerosol risk from mastoidectomy and other open surgeries involving drilling. METHODS: Cadaveric and fluorescent three-dimensional printed temporal bone models were drilled under variable conditions and mitigation methods. Aerosol production was measured with a cascade impactor set to detect particle sizes under 14.1 µm. Field contamination was determined with examination under UV light. RESULTS: Drilling of cadaveric bones and three-dimensional models resulted in strongly positive aerosol production, measuring positive in all eight impactor stages for the cadaver trials. This occurred regardless of using coarse or cutting burs, irrigation, a handheld suction, or an additional parked suction. The only mitigation factor that led to a completely negative aerosol result in all eight stages was placing an additional microscope drape to surround the field. Bone dust was scattered in all directions from the drill, including on the microscope, the surgeon, and visually suspended in the air for all but the drape trial. CONCLUSIONS: Aerosols are generated with drilling the mastoid. Using an additional microscope drape to cover the surgical field was an effective mitigation strategy to prevent fine aerosol dispersion while drilling.

BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

While many studies have examined the relationship between social ties and joining social movements and religious groups, few studies have investigated the relationship between social ties and the likelihood of exiting such groups. Additionally, research has not considered how geography affects the membership dynamics of geographically-based congregations, specifically whether factors associated with residential mobility may also affect congregational exit in geographically-based congregations. The purpose of this study is to examine how familial ties and place of employment affect congregational exit in geographically-based congregations. Drawing on social network and residential mobility research, this study hypothesizes that having parents and/or adult children in the same congregation and having minor children decreases the likelihood of congregational exit and working farther away from the congregation increases it. This study draws on longitudinal archival data from one Amish congregation in the Holmes County Ohio Settlement. It tests the hypotheses using logistic regression models. The results show that having one’s parents/adult children in the congregation and working close to the congregation are associated with a reduced likelihood of congregational exit. Having minor children in one’s household is not associated with congregational exit. This is one of the first studies to consider how geographical requirements for congregational membership has implications for congregational exit. Given the results, congregations may be able to increase member retention by creating multigenerational ministries that support extended families and by advertising in local places of employment. As occupations increasingly shift to being primarily outside the home, Amish congregations in particular may experience more member turnover and membership instability.

Objective: During the COVID-19 era, a reliable method for tracing aerosols and droplets generated during otolaryngology procedures is needed to accurately assess contamination risk and to develop mitigation measures. Prior studies have not investigated the reliability of different fluorescent tracers for the purpose of studying aerosols and small droplets. Objectives include (1) comparing vitamin B2, fluorescein, and a commercial fluorescent green dye in terms of particle dispersion pattern, suspension into aerosols and small droplets, and fluorescence in aerosolized form and (2) determining the utility of vitamin B2 as a fluorescent tracer coating the aerodigestive tract mucosa in otolaryngology contamination models. Methods: Vitamin B2, fluorescein, and a commercial fluorescent dye were aerosolized using a nebulizer and passed through the nasal cavity from the trachea in a retrograde-intubated cadaveric head. In another scenario, vitamin B2 was irrigated to coat the nasal cavity and nasopharyngeal mucosa of a cadaveric head for assessment of aerosol and droplet generation from endonasal drilling. A cascade impactor was used to collect aerosols and small droplets ≤14.1 µm based on average aerodynamic diameter, and the collection chambers were visualized under UV light. Results: When vitamin B2 was nebulized, aerosols ≤5.4 µm were generated and the collected particles were fluorescent. When fluorescein and the commercial water tracer dye were nebulized, aerosols ≤8.61 µm and ≤2.08 µm respectively were generated, but the collected aerosols did not appear visibly fluorescent. Endonasal drilling in the nasopharynx coated with vitamin B2 irrigation yielded aerosols ≤3.30 µm that were fluorescent under UV light. Conclusion: Vitamin B2’s reliability as a fluorescent tracer when suspended in aerosols and small droplets ≤14.1 µm and known mucosal safety profile make it an ideal compound compared to fluorescein and commercial water-based fluorescent dyes for use as a safe fluorescent tracer in healthcare contamination models especially with human subjects.

National and international guidelines recommend droplet/airborne transmission and contact precautions for those caring for coronavirus disease 2019 (COVID-19) patients in ambulatory and acute care settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, an acute respiratory infectious agent, is primarily transmitted between people through respiratory droplets and contact routes. A recognized key to transmission of COVID-19, and droplet infections generally, is the dispersion of bioaerosols from the patient. Increased risk of transmission has been associated with aerosol generating procedures that include endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, turning the patient to the prone position, disconnecting the patient from the ventilator, noninvasive positive-pressure ventilation, tracheostomy, and cardiopulmonary resuscitation. The knowledge that COVID-19 subjects can be asymptomatic and still shed virus, producing infectious droplets during breathing, suggests that health care workers (HCWs) should assume every patient is potentially infectious during this pandemic. Taking actions to reduce risk of transmission to HCWs is, therefore, a vital consideration for safe delivery of all medical aerosols. Guidelines for use of personal protective equipment (glove, gowns, masks, shield, and/or powered air purifying respiratory) during high-risk procedures are essential and should be considered for use with lower risk procedures such as administration of uncontaminated medical aerosols. Bioaerosols generated by infected patients are a major source of transmission for SARS CoV-2, and other infectious agents. In contrast, therapeutic aerosols do not add to the risk of disease transmission unless contaminated by patients or HCWs.

In this article we use network theory to explain the adoption of the Protestant Reformation. We use new historical data on the connections between Hansa towns that allow us to conduct the first social network study of the Protestant Reformation. Based on an analysis of cities in central and Western Europe between 1517 and 1530, we find evidence for diffusion through both simple and complex contagion. Our operationalization of network data based on medieval Hansa Diets points to the complex association between tie weights (i.e., the strength of ties) and numbers of ties in network diffusion. Using optimal tuning parameters for simple adoption models, we show that a combination of strong ties and weak ties fostered Protestant adoption in northern cities.

Across the globe, governments restricted social life to slow the spread of COVID-19. Several conservative Protestant sects resisted these policies in the United States. We do not yet know if theology shaped the resistance or if it was more a product of a polarized national political context. We argue that the country context likely shapes how conservative Protestants’ moral worldview affects their perceptions of the pandemic and government restrictions. Countries implementing more regulations, those with limited access to healthcare, food, and other essential services, and those with past histories of epidemics may all shape residents’ perceptions. Drawing on the case of American Amish and Mennonite missionaries stationed abroad, we content-analyzed accounts of the pandemic from an international Amish and Mennonite correspondence newspaper. We found that the missionaries’ perceptions of the pandemic and governmental restrictions differ from those of their U.S. counterparts, which suggests that context likely shapes how religious moral worldviews express themselves concerning public health interventions.

Rationale: OPEP therapy when combined with nebulised drug delivery or hypertonic saline offers the potential to reduce combined treatment time. Aerosol deposition scintigraphy was undertaken to assess in vivo pulmonary deposition from a BAN (AEROECLIPSE* II) coupled to an OPEP device (Aerobika*) compared to deposition from the nebuliser alone. Methods: Eight healthy subjects received albuterol (2.5 mg/3mL) admixed with 2 mCi of Tc-DTPA (Technetium-99m bound to diethylenetriaminepentaacetic acid) administered using the BAN alone and again when the BAN was combined with the OPEP device. Regional doses were then determined from anterior and posterior gamma camera images collected after delivery. Lung perimeters were defined using Cobalt-57 transmission scans and applied to Tc-DTPA deposition images. Results were expressed as a percentage of baseline counts. Results: Average age of all 8 subjects (4 male, 4 female) was 33 years. Whole lung deposition was, on average, 31±13 vs 32±13% of loaded dose for BAN alone and BAN+OPEP respectively. Conclusions: The delivery of medication from the AEROECLIPSE* II BAN to the lungs was not significantly affected by the incorporation of the Aerobika* OPEP device. This therapy could offer the clinician the opportunity for combined aerosol/OPEP therapy (ie in cystic fibrosis patients) thereby reducing the time needed for the patient to take nebuliser and OPEP treatment separately.

BACKGROUND A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. METHODS Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. RESULTS Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (

Pediatric patients are very dependent on inhaled aerosol medications. There are significant differences in how these aerosols deposit in the lungs of children vs. adults that may affect the efficacy of the therapies. Inefficient aerosol delivery to children, caused by factors such as high mouth and throat deposition during oral inhalation, significant losses within adjunct devices such as masks, and high rates of nasal deposition during cannula delivery, can lead to dosing that is difficult to control. Here we discuss the methods, such as deposition scintigraphy, that are used to assess inhaled dose in vivo and review previous studies where these techniques have been applied to measure dosing in children. This includes studies of nebulizers and metered dose inhalers and delivery through adjuncts such as facemasks and nasal cannulas. We discuss the factors that can lead to inefficient inhaled drug delivery and high levels of mouth and throat deposition in children. Finally, we propose areas of innovation to improve inhaled drug delivery to this population. There is a need for child-specific technologies for inhaled drug delivery. This includes the use of smart devices that can guide pediatric breathing patterns and better engage children during treatments, the use of smaller aerosols which are less likely to deposit in the upper airways after inhalation, and the design of better nasal cannula interfaces for aerosol delivery to infants.

Background: The cryopyrin-associated periodic syndromes (CAPS) are a group of inherited disorders associated with systemic auto-inflammation. CAPS result from gain-of-function mutations in NLRP3, which result in formation of an intracellular protein complex known as the NLRP3 inflammasome. This leads to overproduction of IL-1β and other pro-inflammatory signals, resulting in inflammatory symptoms. Treatments for NLRP3-related diseases are biologic agents that directly target IL-1β. We sought to determine if the orally available small molecule NLRP3 inhibitor MCC950 could inhibit IL-1β ex vivo in a cohort of patients with autoinflammatory disease. Methods: Patients were recruited to donate blood, from which PBMCs were isolated and assayed in the presence of MCC950 to determine inhibitory efficacy. Results: We found that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and mature IL-1β was higher in ex vivo PBMCs from CAPS patients than healthy donors. MCC950 inhibited production of mature IL-1β in PBMC from CAPS patients with a range of mutations and blocked NLRP3 activity in an in vitro mutation reconstitution assay. Similar results were observed with PBMC from two patients with Schnitzler’s Syndrome, another auto-inflammatory disease. Conclusions: The NLRP3 inflammasome inhibitor MCC950 blocked constitutive activation of NLRP3 observed in the PBMCs of CAPS patients. This study highlights the potential utility of NLRP3 inhibition by a small molecule for rare autoinflammatory diseases that are driven by NLRP3.

Background The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes. Methods We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures. Results Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores. Conclusions Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function. Trial registration ClinicialTrials.gov, NCT01521338. Funding CFF Therapeutics (GOAL11K1).

Aim Nasal cannulas are used to provide oxygen support for infants and have been considered as a means for delivering aerosols to the lungs. To measure mucociliary clearance in the lungs of infants with congenital heart defects, we delivered radiopharmaceutical aerosols via a nasal cannula. Here we report on the pulmonary and nasal deposition of these aerosols. Method A total of 18 infants (median age = 26 days; quartiles = 11-74 days) performed clearance measurements soon before or after corrective cardiac surgery. The regional aerosol deposition was assessed using gamma camera imaging. Results Cannula flow rate significantly affected pulmonary dosing. Flow rates useful for oxygen support were associated with low pulmonary deposition (2 L/min; mean, 4.5% of deposited dose; range, 2%-9%; n = 7) and high nasal deposition. Much lower cannula flow rates increased the pulmonary deposition (0.2 L/min; mean, 33.5% of deposited dose; range, 15%-51%; n = 5; P = 0.005 vs 2 L/min). The ratio of nose/lung dosing was approximately 26:1 at 2 L/min and 2:1 at 0.2 L/min. Bench studies demonstrated cannula output rates of 10.2 ± 1.7% (2 L/min) and 3.3 ± 0.4% (0.2 L/min) of the loaded nebulizer dose during a 2-minute delivery. Combining in vitro and in vivo results, we estimate that 0.46% of the loaded nebulizer dose reaches the lungs at 2 L/min vs 1.10% at 0.2 L/min during a 2-minute delivery. Conclusion With the delivery system used here, pulmonary aerosol delivery via nasal cannula was very inefficient at the flow rates required to provide oxygen support. Even at low flows, nasal deposition was substantial and local toxicity must be considered.

Skin damage is a clinical manifestation of both urinary incontinence (UI) and/or fecal incontinence (FI). Incontinence associated dermatitis (IAD) is characterized by irritation and inflammation of the skin from prolonged exposure to urine or stool. IAD can affect many different groups of patients but is most prevalent in the elderly and those with medical comorbidities. Prevention should be targeted to this “at risk” population, however it is known that the prevalence and incidence rates for IAD are significant across all care settings. Complications include infections, pain, skin damage, and pressure ulcers. Management goals should address skin maintenance, protection from fecal and urinary irritants, pain management, and treatment of secondary infections (www.wocn.org, Doughty et al., J Wound Ostomy Continence Nurs 39(3):303–315, 2012).

Aim: Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. Method: In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. Results: Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. Conclusions: The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways.

Inhaled cyclosporine (CsA) is being investigated as a prophylaxis for lung transplant rejection. Lung deposition and systemic exposure of nebulized CsA in lung transplant patients was evaluated as part of the Phase 3 cyclosporine inhalation solution (CIS) trial (CYCLIST).Ten patients received 300 mg of CIS (62.5 mg/mL CsA in propylene glycol) admixed with 148 MBq of Tc-DTPA (technetium-99m bound to diethylenetriaminepentaacetic acid) administered using a Sidestream(®) disposable jet nebulizer. Deposition was assessed using a dual-headed gamma camera. Blood samples were collected over a 24-hr time period after aerosol dosing and analyzed for CsA levels. A pharmacokinetic analysis of the resulting blood concentration versus time profiles was performed.The average total deposited dose was 53.7 ± 12.7 mg. Average pulmonary dose was 31.8 ± 16.3 mg, and stomach dose averaged 15.5 ± 11.1 mg. Device performance was consistent, with breathing maneuvers influencing dose variation. Predose coaching with five of 10 patients reduced stomach deposition (22.6 ± 11.2 vs. 8.3 ± 5.2 mg; p=0.03). Blood concentrations declined quickly from a maximum of 372 ± 140 ng/mL to 15.3 ± 9.7 ng/mL at 24 hr post dose. Levels of AUC(0-24) [area under the concentration vs. time curve from 0 to 24 hr] averaged 1,493 ± 746 ng hr/mL. On a three times per week dose regimen, this represents5% of the weekly systemic exposure of twice per day oral administration.Substantial doses of CsA can be delivered to the lungs of lung transplant patients by inhaled aerosol. Systemic levels are small relative to typical oral CsA administration.

New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ∼ 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

Airborne particulate matter may induce health risk with inhalation. Special concerns exist for deployed military personnel with inhaled particulate matter in desert environments. Continuous positive airway pressure (CPAP) used in obstructive sleep apnea may facilitate inhalation of particulate matter. We evaluated the ability of commercial CPAP filter systems to eliminate inhalation of particulate matter. An ultrasonic medical nebulizer (DeVilbliss Ultraneb, DeVilbliss, Somerset, PA) atomized liquid producing “respirable” aerosol. Technetium-99m diethylene triamine pentaacetic acid dissolved in water was also aerosolized to quantify aerosol inhalation. A high efficiency particulate air (HEPA) filter placed at the patient–hose connection port in the bilevel positive airway pressure (BPAP) device captured the aerosol inbound to the patient. The HEPA filter provided a means to quantify aerosol dose delivered to a simulated patient. Commercial foam and ultrafine filters were assessed with aerosol to determine the simulated patient exposure. Foam and ultrafine filters used together allowed 1.5% or less of aerosol volume to pass through the BPAP system. Foam filters alone allowed an average of 18.9% of aerosol delivered to pass through the BPAP system. Foam and ultrafine filters used together in BPAP systems provide excellent aerosol filtration in this laboratory simulation of BPAP use.

Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients.We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B.Concentrations of amphotericin B in ELF (median, 25-75 IQR) were at 4 hr (n=5) 7.20 μg/mL (1.3-17.6), 24 hr (n=6) 8.26 μg/mL (3.9-82.7), 48 hr (n=5) 2.15 μg/mL (1.4-5.5), 72 hr (n=4) 1.25 μg/mL (0.75-5.5), 96 hr (n=6) 0.86 μg/mL (0.55-1.4), 120 hr (n=4) 1.04 μg/mL (0.44-1.6), 144 hr (n=1), 4.25 μg/mL, 168 hr (n=3) 1.14 μg/mL, and 192 hr (n=1) 1 μg/mL. The plasma concentration of the drug remained below 0.08 μg/mL at all time points. During the study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec.We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.

Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption. The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption. Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42% x h( -1) versus 32% x h(-1), p = 0.03). The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.

Helium and oxygen gas mixtures (heliox) have become an area of renewed interest in pediatric emergency and critical care for the treatment of acute asthma exacerbations and bronchiolitis. After a review of recent literature on heliox, this article will provide an overview of delivery techniques. This article will primarily focus on heliox inhalation therapy and heliox-driven nebulizer therapy for acute asthma exacerbations. The emergence of heliox inhalation therapy for acute viral bronchiolitis will also be addressed.

In most circumstances, a nasal route for the delivery of pulmonary aerosol medications is rarely considered; however, in specific instances, this route may be quite useful. Consider, for example, the delivery of aerosol treatments during humidified high-flow nasal cannula use in pediatric critical care, or continuous aerosol delivery via cannula for medications with short durations of action. The goal of this study was to evaluate the potential for delivering aerosols via nasal cannula through in vitro studies of aerosol output and size. The system utilized for testing included an Aerogen Solo nebulizer downstream of a heater/humidifier system, followed by a nasal cannula and an aerosol collection apparatus. Adult, pediatric, and infant cannulas were tested with and without an inhalation-only breathing simulator. The cannulas were driven by 3 lpm (50 psig) oxygen flows. Dose quantification was performed using radioisotope techniques. Total cannula output and system losses were measured. Aerosol size measurements were made from the nebulizer, from the heating tube, and from the prongs of the adult and pediatric cannulas, using laser-diffraction techniques. Total cannula output ranged from 8.4-25.1% and 18.6-26.9% of loaded dose, without and with the addition of inhalation flows. Volume median diameters were 2.2 +/- 0.2 microm from the adult cannula and 1.9 +/- 0.3 microm from the pediatric cannula. Ninety percent of the aerosol volume was in sizes smaller than 4.2 +/- 0.4 microm (adult) and 3.8 +/- 0.5 microm (pediatric). System losses were highest in the nebulizer-humidifier connectors, heated tube, and humidifier. Losses in the nebulizer were very low (2.2-3.5%). This study demonstrates that aerosols can be efficiently delivered through a humidified high-flow nasal cannula system. Further study is required to determine if this route is viable for pulmonary delivery.

Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis.

Imaging techniques have been used extensively to study the delivery of inhaled medications. Deposition scintigraphy involves the quantification of deposited aerosol dose and is performed using 2-dimensional planar or 3-dimensional positron emission tomography (PET) or single-photon-emission computed tomography (SPECT) imaging techniques. Planar techniques have an extensive history of use, and quantification methods are well established. SPECT and PET techniques can provide better dose localization, but quantification is more complex, and the techniques are in more limited use. Aerosols have also been used to deliver radiopharmaceutical probes for the imaging of lung physiology. These studies include measurements of ventilation, mucus and cough clearance, and, more recently, liquid absorption in the airways. Clearance measurements have been used to assess therapeutic response in conditions such as cystic fibrosis. Future directions in aerosol-based imaging are likely to include use of novel probes to measure new physiological processes in the lung, more thorough integration of anatomical imaging, and use of multiple probes to simultaneously image drug and disease or interacting physiological processes.

Though new local anesthetics (LA), effective test-dosing, and new regional anesthetic techniques may have improved the safety of regional anesthesia, the optimal management plan for LA-induced cardiac toxicity remains uncertain. Accordingly, we evaluated current approaches to LA cardiotoxicity among academic anesthesiology departments in the United States. A 19-question survey regarding regional anesthesia practices and approaches to LA cardiac toxicity was sent to the 135 academic anesthesiology departments listed by the Society of Academic Anesthesiology Chairs-Association of Anesthesiology Program Directors. Ninety-one anonymously completed questionnaires were returned, at a response rate of 67%. The respondents were categorized into groups according to the number of peripheral nerve blocks (PNBs) performed each month:70 PNBs (38%), 51-70 PNBs (13%), 31-50 PNBs (20%), 11-30 PNBs (23%), and10 PNBs (6%). Anesthesia practices administering70 PNBs were 1.7-times more likely to use ropivacaine (NS), 3.9-times more likely to consider lipid emulsion infusions for resuscitation (P = 0.008), and equally as likely to have an established plan for use of invasive mechanical cardiopulmonary support in the event of LA cardiotoxicity (NS) than low-PNB volume centers. We conclude that there are differences in the management and preparedness for treatment of LA toxicity among institutions, but the safety implications of these differences are undetermined.

To date, breast cancer (BC) research is mainly studied with cell lines. These cells were passaged multiple times, acquiring phenotypes, additional mutations and epigenetic changes. These changes make the passaged cell lines different from the original malignancy. Thus cell lines, although useful as models could be improved with additional studies with primary BC. It is difficult to obtain malignant cells from breast tissues without contamination from surrounding healthy cells. Selection and expansion of malignant cells from surgical tissues have proved to be daunting tasks. This study describes a reliable and reproducible method for isolating and expanding malignant cells from surgical breast tissues. The method uses co-cultures with BM stroma to select for the cancer cells while the healthy cells undergo rapid cell death. Studies are described to show the cloning efficiencies and sensitivity of the method using surgical samples of varying sizes, different stages of BC, and samples from needle biopsies.

The impact of HLA-specific antibodies is not well established in the acute rejection of lung allografts. Acute rejection represents the most important risk factor for the development of chronic lung allograft dysfunction.We analyzed the pattern of HLA antibodies before and after transplantation in 54 patients, and correlated our data with the presence and frequency of high-grade and persistent-recurrent acute rejection, during the first 18 post-operative months. The diagnosis of acute rejection was based on histologic International Society for Heart and Lung Transplantation (ISHLT)-published criteria.Ten of 54 patients had a positive enzyme-linked immunoassay (ELISA) post-transplantation. In 90% of ELISA-positive patients, the presence of HLA antibodies was associated with persistent-recurrent acute rejections, compared with 34% in the ELISA-negative group (p0.005). There were 28 high-grade acute rejection episodes in the ELISA-positive group, compared with 36 in the ELISA-negative group (p0.0001). The ELISA-positive patients required a greater intensity of immunosuppressive therapy. The patients with ELISA-detected anti-HLA antibodies were at least 3-fold more likely to develop high-grade acute rejection and persistent-recurrent acute rejection, and 7-fold more likely to develop multiple episodes of persistent-recurrent acute rejection, compared with ELISA-negative patients.ELISA-based screening for the development of HLA antibodies is a reliable method that can identify lung transplant recipients at increased risk for high-grade and persistent-recurrent acute rejection. Although bronchiolitis obliterans appears as a point of no return in the evolution of lung-transplanted patients, early detection of risk factors for acute rejection could indirectly decrease the incidence of bronchiolitis obliterans. These lung-transplanted patients may benefit from an altered strategy of immunosuppression.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositingor = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

Deposition of a series of monodisperse aerosol injections in 70/30 helium/oxygen (Heliox) and air for the larynx and trachea was numerically analyzed with Computational Fluid Dynamics (CFD) software. The CFD mesh was prepared from a cadaver-based throat (female, aged 84). Monosize droplets ranging between 0.25 and 10 μm in droplet radius were used for both Heliox and air simulations. The coupled simulation was performed with the KIVA-3V software for a flow rate of 18 l / min , an approximate adult breathing condition. Flow measurements were validated against previous experimental simulations of this cadaver model. It was found that Heliox and air had highly similar flow structures in the simulated region. Flow measurements such as turbulent kinetic energy and velocity magnitude typically differed by less than 5%. Particle deposition was shown to be affected by these small differences in the carrier gas. The use of Heliox led to less particle deposition for all droplet sizes indicating that Heliox will lead to a reduction of in vivo extrathoracic deposition due to the intrinsic properties of the gas phase. This numerical simulation suggests that a continuous Heliox phase provides a stronger steering force to the discrete phase.

Purpose. Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period.

An inhalation airflow through a simple model of the human larynx and trachea, containing dispersed drug spray droplets, is studied numerically using the Computational Fluid Dynamics (CFD) code KIVA-3V (Amsden 1997) and experimentally using phase doppler interferometry. Flow conditions within the larynx and trachea affect the delivery of inhaled medications to the lungs. Deposition in these regions is considered undesirable and has been shown to be a particular problem for pediatric patients. The larynx geometry is represented by a constricted portion inside a straight tube. This constriction simulates the vocal folds within the larynx. The experimental model was 3.2 cm in diameter (approximately twice human scale) and 90 cm long. The constriction was 0.7 cm thick and was placed 30 cm from the inlet of the tube. The area of the constricted opening is approximately 40% of the tube area. Water droplets are introduced into the low-turbulence upstream airflow using a jet nebulizer. Measurements of axial veloci...

Background: Cystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data. Methods: Using functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity. Results: This model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment. Conclusions: We postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway.

The Medical Outcomes Study Short Form 36 (SF-36) may prove to be a useful tool to evaluate the impact of critical paths (path) on discharged patients. Its ability to measure effects of the path must first be evaluated. The purposes of this study are to evaluate the path using the SF-36, and evaluate its ability to measure path outcomes. Subjects cared for through a coronary artery bypass critical path completed the SF-36 and were compared against a similar baseline sample. The specificity to measure the path influence was inconclusive, because comorbidities and activity restrictions present misleading results in the measurement of disability in its current use.

Five spray analysis instruments are compared by measurement of identical medical nebulizer sprays. The instruments tested include a phase Doppler interferometer (Aerometrics), a time-of-flight instrument (Amherst Process Instruments) and three diffraction instruments (all by Malvern). Two different jet nebulizers were used for testing. Each was tested with both water and propylene glycol. Volume distributions, mass median aerodynamic diameters (MMAD), and ninety-percent volume aerodynamic diameter measurements (d.90) are compared. MMAD results from the Aerosizer were consistently higher than those from the diffraction instruments. MMAD and d.90 results from the Phase Doppler system agreed well with the diffraction instruments for water sprays, but varied from the other instruments for propylene glycol sprays. This occurred because the Phase Doppler Interferometer reported larger droplets present in the propylene glycol sprays that in some cases significantly affected the otherwise smaller sized volume distributions. These droplets were not apparent in the results from the other instruments but were noted during visualization studies. Volume distribution results demonstrate that the Malvern 2600 is inappropriate for use with sprays in the examined size range. The other volume distributions were similar with the exception of the Aerosizer, which reported higher, more normally distributed volume distributions compared to the other instruments.

Background Elderly patients – those aged 65 years and over – use more medications than their younger counterparts and experience higher risks for polypharmacy, drug interactions, adverse drug reactions, and noncompliance for this age-group. Methods The data on polypharmacy in the aged is reviewed, supplemented with preliminary information from studies performed on elderly patients with cancer at our institution. Results Polypharmacy occurs in ambulatory, extended care, and institutional settings. Over-the-counter medications are underreported. The number of potential drug-related problems is related to the total number of prescriptions. Methods for evaluating the extent of polypharmacy include the “brown-bag” technique and careful medication histories. Conclusions The risks of polypharmacy may be reduced with patient and physician education, intervention, and drug monitoring. Further pharmacokinetic investigations of anticancer medications are needed to recognize the potential for harmful drug interactions, to understand their toxicity profiles, and to avoid the clinical implications of drug interactions.

In order to manage the rise in life expectancy and the concomitant increased occurrence of age-related diseases, research into ageing has become a strategic priority. Mouse models are commonly utilised as they share high homology with humans and show many similar signs and diseases of ageing. However, the time and cost needed to rear aged cohorts can limit research opportunities. Sharing of resources can provide an ethically and economically superior framework to overcome some of these issues but requires dedicated infrastructure. Shared Ageing Research Models (ShARM) ( www.ShARMUK.org ) is a new, not-for-profit organisation funded by Wellcome Trust, open to all investigators. It collects, stores and distributes flash frozen tissues from aged murine models through its biorepository and provides a database of live ageing mouse colonies available in the UK and abroad. It also has an online environment (MICEspace) for collation and analysis of data from communal models and discussion boards on subjects such as the welfare of ageing animals and common endpoints for intervention studies. Since launching in July 2012, thanks to the generosity of researchers in UK and Europe, ShARM has collected more than 2,500 tissues and has in excess of 2,000 mice registered in live ageing colonies. By providing the appropriate support, ShARM has been able to bring together the knowledge and experience of investigators in the UK and Europe to maximise research outputs with little additional cost and minimising animal use in order to facilitate progress in ageing research.

A standardized protocol for measuring mucociliary (MCC) and cough clearance (CC) was developed and tested at the University of North Carolina at Chapel Hill, NC (UNC), Johns Hopkins University (JHU), and the University of Pittsburgh (Pitt).A total of 50 healthy nonsmoking adults with normal lung function were studied at the three sites: 30 [21 males/9 females (21M/9F)] at UNC, 10 (6M/4F) at JHU, and 10 (4M/6F) at Pitt. Subjects inhaled an aerosol of (99m)technetium sulfur colloid in 0.9% saline (mass median aerodynamic diameter=5.4 μm) under controlled breathing conditions (500 mL/sec, 30 breaths/min) by following a metronome and flow signal from a commercial dosimeter. Following inhalation, subjects sat in front of a gamma camera as sequential lung images were acquired for 60 min. Subjects then coughed 60 times, and images were acquired after each set of 20 coughs, i.e., at 70, 80, and 90 min. Subjects returned to the laboratory approximately 24 hr later for a final image of residual lung activity. Initial aerosol distribution was measured as a central/peripheral (C/P) ratio of activity. MCC/CC was expressed as the area under the retention versus time curve over 90 min (AUC90).A multivariate analysis of clearance versus time with site and C/P as covariates showed no significant site-specific differences. Interestingly, MCC/CC was greater in females (n=19) versus males (n=31), with AUC90=0.84 ± 0.11 and 0.90±0.07, respectively (p=0.03), for the combined data set from all sites (not significant for any given site). There were no gender differences for either C/P ratio or 24-hr clearance.This standardized protocol may prove beneficial in multicenter trials for testing new therapies that are designed to improve MCC/CC.