Optofluidic Force Induction Meets Raman Spectroscopy and Inductively Coupled Plasma-Mass Spectrometry: A New Hyphenated Technique for Comprehensive and Complementary Characterizations of Single Particles.

Nanoparticles are produced at accelerating rates, are increasingly integrated into scientific and industrial applications, and are widely discharged into the environment. Analytical techniques are required to characterize parameters such as particle number concentrations, mass and size distributions, molecular and elemental compositions, and particle stability. This is not only relevant to investigate their utility for various industrial or medical applications and for controlling the manufacturing processes but also to assess toxicity and environmental fate. Different analytical strategies aim to characterize certain facets of particles but are difficult to combine to retrieve relevant parameters coherently and to provide a more comprehensive picture. In this work, we demonstrate the first online hyphenation of optofluidic force induction (OF2i) with Raman spectroscopy and inductively coupled plasma-time-of-flight-mass spectrometry (ICP-TOFMS) to harness their complementary technology-specific advantages and to promote comprehensive particle characterizations. We optically trapped individual particles on a weakly focused vortex laser beam by aligning a microfluidic flow antiparallelly to the laser propagation direction. The position of particles in this optical trap depended on the hydrodynamic diameter and therefore enabled size calibration as well as matrix elimination. Additionally, laser light scattered on particles was analyzed in a single particle (SP) Raman spectroscopy setup for the identification of particulate species and phases. Finally, particles were characterized regarding elemental composition and their distributions in mass and size using SP ICP-TOFMS. In a proof of concept, we analyzed polystyrene-based microplastic and TiO2 nanoparticles and demonstrated the opportunities provided through the coupling of OF2i with SP Raman and SP ICP-TOFMS.

Optofluidic force induction as a process analytical technology.

Manufacturers of nanoparticle-based products rely on detailed information about critical process parameters, such as particle size and size distributions, concentration, and material composition, which directly reflect the quality of the final product. These process parameters are often obtained using offline characterization techniques that cannot provide the temporal resolution to detect dynamic changes in particle ensembles during a production process. To overcome this deficiency, we have recently introduced Optofluidic Force Induction (OF2i) for optical real-time counting with single particle sensitivity and high throughput. In this paper, we apply OF2i to highly polydisperse and multi modal particle systems, where we also monitor evolutionary processes over large time scales. For oil-in-water emulsions we detect in real time the transition between high-pressure homogenization states. For silicon carbide nanoparticles, we exploit the dynamic OF2i measurement capabilities to introduce a novel process feedback parameter based on the dissociation of particle agglomerates. Our results demonstrate that OF2i provides a versatile workbench for process feedback in a wide range of applications.

Trends in smoking documentation rates in safety net clinics.

OBJECTIVE: To assess the impact of provider incentive policy on smoking status documentation. DATA SOURCES: Primary data were extracted from structured electronic medical records (EMRs) from 15 community health centers (CHCs). STUDY DESIGN: This was an observational study of data from 2006 to 2013, assessing changes in documentation of smoking status over time. DATA EXTRACTION METHODS: We extracted structured EMR data for patients age 18 and older with at least one primary care visit. PRINCIPAL FINDINGS: Rates of documented smoking status rose from 30 percent in 2006 to 90 percent in 2013; the largest increase occurred from 2011 to 2012 following policy changes (21.3% [95% CI, 8.2%, 34.4%] from the overall trend). Rates varied by clinic and across patient subgroups. CONCLUSIONS: Documentation of smoking status improved markedly after introduction of new federal standards. Further improvement in documentation is still needed, especially for males, nonwhite patients, those using opioids, and HIV + patients. More research is needed to study whether changes in documentation lead to improvements in counseling, cessation, and patient outcomes.

JDP2 overexpression provokes cardiac dysfunction in mice.

The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.

Cardiovascular care guideline implementation in community health centers in Oregon: a mixed-methods analysis of real-world barriers and challenges.

BACKGROUND: Spreading effective, guideline-based cardioprotective care quality improvement strategies between healthcare settings could yield great benefits, particularly in under-resourced contexts. Understanding the diverse factors facilitating or impeding such guideline implementation could improve cardiovascular care quality and outcomes for vulnerable patients. METHODS: We sought to identify multi-level factors affecting uptake of cardioprotective care guidelines in community health centers (CHCs), within a successful trial of cross-setting implementation of an effective intervention. Quantitative analyses used multivariable logistic regression to examine in-person patient encounters at 10 CHCs from June 2011-May 2014. At these encounters, a point-of-care alert flagged adults with diabetes who were clinically indicated for, but not currently prescribed, cardioprotective medications. The main outcome measure was the rate of relevant prescriptions issued within two days of encounters. Qualitative analyses focused on CHC providers and staff, and, guided by the constant comparative method, were used to enhance understanding of the factors that influenced this prescribing. RESULTS: Recommended prescribing occurred at 13-16% of encounters with patients who were indicated for such prescribing. The odds of this prescribing were higher when the patient was male, had HbA1c ≥7, was previously prescribed a similar medication, gave diabetes as the chief complaint, saw a mid-level practitioner, or saw their primary care provider. The odds were lower when the patient was insured, had ≥1 clinic visits in the past year, had kidney disease, or was prescribed certain other medications. Additional factors were associated with prescribing of each medication class. Qualitative results both supported and challenged the quantitative findings, illustrating important tensions involved in guideline-based prescribing. Clinic staff stressed the importance of the provider-patient relationship in guiding prescribing decisions in the face of competing priorities and care needs, and the impact of rapidly changing guidelines. CONCLUSIONS: Diverse factors associated with guideline-concordant prescribing illuminate the complexity of delivering evidence-based care in CHCs. We present possible strategies for addressing barriers to guideline-based prescribing. CLINICAL TRIALS REGISTRATION: This trial was registered retrospectively. Currently Controlled Trials NCT02299791 . Retrospectively registered 10 November 2014.

Predicting Life Expectancy for Pirfenidone in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Conducting an adequately powered survival study in idiopathic pulmonary fibrosis (IPF) is challenging due to the rare nature of the disease and the need for extended follow-up. Consequently, registration trials of IPF treatments have not been designed to estimate long-term survival. OBJECTIVE: To predict life expectancy for patients with IPF receiving pirfenidone versus best supportive care (BSC) in a population that met the inclusion criteria of patients enrolled in the ASCEND and CAPACITY trials. METHODS: Kaplan-Meier survival data for pirfenidone and BSC were obtained from randomized controlled clinical studies (CAPACITY, ASCEND), an open-label extension study (RECAP), and the Inova Fairfax Hospital database. Data from the Inova registry were matched to the inclusion criteria of the CAPACITY and ASCEND trials. Life expectancy was estimated by the area under the curve of parametric survival distributions fit to the Kaplan-Meier data. RESULTS: Mean (95% confidence interval) life expectancy was calculated as 8.72 (7.65-10.15) years with pirfenidone and 6.24 (5.38-7.18) years with BSC. Therefore, pirfenidone improved life expectancy by 2.47 (1.26-4.17) years compared with BSC. In addition, treatment with pirfenidone recuperated 25% of the expected years of life lost due to IPF. Sensitivity analyses found that results were sensitive to the choice of parametric survival distribution, and alternative piecewise and parametric approaches. CONCLUSIONS: This analysis suggests that this population of patients with IPF has an improved life expectancy if treated with pirfenidone compared with BSC. DISCLOSURES: This study was funded by InterMune International AG, a wholly owned Roche subsidiary since 2014. Fisher was previously employed by InterMune UK, a wholly owned Roche subsidiary, until July 2015. He is currently employed by FIECON, which has received funding from F. Hoffmann-La Roche for consulting services. Nathan has received consulting fees from Roche-Genentech and Boehringer Ingelheim. He is also on the speakers' bureau for Roche-Genentech and Boehringer Ingelheim and has received research funding from both companies. Hill was previously employed by InterMune UK until October 2014. Hill and Marshall are employees of MAP BioPharma, which has received funding from F. Hoffmann-La Roche for consulting services. Dejonckheere and Thuresson are employees of F. Hoffmann-La Roche. Maher has received grants, consulting fees, and speaker fees from GlaxoSmithKline and UCB, and grants from Novartis. He has also received consulting fees and speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Lanthio, InterMune International AG, F. Hoffmann-La Roche, Sanofi-Aventis, and Takeda. Maher is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR Ref: CS: -2013-13-017). Study concept and design were contributed by Fisher, Hill, Marshall, and Dejonckheere. Fisher, Nathan, and Thuresson collected the data, along with Hill and Marshall. Data interpretation was performed by Fisher, Maher, Nathan, and Dejonckheere. The manuscript was written primarily by Fisher, along with Maher and Dejonckheere, and revised by Fisher and Maher, along with the other authors.

Feasibility and impact of implementing a private care system's diabetes quality improvement intervention in the safety net: a cluster-randomized trial.

BACKGROUND: Integrated health care delivery systems devote considerable resources to developing quality improvement (QI) interventions. Clinics serving vulnerable populations rarely have the resources for such development but might benefit greatly from implementing approaches shown to be effective in other settings. Little trial-based research has assessed the feasibility and impact of such cross-setting translation and implementation in community health centers (CHCs). We hypothesized that it would be feasible to implement successful QI interventions from integrated care settings in CHCs and would positively impact the CHCs. METHODS: We adapted Kaiser Permanente's successful intervention, which targets guideline-based cardioprotective prescribing for patients with diabetes mellitus (DM), through an iterative, stakeholder-driven process. We then conducted a cluster-randomized pragmatic trial in 11 CHCs in a staggered process with six "early" CHCs implementing the intervention one year before five "'late" CHCs. We measured monthly rates of patients with DM currently prescribed angiotensin converting enzyme (ACE)-inhibitors/statins, if clinically indicated. Through segmented regression analysis, we evaluated the intervention's effects in June 2011-May 2013. Participants included ~6500 adult CHC patients with DM who were indicated for statins/ACE-inhibitors per national guidelines. RESULTS: Implementation of the intervention in the CHCs was feasible, with setting-specific adaptations. One year post-implementation, in the early clinics, there were estimated relative increases in guideline-concordant prescribing of 37.6 % (95 % confidence interval (CI); 29.0-46.2 %) among patients indicated for both ACE-inhibitors and statins and 38.7 % (95 % CI; 23.2-54.2 %) among patients indicated for statins. No such increases were seen in the late (control) clinics in that period. CONCLUSIONS: To our knowledge, this was the first clinical trial testing the translation and implementation of a successful QI initiative from a private, integrated care setting into CHCs. This proved feasible and had significant impact but required considerable adaptation and implementation support. These results suggest the feasibility of adapting diverse strategies developed in integrated care settings for implementation in under-resourced clinics, with important implications for efficiently improving care quality in such settings. CLINICALTRIALS.gov: NCT02299791 .

Study of the electronic and rovibronic structure of the X ²Σ⁺, A ²Π, and B ²Σ⁺ states of AlO.

The electronic structure of the X (2)Σ(+), A (2)Π, and B (2)Σ(+) states of aluminum monoxide (AlO) are studied via ab initio multi-reference configuration interaction calculations. Core correlation corrections, several basis sets, and active space choices are considered. Angular momentum and spin-orbit coupling terms are obtained at different levels of theory. The resulting ab initio curves are used to solve the associated rovibronic problem for the total angular momentum J up to 112.5 and then also refined by fitting to the experimental wavenumbers available in the literature, reproducing them with the root-mean-square error of 0.07 cm(-1). Theoretical rovibronic energy levels of AlO in its X (2)Σ(+), A (2)Π, and B (2)Σ(+) electronic states are presented including those from the X - B blue-green system.

"Not a kidney or a lung:" research challenges in a network of safety net clinics.

BACKGROUND AND OBJECTIVES: To gain a better understanding of the facilitators and barriers to creating a practice-based research network (PBRN) of safety net clinics, we conducted a qualitative study within our network of safety net health centers. METHODS: Utilizing snowball sampling, we conducted interviews with 19 of our founding stakeholders and analyzed these interviews to draw out common themes. RESULTS: The results showed four barriers to research in our network: lack of research generated from clinician questions, lack of appropriate funding, lack of clinician time, and lack of infrastructure. We discuss these results and suggest that inadequate funding for practice-based research, particularly in the health care safety net, is a unifying theme of these four barriers. CONCLUSIONS: Our results suggest that the national funding strategy for research relevant to underserved populations and all of primary care must undergo a fundamental shift. We discuss the features of possible models to meet this need.

Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction.

AIMS: Expression and activity of the transcription factor AP-1 are enhanced during cardiac remodelling and heart failure progression. In order to test if AP-1 inhibition may limit processes contributing to cardiac remodelling, ventricular cardiomyocytes of mice with cardiac overexpression of the AP-1 inhibitor JDP2 were analysed under stimulation of hypertrophy, apoptosis, or contractile function. METHODS AND RESULTS: Three models of JDP2 overexpressing mice were analysed: JDP2 was overexpressed either life-long, for 7 weeks, or 1 week. Then cardiomyocytes were isolated and stimulated with ß-adrenoceptor agonist isoprenaline (ISO, 50 nM). This enhanced cross-sectional area and the rate of protein synthesis in WT but not in JDP2 overexpressing cardiomyocytes. To induce apoptosis, cardiomyocytes were stimulated with 3 ng/mL TGFß1. Again, JDP2 overexpression prevented apoptosis induction compared with WT cells. Determination of contractile function under electrical stimulation at 2 Hz revealed enhancement of cell shortening, and contraction and relaxation velocities under increasing ISO concentrations (0.3-30 nM) in WT cells. This inotropic effect was abrogated in JDP2 overexpression cells. Responsiveness to increased extracellular calcium concentrations was also impaired in JDP2 overexpressing cardiomyocytes. Simultaneously, a reduction of SERCA expression was found in JDP2 mice. CONCLUSION: A central role of AP-1 in the induction of hypertrophy and apoptosis in cardiomyocytes is demonstrated. Besides these protective effects of AP-1 inhibition on factors of cardiac remodelling, AP-1-inhibition impairs contractile function. Therefore, AP-1 acts as a double-edged sword that mediates mal-adaptive cardiac remodelling, but is required for maintaining a proper contractile function of cardiomyocytes.

Determination of susceptibility to fosfomycin and tigecycline of Enterobacteriaceae, particularly Escherichia coli isolates, producing extended-spectrum ß-lactamases from multiple regional Canadian hospitals.

BACKGROUND: The worldwide spread of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, particularly Escherichia coli, has significantly limited therapeutic options, especially for urinary tract infections. Although limited in their indications, fosfomycin and tigecycline are potential agents to treat infections due to ESBL-producing organisms. Although not routinely performed, susceptibility testing to both is necessary to ensure there is not an increase in resistance. METHODS: A total of 160 isolates of ESBL-producing E coli were isolated from patients at multiple regional hospitals in the Interior Health Region of British Columbia from June 2009 to January 2012. Isolates were obtained from various body fluids and sites including urine (78.2%), wounds, blood, gall bladder drain and respiratory specimens. All isolates were tested using the E-test method (Etest, bioMérieux, France) for tigecycline and Kirby Bauer disk diffusion method for fosfomycin using European Committee of Antimicrobial Susceptibility Testing breakpoints for tigecycline and Clinical and Laboratory Standards Institute zone sizes for fosfomycin. RESULTS: All 160 isolates were found to be susceptible to tigecycline, while five isolates (3.1%) were resistant to fosfomycin (four resistant, one intermediate). CONCLUSION: Although resistance to these antibiotics has previously been reported, the present study confirmed that isolates of ESBL-producing E coli from the Interior Health Region of British Columbia remain highly susceptible to both tigecycline and fosfomycin.

HISTORIQUE: La propagation mondiale des entérobactériacées produisant des ß-lactamases à large spectre (BLLS), notamment l'Escherichia coli, se heurte à un nombre d'options thérapeutiques très limité, particulièrement en cas d'infections urinaires. Même si leurs indications sont limitées, la fosfomycine et la tigécycline sont des agents potentiels pour traiter les infections causées par des organismes produisant des BLLS. Les tests de susceptibilité ne sont pas effectués systématiquement, mais ils sont nécessaires pour s'assurer que la résistance à ces deux agents n'augmente pas. MÉTHODOLOGIE: Au total, 160 isolats d'E coli produisant des BLLS ont été isolés chez des patients provenant de multiples hôpitaux régionaux de la régie régionale de la santé Interior de la Colombie-Britannique entre juin 2009 et janvier 2012. Ces isolats provenaient de divers foyers de liquides corporels, y compris l'urine (78,2 %), les plaies, le sang, le drain de la vésicule biliaire et des spécimens respiratoires. Les chercheurs ont testé tous les isolats au moyen de la méthode E-test (Etest, bioMérieux, France) pour la tigécycline, selon le point de cassure du Comité européen des antibiogrammes, et au moyen de la méthode par diffusion des disques imprégnés de Kirby Bauer pour la fosfomycine, selon les dimensions de la zone du Clinical and Laboratory Standards Institute. RÉSULTATS: Les 160 isolats étaient susceptibles à la tigécycline, tandis que cinq isolats (3,1 %) étaient résistants à la fosfomycine (quatre résistants, un intermédiaire). CONCLUSION: Même si des cas de résistance à ces antibiotiques ont déjà été déclarés, la présente étude confirme que les isolats d'E coli produisant des BLLS provenant de la régie régionale de la santé Interior de la Colombie-Britannique demeurent hautement susceptibles à la fois à la tigécycline et à la fosfomycine.

Lessons learned and challenges ahead: report from the OCHIN Safety Net West practice-based research network (PBRN).

INTRODUCTION: We recently completed a strategic planning process to better understand the development of our 5-year-old practice-based research network (PBRN) and to identify gaps between our original vision and current progress. Although many of our experiences are not new to the PBRN community, our reflections may be valuable for those developing or reshaping PBRNs in a changing health care environment. LESSONS LEARNED: We learned about the importance of (1) shared vision and commitment to a unique patient population; (2) strong leadership, mentorship, and collaboration; (3) creative approaches to engaging busy clinicians and bridging the worlds of academia and community practice; and (4) harnessing data from electronic health records and navigating processes related to data protection, sharing, and ownership. CHALLENGES AHEAD: We must emphasize research that is timely, relevant, and integrated into practice. One model supporting this goal involves a broader partnership than was initially envisioned for our PBRN--one that includes clinicians, researchers, information architects, and quality improvement experts partnering to develop an innovation center. This center could facilitate development of relevant research questions while also addressing "quick-turnaround" needs. CONCLUSIONS: Gaps remain between our PBRN's initial vision and current reality. Closing these gaps may require future creativity in building partnerships and finding nontraditional funding sources.

Collaborative development of a randomized study to adapt a diabetes quality improvement initiative for federally qualified health centers.

This case study describes how we are translating a diabetes care quality improvement initiative from an insured (HMO) setting into federally qualified health centers (FQHCs). We outline the innovative collaborative processes whereby researchers and FQHC providers adapted this initiative, which includes health information technology tools, to meet the FQHCs' needs.

The rotational spectrum of the NH+ radical in its X 2Pi and a 4Sigma- states.

Transitions between the spin-rotational levels of the (14)NH(+) radical in the v = 0 levels of its X (2)Pi and a (4)Sigma(-) states have been studied by the technique of laser magnetic resonance at far-infrared wavelengths. The data have been combined with a previous zero-field measurement of the J = 1 1/2 - 1/2 transition frequencies at 1.01 THz to determine a much improved set of molecular parameters for NH(+) in the X (2)Pi state; the major parameters for the a (4)Sigma(-) state have also been determined. A full determination of the hyperfine parameters for both (14)N and (1)H nuclei has been achieved for the first time. Accurate predictions of the transition frequencies between the low-lying levels of the radical in the absence of a magnetic field have also been made, including lambda-doubling frequencies for use by radio astronomers.