Fluorescence characterization of clinically-important bacteria

Healthcare-associated infections (HCAI/HAI) represent a substantial threat to patient health during hospitalization and incur billions of dollars additional cost for subsequent treatment. One promising method for the detection of bacterial contamination in a clinical setting before an HAI outbreak occurs is to exploit native fluorescence of cellular molecules for a hand-held, rapid-sweep surveillance instrument. Previous studies have shown fluorescence-based detection to be sensitive and effective for food-borne and environmental microorganisms, and even to be able to distinguish between cell types, but this powerful technique has not yet been deployed on the macroscale for the primary surveillance of contamination in healthcare facilities to prevent HAI. Here we report experimental data for the specification and design of such a fluorescence-based detection instrument. We have characterized the complete fluorescence response of eleven clinically-relevant bacteria by generating excitation-emission matrices (EEMs) over broad wavelength ranges. Furthermore, a number of surfaces and items of equipment commonly present on a ward, and potentially responsible for pathogen transfer, have been analyzed for potential issues of background fluorescence masking the signal from contaminant bacteria. These include bedside handrails, nurse call button, blood pressure cuff and ward computer keyboard, as well as disinfectant cleaning products and microfiber cloth. All examined bacterial strains exhibited a distinctive double-peak fluorescence feature associated with tryptophan with no other cellular fluorophore detected. Thus, this fluorescence survey found that an emission peak of 340nm, from an excitation source at 280nm, was the cellular fluorescence signal to target for detection of bacterial contamination. The majority of materials analysed offer a spectral window through which bacterial contamination could indeed be detected. A few instances were found of potential problems of background fluorescence masking that of bacteria, but in the case of the microfiber cleaning cloth, imaging techniques could morphologically distinguish between stray strands and bacterial contamination

Conference on Best Practices for Managing \u3cem\u3eDaubert\u3c/em\u3e Questions

This article is a transcript of the Philip D. Reed Lecture Series Conference on Best Practices for Managing Daubert Questions, held on October 25, 2019, at Vanderbilt Law School under the sponsorship of the Judicial Conference Advisory Committee on Evidence Rules. The transcript has been lightly edited and represents the panelists’ individual views only and in no way reflects those of their affiliated firms, organizations, law schools, or the judiciary

Love and Taxes – And Matching Institutions

We study a setting with search frictions in the marriage market and with incomplete contracting inside the family. Everyone prefers a partner that has high income and is a perfect emotional match, but compromises must often be struck. A high income earner may abstain from marrying a low-income earner even though they would be a perfect match emotionally, because the highincome earner may dislike the implicit income redistribution implied by the marriage. Redistributive income taxation may ease this problem. Income matching institutions that secure that people largely from the same income groups meet each other can substitute for redistribution, so that optimal redistribution is reduced. We also introduce a divorce option. Redistributive taxation is shown both to further and stabilize marriage.Wenn Menschen mit unterschiedlichem Einkommen heiraten, führt dies zu einer Umverteilung innerhalb der Ehe von der wirtschaftlich stärkeren zur wirtschaftlich schwächeren Person. Zwei Personen, die zufällig aufeinander treffen und aufgrund ähnlicher Interessen und Neigungen gut zueinander passen, werden auch die finanziellen Folgen einer Heirat berücksichtigen. Falls die Person mit hohem Einkommen diese Umverteilung als zu stark empfindet, kommt die Ehe nicht zustande. Die Rente, die z.B. dadurch entsteht, dass das Paar ähnliche Interessen hat oder gemeinsamen Hobbys nachgehen kann, geht in diesem Fall verloren. Progressive Besteuerung führt zu einer Angleichung der Einkommensverteilung und verringert daher die Wahrscheinlichkeit, dass Ehen aufgrund hoher Einkommensunterschiede nicht zustande kommen. Aus wohlfahrtstheoretischer Sicht ist dies ein positiver Aspekt umverteilender Besteuerung, der bisher in der Literatur nicht berücksichtigt wurde. Die optimale Höhe der Besteuerung hängt von den Matching-Institutionen ab, d.h. davon wer wen auf dem Heiratsmarkt trifft. Treffen vorwiegend Personen mit unterschiedlichem Einkommen und ähnlichen Interessen aufeinander, ist der positive Effekt der Besteuerung besonders wirksam. In diesem Fall ist der optimale Steuersatz umso höher, je ähnlicher die Interessen der potentiellen Partner ist. Umgekehrt kann progressive Besteuerung in einer Gesellschaft, in der vorwiegend Personen mit ohnehin ähnlichem Einkommen aufeinandertreffen, kaum etwas bewirken. Daher fällt in diesem Fall der optimale Steuersatz umso geringer aus, je ähnlicher die Einkommen der potentiellen Paare auf dem Heiratsmarkt sind

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial

Objectives SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). Background AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. Methods The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). Conclusions This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome

Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4(+) BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment. OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC. METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 10 RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group. CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC

The Responsiveness of Married Women's Labor Force Participation to Income and Wages: Recent Changes and Possible Explanations

One contributor to the twentieth century rise in married women's labor force participation was declining responsiveness to husbands' wages and other family income. Now that the rapid rise in married women's participation has slowed and even begun to reverse, this paper asks whether married women's cross-wage elasticities have continued to fall. Using the outgoing rotation group of the monthly Current Population Survey (CPS) and estimating coefficients separately for each year from 1994 through 2006, we find that the decline in responsiveness to husbands' wages has come to an endat least for the time beingand even find evidence of rising responsiveness to husbands' wages. This increase in the cross-wage elasticity of participation occurs largely between 1997 and 2002 and is concentrated among younger women and women with children. We also explore a number of possible explanations for this development. We conclude that declining divorce rates, rising child care costs, and the increasing prevalence of high work hours for high payall of which were more pronounced at the high end of the income distributionalong with rising income inequality may have played a role. Also possible is that some of the decline is an artifact of changes in the tax system and the way income is measured. In addition, we observe some backsliding in attitudes supportive of gender equality in the market and at home, and perhaps a change in lifecycle timing among Generation X women

Spectroscopic and computational insights on catalytic synergy in bimetallic aluminophosphate catalysts

A combined electronic structure computational and X-ray absorption spectroscopy study was used to investigate the nature of the active sites responsible for catalytic synergy in Co-Ti bimetallic nanoporous frameworks. Probing the nature of the molecular species at the atomic level has led to the identification of a unique Co-O-Ti bond, which serves as the loci for the superior performance of the bimetallic catalyst, when compared with its analogous monometallic counterpart. The structural and spectroscopic features associated with this active site have been characterized and contrasted, with a view to affording structure property relationships, in the wider context of designing sustainable catalytic oxidations with porous solids

Antimalarial Therapy Selection for Quinolone Resistance among Escherichia coli in the Absence of Quinolone Exposure, in Tropical South America

BACKGROUND: Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. METHODS: Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant gram-negative bacilli (GNB). Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR) mutations. RESULTS: In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p<0.01). Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. CONCLUSIONS: In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas