Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury.

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.

An absorption profile centred at 78 megahertz in the sky-averaged spectrum.

After stars formed in the early Universe, their ultraviolet light is expected, eventually, to have penetrated the primordial hydrogen gas and altered the excitation state of its 21-centimetre hyperfine line. This alteration would cause the gas to absorb photons from the cosmic microwave background, producing a spectral distortion that should be observable today at radio frequencies of less than 200 megahertz. Here we report the detection of a flattened absorption profile in the sky-averaged radio spectrum, which is centred at a frequency of 78 megahertz and has a best-fitting full-width at half-maximum of 19 megahertz and an amplitude of 0.5 kelvin. The profile is largely consistent with expectations for the 21-centimetre signal induced by early stars; however, the best-fitting amplitude of the profile is more than a factor of two greater than the largest predictions. This discrepancy suggests that either the primordial gas was much colder than expected or the background radiation temperature was hotter than expected. Astrophysical phenomena (such as radiation from stars and stellar remnants) are unlikely to account for this discrepancy; of the proposed extensions to the standard model of cosmology and particle physics, only cooling of the gas as a result of interactions between dark matter and baryons seems to explain the observed amplitude. The low-frequency edge of the observed profile indicates that stars existed and had produced a background of Lyman-α photons by 180 million years after the Big Bang. The high-frequency edge indicates that the gas was heated to above the radiation temperature less than 100 million years later.

Bringing Rounds Back to the Patient: A One-Year Evaluation of the Chiefs' Service Model for Inpatient Teaching.

PURPOSE: The Chiefs' Service (CS), a structured approach to inpatient teaching rounds, focuses on resident education and patient-centered care without disrupting patient census sizes or admitting cycles. It has five key elements: morning huddles; bedside rounds; diagnostic "time-outs"; day-of-discharge rounds; and postdischarge follow-up rounds. The authors hypothesized the CS model would be well received by residents and considered more effective than more-traditional rounds. METHOD: The CS was implemented on Penn Presbyterian Medical Center's general medicine inpatient service using a quasi-experimental design. Its first year (January 2013-January 2014) was evaluated with a mixed-methods approach. Residents completed end-of-rotation evaluation questionnaires; 20 CS and 10 traditional service (TS) residents were interviewed. Measures of resident agreement on questionnaire items were compared across groups using independent sample t testing. A modified grounded theory approach was used to assess CS residents' perspectives on the CS elements and identify emergent themes. RESULTS: The questionnaires were completed by 183/188 residents (response rate 97%). Compared with TS residents, CS residents reported significantly greater satisfaction in the domains of resident education and patient care, and they rated the overall value of the rotation significantly higher. The majority of CS residents found the CS elements to be effective. CS residents described the CS as focused on resident education, patient-centered care, and collaboration with an interdisciplinary team. CONCLUSIONS: The CS approach to inpatient rounding is seen by residents as valuable and is associated with positive outcomes in terms of residents' perceptions of learning, interdisciplinary communication, and patient care.

Advancing LGBT Health at an Academic Medical Center: A Case Study.

Academic health centers are strategically positioned to impact the health of lesbian, gay, bisexual and transgender (LGBT) populations by advancing science, educating future generations of providers, and delivering integrated care that addresses the unique health needs of the LGBT community. This report describes the early experiences of the Penn Medicine Program for LGBT Health, highlighting the favorable environment that led to its creation, the mission and structure of the Program, strategic planning process used to set priorities and establish collaborations, and the reception and early successes of the Program.

Lung volumes: measurement, clinical use, and coding.

Measurement of lung volumes is an integral part of complete pulmonary function testing. Some lung volumes can be measured during spirometry; however, measurement of the residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) requires special techniques. FRC is typically measured by one of three methods. Body plethysmography uses Boyle's Law to determine lung volumes, whereas inert gas dilution and nitrogen washout use dilution properties of gases. After determination of FRC, expiratory reserve volume and inspiratory vital capacity are measured, which allows the calculation of the RV and TLC. Lung volumes are commonly used for the diagnosis of restriction. In obstructive lung disease, they are used to assess for hyperinflation. Changes in lung volumes can also be seen in a number of other clinical conditions. Reimbursement for measurement of lung volumes requires knowledge of current procedural terminology (CPT) codes, relevant indications, and an appropriate level of physician supervision. Because of recent efforts to eliminate payment inefficiencies, the 10 previous CPT codes for lung volumes, airway resistance, and diffusing capacity have been bundled into four new CPT codes.

A lower limit of Δz > 0.06 for the duration of the reionization epoch.

Observations of the 21-centimetre line of atomic hydrogen in the early Universe directly probe the history of the reionization of the gas between galaxies. The observations are challenging, though, because of the low expected signal strength (∼10 mK), and contamination by strong (>100 K) foreground synchrotron emission in the Milky Way and extragalactic continuum sources. If reionization happened rapidly, there should be a characteristic signature visible against the smooth foreground in an all-sky spectrum. Here we report an all-sky spectrum between 100 and 200 MHz, corresponding to the redshift range 6 < z < 13 for the 21-centimetre line. The data exclude a rapid reionization timescale of Δz < 0.06 at the 95% confidence level.

Impact of a computerized physician order-entry system.

BACKGROUND: The Institute of Medicine has urged the adoption of electronic prescribing systems in all health-care organizations by 2010. Accordingly, computerized physician order entry (CPOE) warrants detailed evaluation. Mixed results have been reported about the benefit of this system. No review of its application in surgical patients has been reported to date. We present the implementation of CPOE in the management of surgical patients within an academic multispecialty practice. STUDY DESIGN: Retrospective and prospective analyses of patient-safety measures were done pre- and post-CPOE institution, respectively. Other metrics evaluated included medication errors, order-implementation times, efficiencies, personnel requirements, and physician time. Sampling of time span for the order placement process was assessed with direct hidden observation of the provider. RESULTS: A total of 15 (0.22%) medication errors were discovered in 6,815 surgical procedures performed during the 6 months before CPOE use. After implementation, 10 medication errors were found (5,963 surgical procedures [0.16%]) in the initial 6 months and 13 (0.21%) in the second 6 months (6,106 surgical procedures) (p = NS). Mean total time from placement of order to nurse receipt before implementation was 41.2 minutes per order (2.05 minutes finding chart, 0.72 minutes writing order, 38.4 minutes for unit secretary transcription) compared with 27 seconds per order using CPOE (p < 0.01). Four additional informational technology specialists were temporarily required for assistance in implementing CPOE. After CPOE adoption, 11 of 56 (19.6%) ancillary personnel positions were eliminated related to order-entry efficiencies. CONCLUSIONS: Present CPOE technology can allow major efficiency gains, but refinements will be required for improvements in patient safety.

Identification of mosquito bloodmeals using mitochondrial cytochrome oxidase subunit I and cytochrome b gene sequences.

Primer pairs were designed and protocols developed to selectively amplify segments of vertebrate mitochondrial cytochrome oxidase subunit 1 (COI) and cytochrome b (Cyt b) mtDNA from the bloodmeals of mosquitoes (Diptera: Culicidae). The protocols use two pairs of nested COI primers and one pair of Cyt b primers to amplify short segments of DNA. Resultant sequences are then compared with sequences in GenBank, using the BLAST function, for putative host identification. Vertebrate DNA was amplified from 88% of our sample of 162 wild-caught, blood-fed mosquitoes from Oregon, U.S.A. and GenBank BLAST searches putatively identified 98% of the amplified sequences, including one amphibian, seven mammalian and 14 avian species. Criteria and caveats for putative identification of bloodmeals are discussed.

Psychotherapy with brain injury survivors: an investigation of the challenges encountered by clinicians and their modifications to therapeutic practice.

OBJECTIVE: The aim of this study is to elicit practitioners' views and experiences of the challenges to forming a therapeutic alliance with brain injury survivors, with a view to informing current psychotherapeutic practice. METHODS: The present research utilised the data-display method, a qualitative technique, to examine the questionnaire responses of 21 psychologists who provide forms of psychotherapy for brain injury survivors at rehabilitation units in the UK. An anonymous postal return questionnaire was used for data collection. RESULTS: The main challenges to forming a working alliance comprised a range of cognitive, behavioural and emotional sequelae. A combination of educational, psychosocial and cognitive strategies were identified as being most effective in addressing the challenges encountered. CONCLUSIONS: A qualitative research approach has proved useful in identifying challenges to the formation of a working alliance and also the modifications to psychotherapeutic practice these challenges have engendered.

Polyoxometalate HIV-1 protease inhibitors. A new mode of protease inhibition.

Nb-containing polyoxometalates (POMs) of the Wells-Dawson class inhibit HIV-1 protease (HIV-1P) by a new mode based on kinetics, binding, and molecular modeling studies. Reaction of alpha(1)-K(9)Li[P(2)W(17)O(61)] or alpha(2)-K(10)[P(2)W(17)O(61)] with aqueous H(2)O(2) solutions of K(7)H[Nb(6)O(19)] followed by treatment with HCl and KCl and then crystallization affords the complexes alpha(1)-K(7)[P(2)W(17)(NbO(2))O(61)] (alpha(1)()1) and alpha(2)-K(7)[P(2)W(17)(NbO(2))O(61)] (alpha(2)()1) in 63 and 86% isolated yields, respectively. Thermolysis of the crude peroxoniobium compounds (72-96 h in refluxing H(2)O) prior to treatment with KCl converts the peroxoniobium compounds to the corresponding polyoxometalates (POMs), alpha(1)-K(7)[P(2)W(17)NbO(62)] (alpha(1)()2) and alpha(2)-K(7)[P(2)W(17)NbO(62)] (alpha(2)()2), in moderate yields (66 and 52%, respectively). The identity and high purity of all four compounds were confirmed by (31)P NMR and (183)W NMR. The acid-induced dimerization of the oxo complexes differentiates sterically between the cap (alpha(2)) site and the belt (alpha(1)) site in the Wells-Dawson structure (alpha(2)()2 dimerizes in high yield; alpha(1)()2 does not). All four POMs exhibit high activity in cell culture against HIV-1 (EC(50) values of 0.17-0.83 microM), are minimally toxic (IC(50) values of 50 to >100 microM), and selectively inhibit purified HIV-1 protease (HIV-1P) (IC(50) values for alpha(1)()1, alpha(2)()1, alpha(1)()2, and alpha(2)()2 of 2.0, 1.2, 1.5, and 1.8 microM, respectively). Thus, theoretical, binding, and kinetics studies of the POM/HIV-1P interaction(s) were conducted. Parameters for [P(2)W(17)NbO(62)](7)(-) were determined for the Kollman all-atom (KAA) force field in Sybyl 6.2. Charges for the POM were obtained from natural population analysis (NPA) at the HF/LANL2DZ level of theory. AutoDock 2.2 was used to explore possible binding locations for the POM with HIV-1P. These computational studies strongly suggest that the POMs function not by binding to the active site of HIV-1P, the mode of inhibition of all other HIV-1P protease inhibitors, but by binding to a cationic pocket on the "hinge" region of the flaps covering the active site (2 POMs and cationic pockets per active homodimer of HIV-1P). The kinetics and binding studies, conducted after the molecular modeling, are both in remarkable agreement with the modeling results: 2 POMs bind per HIV-1P homodimer with high affinities (K(i) = 1.1 +/- 0.5 and 4.1 +/- 1.8 nM in 0.1 and 1.0 M NaCl, respectively) and inhibition is noncompetitive (k(cat) but not K(m) is affected by the POM concentration).

Comparison of hydrophobic charge induction chromatography with affinity chromatography on protein A for harvest and purification of antibodies.

Efficient harvest and recovery of high-purity monoclonal antibodies was achieved using hydrophobic charge induction chromatography (HCIC). Both simple and complex feedstocks were studied, including protein-free cell culture supernatant and the clarified/concentrated milk of transgenic goats. Viral clearance studies demonstrated a 4-log reduction of MVM virus (minute virus of mice), along with substantial reduction of DNA content. Sorbent characterization studies confirmed that HCIC is based on the pH-dependent behavior of a dual-mode, ionizable ligand. Binding, based on hydrophobic interaction, was achieved under near-physiological conditions, and in the absence of lyotropic salt. Desorption was accomplished under mild conditions--pH 4.0. At this pH, both ligand and antibody carry a net positive charge, and desorption occurs on the basis of electrostatic charge repulsion. pH-based control of chromatographic function was demonstrated. Chromatography on this antibody-selective HCIC sorbent was evaluated as a cost-effective, process-compatible alternative to affinity chromatography protein A sorbents.

Evaluation of a post-professional master's program in allied health.

Changes in allied health education have precipitated a need to review existing educational programs. As more disciplines require a graduate degree for professional entry, it becomes important to articulate the benefits of advanced, post-professional graduate education for allied health professionals. This article reports results from a study of one interdisciplinary Master of Health Sciences (MHS) program. The intent of the study was to 1) analyze graduates' satisfaction with components of the MHS program; 2) explore the perceived impact of the MHS program on graduates' professional practices; and 3) examine employers' perceptions of the program's effect on graduates' professional behaviors. An investigator-developed written questionnaire was used to gather perspectives from 53 graduates and 27 of their employers. Graduates believed the MHS program had had a positive influence on their employment. Graduates' employers concurred, giving high marks to graduates' skill levels and job performances. Program graduates were active in professional organizations, but few were involved in scholarly activities such as research. Implications for curriculum design of advanced master's programs in allied health are discussed.

Where are the GaPs? A rational approach to monomer acquisition and selection.

Gridding and partitioning (GaP) is a computational method for the classification and selection of monomers for combinatorial libraries. The molecules are described in terms of the pharmacophoric groups they contain and where those pharmacophoric groups can be located in three-dimensional space. The approach involves a detailed conformational analysis of each molecule. This conformational analysis is done within a common coordinate frame, thus enabling the monomers to be compared. The use of a partitioned space is central to this particular application as it facilitates the identification of regions of space which are not well represented by existing compounds. Several ways to extend the use of partitioned pharmacophore spaces are described. Applications of the approach in monomer acquisition and in library design are outlined.

Efficient gene transfer to airway epithelium using recombinant Sendai virus.

Clinical studies of gene therapy for cystic fibrosis (CF) suggest that the key problem is the efficiency of gene transfer to the airway epithelium. The availability of relevant vector receptors, the transient contact time between vector and epithelium, and the barrier function of airway mucus contribute significantly to this problem. We have recently developed recombinant Sendai virus (SeV) as a new gene transfer agent. Here we show that SeV produces efficient transfection throughout the respiratory tract of both mice and ferrets in vivo, as well as in freshly obtained human nasal epithelial cells in vitro. Gene transfer efficiency was several log orders greater than with cationic liposomes or adenovirus. Even very brief contact time was sufficient to produce this effect, and levels of expression were not significantly reduced by airway mucus. Our investigations suggest that SeV may provide a useful new vector for airway gene transfer.

Plasma norepinephrine and atrial natriuretic peptide in heart failure: influence of felodipine in the third Vasodilator Heart Failure Trial. V-HeFT III investigators.

BACKGROUND: Reflex activation of the sympathetic nervous system by short-acting dihydropyridine calcium channel antagonists has been reported to harm hypertensive patients. Different neurohormonal profiles and their response to treatment may influence the effectiveness of dihydropyridine vasodilator treatment of heart failure. METHODS: Four hundred fifty men with left ventricular (LV) systolic dysfunction were administered standard heart failure treatment and felodipine extended release (ER) or placebo in the Vasodilator Heart Failure Trial III (V-HeFT III). Plasma norepinephrine (PNE) levels, atrial natriuretic peptide (ANP) levels, exercise capacity, LV ejection fraction (EF), cardiac dimensions and function, and arrhythmia frequency were measured. Hospital-free survival for baseline neurohormonal classes was assessed. RESULTS: Distributions of ANP and PNE levels at baseline in patients with heart failure of ischemic and nonischemic causes were virtually identical. ANP levels at baseline were inversely related to LVEF (r = -0.39; P = .0001), exercise duration (r = -0.19; P = .0001), and peak oxygen consumption (r = -0.27; P = .008) and directly related to LV (r = 0.23; P = .0006) and right ventricular dilatation (r = 0.23; P = .0008). The increase in ANP levels between baseline and 3 months (P = .02) and 1 year (P = .03) was significantly less in the felodipine-ER group than in the placebo group, but PNE levels did not differ between treatment groups. Hospital-free survival was directly related to baseline ANP (P = .0002) and PNE levels (P = .004). All-cause mortality was related to baseline PNE levels (P = .02) but not baseline ANP levels. CONCLUSION: Levels of ANP and PNE hormones are related to LV dysfunction, exercise performance, and hospital-free survival in heart failure and PNE levels are related to all-cause mortality. Treatment with felodipine ER did not adversely affect survival in any neurohormone subclass.