Diagnostic accuracy of ultrasonography and magnetic resonance imaging for the detection of fetal anomalies: a blinded case-control study.

OBJECTIVES: To compare the accuracy of two-dimensional ultrasound (2D-US), three-dimensional ultrasound (3D-US) and magnetic resonance imaging (MRI) for the diagnosis of congenital anomalies without prior knowledge of indications and previous imaging findings. METHODS: This was a prospective, blinded case-control study comprising women with a singleton pregnancy with fetal congenital abnormalities identified on clinical ultrasound and those with an uncomplicated pregnancy. All women volunteered to undergo 2D-US, 3D-US and MRI, which were performed at one institution. Different examiners at a collaborating institution performed image interpretation. Sensitivity and specificity of the three imaging methods were calculated for individual anomalies, based on postnatal imaging and/or autopsy as the definitive diagnosis. Diagnostic confidence was graded on a four-point Likert scale. RESULTS: A total of 157 singleton pregnancies were enrolled, however nine cases were excluded owing to incomplete outcome, resulting in 148 fetuses (58 cases and 90 controls) included in the final analysis. Among cases, 13 (22.4%) had central nervous system (CNS) anomalies, 40 (69.0%) had non-CNS anomalies and five (8.6%) had both CNS and non-CNS anomalies. The main findings were: (1) MRI was more sensitive than 3D-US for diagnosing CNS anomalies (MRI, 88.9% (16/18) vs 3D-US, 66.7% (12/18) vs 2D-US, 72.2% (13/18); McNemar's test for MRI vs 3D-US: P = 0.046); (2) MRI provided additional information affecting prognosis and/or counseling in 22.2% (4/18) of fetuses with CNS anomalies; (3) 2D-US, 3D-US and MRI had similar sensitivity for diagnosing non-CNS anomalies; (4) specificity for all anomalies was highest for 3D-US (MRI, 85.6% (77/90) vs 3D-US, 94.4% (85/90) vs 2D-US, 92.2% (83/90); McNemar's test for MRI vs 3D-US: P = 0.03); and (5) the confidence of MRI for ruling out certain CNS abnormalities (usually questionable for cortical dysplasias or hemorrhage) that were not confirmed after delivery was lower than it was for 2D-US and 3D-US. CONCLUSIONS: MRI was more sensitive than ultrasonography and provided additional information that changed prognosis, counseling or management in 22.2% of fetuses with CNS anomalies. False-positive diagnoses for subtle CNS findings were higher with MRI than with ultrasonography. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Determination of orbifloxacin in sheep plasma by high performance liquid chromatography with ultraviolet detection after intravenous and intramuscular administration.

INTRODUCTION: Single-dose pharmacokinetics of orbifloxacin (2.5mg/kg body weight) were determined in clinically normal female Patanwadi sheep (n=6) following intravenous and intramuscular administration. METHODS: Orbifloxacin concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration-time data were analyzed by non-compartmental kinetic method. RESULTS AND DISCUSSION: Following a single intravenous injection, an elimination half-life (t(1/2ß)) of 8.31±0.102h. Steady-state volume of distribution (Vd(ss)) and total body clearance (Cl(B)) were 3.09±0.282L/kg and 0.158±0.006L/kg/h, respectively. Following intramuscular administration, an elimination rate constant (ß), the area under the curve from zero to infinity (AUC(0-∞)) and the mean absorption time (MAT) were 0.015±0.001h(-1), 23.49±1.722µg·h/mL and 7.50±0.58h, respectively. The peak plasma concentration (C(max)) of 1.81±0.005µg/mL was achieved at 1.00±0.00h. The mean residence time (MRT) was 26.25±1.083h and the absolute bioavailability was 150.8±12.35%, respectively. Orbifloxacin could be useful for the treatment of bacterial infections in sheep that are sensitive to this drug.

Plasma disposition of conventional and long-acting moxifloxacin in sheep after intravenous administration.

This study describes disposition of long-acting moxifloxacin and conventional formulations of moxifloxacin in sheep after intravenous administration in five male sheep. Long acting moxifloxacin solution (10% moxifloxacin in solution with L-arginine, N-butyl alcohol, and benzyl alcohol) and conventional moxifloxacin (10%) were injected in jugular vein. Blood samples were collected from contralateral jugular vein in test tubes containing 30-50 IU heparin (anticoagulant) periodically from 0.083 to 72 h of drug administration. Drug concentrations in plasma were determined using High-Performance Liquid Chromatography (HPLC) with fluorescence detector. The mobile phase consisted of a mixture of buffer (10 gm of tetrabutyl ammonium hydrogen sulphate per liter-deionised water) and acetonitrile (80 : 20). The buffer was 0.067M of disodium hydrogen phosphate with pH of 7.5. The flow rate was 1 mL·min(-1) at ambient temperature. The effluent was monitored at 296 nm excitation and 504 nm emissions wavelength. HPLC with fluorescence detector method for plasma moxifloxacin assay was standardized with specific modification for plasma of sheep in the present study. After single-dose intravenous administration of long acting moxifloxacin the plasma concentration of 0.016 ± 0.001 µ g·mL(-1) was maintained for up to 72 h. Conventional formulation of moxifloxacin remained in body for up to 24 h of drug administration with the level of 0.015 ± 0.005 µ g·mL(-1).

Economic benefit of a 1-day reduction in hospital stay for community-acquired pneumonia (CAP).

OBJECTIVE: As a component of healthcare reform, payers, hospital administrators, and physicians are looking for ways to reduce hospital expenditures and improve efficiency. The economic benefit of a reduced hospital stay must be weighed against the cost of the treatment or process necessary to achieve the reduced length of stay (LOS). The objective of this paper was to estimate the potential economic benefit of a reduction in inpatient hospital LOS for a common type of admission, community acquired pneumonia (CAP). RESEARCH DESIGN AND METHODS: Data for this study were from the CAP hospital admissions selected from the 2006 Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS). Potential savings associated with a 1 day reduction in CAP LOS were estimated using three methods: (1) average cost, (2) weighted-average incremental cost of an additional day, and (3) weighted-average predicted mean costs from regression models which were used to estimate incremental cost adjusting for hospitalization characteristics. MAIN OUTCOME MEASURES: Cost per day of CAP hospitalization. RESULTS: A total of 1,471,295 CAP admissions qualified for the analysis. The cost for each day of reduction in LOS in 2009 US dollars was $2273, $2373, and $2319 for the three methods: simple average, incremental, and regression, respectively. Subgroup analysis and regression analysis indicated higher costs were identified: in patients who died in the hospital, had hospital stays in the Northeast or West, and in large hospitals. Longer CAP hospitalizations had a higher cost per additional day. Limitations include those typically associated with the use of administrative claims (e.g., lack of clinical detail, issues related to diagnosis coding). CONCLUSIONS: Eliminating a day during the course of a CAP admission is potentially worth $2273-2373 in economic benefits (2009 dollars). As we strive for greater efficiency in healthcare delivery, changes in processes and/or improved diagnostics or treatments may potentially achieve a reduction in the length of stay. The cost of such changes or improvements must be weighed against the economic benefit of a shorter hospitalization.

Non-invasive fetal lung assessment using diffusion-weighted imaging.

OBJECTIVES: The main goal was to develop a reproducible method for estimating the diffusion of water in human fetal lung tissue using diffusion-weighted imaging (DWI). A secondary objective was to determine the relationship of the apparent diffusion coefficients (ADCs) in the fetal lung to menstrual age and total lung volume. METHODS: Normal pregnant volunteers were scanned on a 1.5-Tesla (T) magnetic resonance imaging (MRI) system. The MRI system was equipped with 40-mT/m gradients (slew rate 200 T/m/s, rise time 0.2 ms). A six-channel body array coil was used for signal reception. Single-shot DWI utilized TE/TR 125/3400 ms, slice thickness 4 mm, field of view 280 mm x 280 mm, interslice gap 0.8 mm and a matrix of 128 x 128. The voxel size was 2.5 mm x 2.5 mm x 4.0 mm. Two b-values (0 and 1000) were chosen along three orthogonal directions. ADC maps were created using assigned b-values. Simple linear regression was performed with Pearson correlation coefficient. Interexaminer and intraexaminer bias, and 95% limits of agreement (LOA) were determined using Bland-Altman plots. RESULTS: Forty-seven scans were performed at a mean +/- SD of 29.2 +/- 4.5 weeks. The median coefficient of variation for ADC was 5.6% (interquartile range, 4.0-8.1%). No differences in ADC values were found between right and left lungs. Normally distributed ADC measurements were not significantly correlated with either total lung volume (r(2) = 0.0001, P = 0.94) or menstrual age (r(2) = 0.003, P = 0.70). The mean ADC value was 1.75 (95% CI, 1.63-1.86). Mean +/- SD intraexaminer bias was -0.15 +/- 2.3 (95% LOA, -4.7 to + 4.4) and interexaminer bias was 2.2 +/- 3.5 (95% LOA, -4.7 to + 9.1). CONCLUSIONS: Our findings suggest that ADC measurements of the fetal lung are reproducible between blinded examiners and are independent of menstrual age, as well as lung volume.

Estimating the economic impact of a half-day reduction in length of hospital stay among patients with community-acquired pneumonia in the US.

BACKGROUND: A recent study suggested that levofloxacin significantly reduces the hospital length of stay (LOS), by 0.5 days (p = 0.02), relative to moxifloxacin in patients with community-acquired pneumonia (CAP). The current analysis evaluated the potential economic impact of this half-day reduction in LOS. METHODS: A cost model was developed to estimate the impact of a half-day reduction in LOS for CAP hospitalizations in the US. CAP incidence, hospitalization rate, and costs were obtained from published studies in PubMed and from publicly available government sources. The average daily cost of hospitalization was estimated for fixed costs, which comprise 59% of total inpatient costs. Costs from prior years were inflated to 2007 US dollars using the consumer price index. A range of cost savings, calculated using inpatient CAP costs from several studies, was extrapolated to the US CAP population. RESULTS: Using the Centers for Disease Control National Hospital Discharge estimate of 5.3 days LOS for CAP, and an average cost (2007 $US) of $13,009 per CAP hospitalization, a daily fixed cost of $1448 was estimated. The resultant half-day reduction in costs associated with LOS was $724/hospitalization (range $457 to $846/hospitalization). When fixed and variable costs were considered, the estimated savings were $1227.27/episode. The incidence of CAP was estimated to be 1.9% (5.7 million cases/year based on current population census), and the estimated rate of CAP hospitalization was 19.6% (1.1 million annual hospitalizations). At $13,009/CAP-related hospitalization, total fixed inpatient costs of $8.6 billion annually were projected. The half-day reduction in LOS would therefore generate potential annual savings of approximately $813 million (range $513 million to $950 million). When total costs (fixed plus variable) were estimated, the mean savings for a half-day reduction would be approximately $1227/episode (range of $775 to $1434) or $1.37 billion annually in the US CAP population (range of $871 million to $1.6 billion). Limitations include the use of a single study for the estimation of fixed costs but a diversity of sources used for estimates of other variables, and lack of data with respect to the effects on costs of diagnostic-related groups, discounted contracts, and capitated payments. CONCLUSIONS: A relatively small decrease in LOS in CAP can have a substantial cost impact, with estimated savings of $457 to $846 per episode or $500-$900 million annually. Additional evaluation is warranted for interpreting these cost-savings in the context of current antibiotic prescribing patterns.

Medical resource utilization among community-acquired pneumonia patients initially treated with levofloxacin 750 mg daily versus ceftriaxone 1000 mg plus azithromycin 500 mg daily: a US-based study.

OBJECTIVE: The 2007 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines recommend that community-acquired pneumonia (CAP) patients admitted to hospital wards initially receive respiratory fluoroquinolone monotherapy or beta-lactam plus macrolide combination therapy. There is little evidence as to which regimen is preferred, or if differences in medical resource utilization exist between therapies. Thus, the authors compared length of hospital stay (LOS) and length of intravenous antibiotic therapy (LOIV) for patients who received initial levofloxacin 750 mg daily versus ceftriaxone 1000 mg plus azithromycin 500 mg daily ('combination therapy'). RESEARCH DESIGN AND METHODS: Adult hospital CAP cases from January 2005 to December 2007 were identified by principal discharge diagnosis code. Patients with a chest infiltrate and medical notes indicative of CAP were included. Direct intensive care unit admits and healthcare-associated cases were excluded. A propensity score technique was used to balance characteristics associated with initial antimicrobial therapy using multivariable regression to derive the scores. Propensity score categories, defined as propensity score quintiles, rather than propensity scores themselves, were used in the least squares regression model to assess the impact of LOS and LOIV. RESULTS: A total of 495 patients from six hospitals met study criteria. Of these, 313 (63%) received levofloxacin and 182 (37%) received combination therapy. Groups were similar with respect to age, sex, most comorbidities, presenting signs and symptoms, and Pneumonia Severity Index (PSI) risk class. Patients on combination therapy were more likely to have heart failure and receive pre-admission antibiotics. Adjusted least squares mean (+/-SE) LOS and LOIV were shorter with levofloxacin versus combination therapy: LOS, 4.6 +/- 0.17 vs. 5.4 +/- 0.22 days, p < 0.01; and LOIV, 3.6 +/- 0.17 vs. 4.8 +/- 0.21 days, p < 0.01. Results for PSI risk class III or IV patients were: LOS, 5.0 +/- 0.30 vs. 5.9 +/- 0.37 days, p = 0.07; and LOIV, 3.7 +/- 0.33 vs. 5.2 +/- 0.39 days, p < 0.01. Due to the retrospective study design, limited sample size, and scope (single health-network), the authors encourage replication of this study in other data sources. CONCLUSIONS: Given the LOS and LOIV reductions of 0.8 and 1.2 days, respectively, utilization of levofloxacin 750 mg daily for CAP patients admitted to the medical floor has the potential to result in substantial cost savings for US hospitals.

Patient reported outcomes and analgesia use in osteoarthritis of the knee.

OBJECTIVE: Non-opioid analgesics (NOAs) are widely used to palliate osteoarthritis (OA) pain, however, their role in health-related quality of life (HRQoL) in OA has not been well studied. Here, we assess the relationship of pain, physical function, and HRQoL to NOA use in symptomatic knee OA. METHODS: NOA dose, pain, physical function, and HRQoL were evaluated longitudinally over 1 year in medial knee OA. Doses provided by subjects' weekly medication diaries were normalized to equi-analgesic ibuprofen-equivalents (IEs). Descriptive analyses at baseline, 1.5, and 12 months, and non-parametric comparisons of NOA with pain, physical function, and HRQoL at 1.5 months and over 12 months were performed. RESULTS: Seventy-one subjects (19 males and 52 females; mean 57+/-10.5 years) used an overall median of 300 mg/week of IE. Twenty-five subjects reported no analgesic use during the study; of the 46 subjects that reported NOA use, the median intake was 1325 mg/week IE. Whereas age, Physical Functioning (PF) and HRQoL were predictive of NOA dose both at 1.5 months and during the entire study, pain level was not. The median NOA dose declined over 12 months (P=0.02), however, the change was not associated with changes in PF, HRQoL or pain. CONCLUSION: Greater age and worse physical function and HRQoL, but not pain severity, are predictive of NOA use in symptomatic knee OA. Longitudinally, NOA use does not change as a function of pain. These data suggest that pain is not the primary determinant of NOA use over time among OA patients.

Haemoglobin level and its clinical impact in a cohort of patients with COPD.

Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.

Correlation of lipid layer thickness measurements with fluorescein tear film break-up time and Schirmer's test.

PURPOSE: This study correlates measurement of lipid layer thickness (LLT) with two frequently used dry eye tests, fluorescein break-up time (FBUT) and Schirmer's test with anaesthesia (STA). METHODS: Subjects (n = 44 eyes) with symptoms of dry eye and positive results for dry eye with either FBUT or STA or both were selected. Quantification of LLT was performed by the observation of colour interference patterns in zones of specular reflection using a custom-designed instrument. RESULTS: All correlations among pairs of tests were strong and exhibited a significance of P < 0.000: STA with FBUT, Pearson's correlation 0.653; STA with LLT, 0.764; FBUT with LLT, 0.751. When LLT was high, ie > or = 120 nm, which occurred in 14 eyes, STA was also elevated in those eyes and FBUT was high in 13 of the 14 eyes. When LLT was low, ie < or = 60, which occurred in 22 eyes, STA was below normal in 14 of the 22 eyes, and FBUT was below normal in 15 of the 22 eyes. These clinical observations paralleled the statistical findings computed from the entire data set. CONCLUSIONS: The correlations demonstrated in this study support the premise (1) that measurement of LLT is a reliable test for the diagnosis of dry eye, and (2) that aqueous deficiency and lipid deficiency, as they apply to dry eye disorders, are not mutually exclusive.

Chimeric Galphaq subunits can distinguish the long form of the Xenopus Mel1c melatonin receptor from the mammalian mt1 and MT2 melatonin receptors.

The family of melatonin receptors is composed of the mt1, MT2, and Mel1c subtypes. The Mel1c is further divided into one long and two short isoforms. A recent study has shown that, unlike mt1 and MT2, the long form of Mel1c is incapable of activating the pertussis toxin-insensitive G16. Here we used three well-characterized Galphaq chimeras to explore the coupling specificity of the melatonin receptors. The qi5, qo5, and qz5 chimeras can link numerous Gi-coupled receptors to the stimulation of phosphoinositide-specific phospholipase C. Both mt1 and MT2 receptors interacted productively with the Galphaq chimeras, while the long form of Mel1c was totally ineffective. Among the Galphaq chimeras, qo5 was less efficiently coupled to the melatonin receptors. Such differential coupling is best explained by structural differences between the melatonin receptors as well as among the Galphaq chimeras. Since the long form of Mel1c receptor possesses an exceptionally large C-terminal tail, we tested the ability of four melatonin receptor C-terminal tail chimeras (Chi 1-4) to interact with the Galphaq chimeras. The presence of the large C-terminal tail of Mel1c in Chi 1 and Chi 3 markedly hindered their coupling to the Galphaq chimeras. On the other hand, the attachment of either the mtl or MT2 C-terminal tail to a Mel1c backbone produced chimeras (Chi 2 and Chi 4) that were capable of activating the Galphaq chimeras. These findings suggest the involvement of C-terminal regions of melatonin receptors in the recognition of G proteins.

Incorporation of Galpha(z)-specific sequence at the carboxyl terminus increases the promiscuity of galpha(16) toward G(i)-coupled receptors.

Although the promiscuous nature of G(16) allows it to interact with numerous G protein-coupled receptors, several G(i)-linked receptors are incapable of activating phospholipase C via G(16). A series of chimeras between Galpha(16) and Galpha(z) were constructed and assayed for their ability to mediate receptor-induced stimulation of phospholipase C. Two Galpha(16/z) chimeras harboring 25 or 44 Galpha(z)-specific sequences at their C termini (named 16z25 and 16z44) were capable of responding to 14 different G(i)-coupled receptors tested, including those that were either unable to associate with Galpha(16) (melatonin Mel1c) or activate Galpha(16) weakly (micro-opioid and type 1 somatostatin). Agonist-induced stimulation of phospholipase C was more efficiently mediated (higher maximal and lower EC(50) value) by 16z44 than by Galpha(16). Both 16z25 and 16z44 were also coupled to G(s)- and G(q)-linked receptors. Incorporation of Galpha(z) sequence at the N terminus of Galpha(16) did not further enhance the ability of the chimeras to interact with G(i)-coupled receptors. Expression of the various chimeras was verified by immunodetection and functional analysis of their constitutively activated mutants. These results show that the incorporation of alpha4/beta6 and alpha5 regions of Galpha(z) into a Galpha(16) backbone can improve the recognition of G(i)-coupled receptors. Galpha(16/z) chimeras with expanded capability to interact with G(i)-linked receptors may be used to link orphan receptors to the stimulation of phospholipase C.

Stenting of proximal venous obstructions to maintain hemodialysis access.

PURPOSE: The purpose of the study was to evaluate the efficacy of stenting central venous obstructions in patients dependent on hemodialysis to preserve or restore central venous patency and allow for continued hemodialysis from the affected side. METHODS: Twenty-five self-expanding (17) and balloon-expandable (8) stainless steel stents were deployed in 19 patients with end-stage renal disease and central venous stenosis or occlusion. Nineteen lesions were treated: 11 subclavian and eight innominate. Twenty-two stents were initially implanted. RESULTS: Stent deployment was successful in all cases and immediately remedied the underlying cause of venous hypertension. Follow-up at up to 17 months revealed three deaths from unrelated causes, one occlusion at 3.25 months, and three restenoses at 16 days, 2.5 and 5 months, respectively, with successful implantation of three additional stents for a primary central patency rate of 68% (+/- 14%) and secondary central patency rate of 93% (+/- 7%). CONCLUSIONS: Stenting of subclavian and innominate venous stenoses and occlusions effectively corrected the underlying lesions responsible for disturbed hemodynamics and, in most cases, prolonged available hemodialysis access from the affected side. Stents seem to be valuable adjuncts in the management of failing hemodialysis access due to central venous stenosis or occlusion.