Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

An understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine response to antimicrobial therapy can provide the clinician with better-informed dosing regimens. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Techniques to better understand antibiotic PK and optimize PD are acknowledged

Large area, label-free imaging of extracellular matrix using telecentricity

Subtle alterations in stromal tissue structures and organizations within the extracellular matrix (ECM) have been observed in several types of tissue abnormalities, including early skin cancer and wounds. Current microscopic imaging methods often lack the ability to accurately determine the extent of malignancy over a large area, due to their limited field of view. In this research we focus on the development of simple mesoscopic (i.e. between microscopic and macroscopic) biomedical imaging device for non-invasive assessment of ECM alterations over a large, heterogeneous area. In our technology development, a telecentric lens, commonly used in machine vision systems but rarely used in biomedical imaging, serves as a key platform to visualize alterations in tissue microenvironments in a label-free manner over a clinically relevant area. In general, telecentric imaging represents a simple, alternative method for reducing unwanted scattering or diffuse light caused by the highly anisotropic scattering properties of biological tissue. In particular, under telecentric imaging the light intensity backscattered from biological tissue is mainly sensitive to the scattering anisotropy factor, possibly associated with the ECM. We demonstrate the inherent advantages of combining telecentric lens systems with hyperspectral imaging for providing optical information of tissue scattering in biological tissue of murine models, as well as light absorption of hemoglobin in blood vessel tissue phantoms. Thus, we envision that telecentric imaging could potentially serve for simple site-specific, tissue-based assessment of stromal alterations over a clinically relevant field of view in a label-free manner, for studying diseases associated with disruption of homeostasis in ECM

Data-driven imaging of tissue inflammation using RGB-based hyperspectral reconstruction toward personal monitoring of dermatologic health

Sensitive and accurate assessment of dermatologic inflammatory hyperemia in otherwise grossly normal-appearing skin conditions is beneficial to laypeople for monitoring their own skin health on a regular basis, to patients for looking for timely clinical examination, and to primary care physicians or dermatologists for delivering effective treatments. We propose that mathematical hyperspectral reconstruction from RGB images in a simple imaging setup can provide reliable visualization of hemoglobin content in a large skin area. Without relying on a complicated, expensive, and slow hyperspectral imaging system, we demonstrate the feasibility of determining heterogeneous or multifocal areas of inflammatory hyperemia associated with experimental photocarcinogenesis in mice. We envision that RGB-based reconstructed hyperspectral imaging of subclinical inflammatory hyperemic foci could potentially be integrated with the built-in camera (RGB sensor) of a smartphone to develop a simple imaging device that could offer affordable monitoring of dermatologic health

Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

Abstract Background The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. Objectives The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. Methods We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. Results We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC 24,SS ) and maximum concentration of sildenafil (C max,SS,SIL ) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC 24,SS ; 1.19 (0.78, 1.82) for C max,SS,SIL . Conclusions We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted

Simulated reductions in consumption of sugar-sweetened beverages improves diet quality in Lower Mississippi Delta adults

Although the effects of replacing sugar-sweetened beverages (SSBs) with water on energy intake and body weight have been reported, little is known about how these replacements affect diet quality.To simulate the effects of replacing SSBs with tap water on diet quality and total energy intake of Lower Mississippi Delta (LMD) adults.Retrospective analysis of cross-sectional dietary intake data using a representative sample of LMD adults (n=1,689). Diet quality was measured using the Healthy Eating Index-2005 (HEI-2005) scores that were computed using the population ratio method. The effects of substituting SSBs with water on diet quality were simulated by replacing the targeted items’ nutrient profile with tap water's profile.Simulating the replacement of SSBs with tap water at 25, 50, and 100% levels resulted in 1-, 2.3-, and 3.8-point increases, respectively, in the HEI-2005 total score. Based on a mean daily intake of 2,011 kcal, 100% substitution of SSBs with tap water would result in 11% reduction in energy intake.Replacing SSBs with water could substantially improve the diet quality of the LMD adult population and potentially lead to significant weight loss overtime. Prioritizing intervention efforts to focus on the replacement of SSBs with energy-free drinks may be the most efficacious approach for conveying potentially substantial health benefits in this and similar disadvantaged populations

Beyond 30 days: Does limiting the duration of surgical site infection follow-up limit detection?

Concern over consistency and completeness of surgical site infection (SSI) surveillance has increased due to public reporting of hospital SSI rates and imminent non-payment rules for hospitals that do not meet national benchmarks. Already, hospitals no longer receive additional payment from the Centers for Medicare & Medicaid Services (CMS) for certain infections following coronary artery bypass graft (CABG) surgery, orthopedic procedures, and bariatric surgery. One major concern is incomplete and differential post-discharge surveillance. At present, substantial variation exists in how and whether hospitals identify SSI events after the hospitalization in which the surgery occurred. Parameters used for SSI surveillance such as the duration of the window of time that surveillance takes place following the surgical procedure can impact the completeness of surveillance data. Determination of the optimal surveillance time period involves balancing the potential increased case ascertainment associated with a longer follow-up period with the increased resources that would be required. Currently, the time window for identifying potentially preventable SSIs related to events at the time of surgery is not fully standardized. The Centers for Disease Control and Prevention (CDC) National Healthcare Surveillance Network (NHSN) requires a 365-day postoperative surveillance period for procedures involving implants and a 30-day period for non-implant procedures. In contrast, the National Surgical Quality Improvement Program (NSQIP) and the Society of Thoracic Surgeons (STS) systems employ 30-day post-operative surveillance regardless of implant. As consensus builds towards national quality measures for hospital-specific SSI rates, it will be important to assess the frequency of events beyond the 30-day post-surgical window that may quantify the value of various durations of surveillance, and ultimately inform the choice of specific outcome measures

Direct analysis of melamine in complex matrices using a handheld mass spectrometer † ‡

A low temperature plasma ambient ionization source, coupled to a portable mass spectrometer (Mini 10.5), is used for the determination of melamine contamination in whole milk and related materials. Thermally assisted desorption and ionization of the analyte was achieved with the plasma probe. The small size, low power consumption and capability for direct sampling without pretreatment makes plasma ionization an appropriate ionization method for use with a handheld mass spectrometer. The standard discontinuous atmospheric pressure interface used to connect atmospheric pressure ion sources to mass spectrometers (Gao et al., Anal. Chem., 2008, 80, 4026-4032) was modified by using supplementary pumping to increase the ion transfer efficiency. Whole milk, fish, milk powder and other complex matrices spiked with melamine were placed on glass slides close to the vacuum inlet and analyzed without sample pretreatment. Quantitation in complex matrices was achieved using MS/MS of protonated melamine m/z 127 to yield the characteristic fragment ion of m/z 85. Analysis rates of two samples per minute, levels of melamine as low as 250 ng/mL in whole milk (below the regulatory level in the US of 1 ppm (1 mg/mL) or the European level of 2.5 ppm (mg/mL)), a linear dynamic range of 0.5-50 mg/mL and a relative standard deviation of ca. 7.6-16.2% were achieved. The importance of melamine to public health and the prior lack of a rapid, sensitive and yet highly specific field analysis method add to the relevance of this study. Introduction Melamine, a nitrogen-rich (66.7% by weight) industrial chemical, has been deliberately added into various foods to artificially increase the apparent protein content as judged by total nitrogen measurement (the Kjeldahl nitrogen determination 1 ). In 2007, pet food adulteration with melamine leading to kidney toxicity in cats and dogs was reported, and in September of 2008, melaminecontaminated milk resulted in kidney stones and renal failure in infants. 2-4 Melamine reacts with its metabolite cyanuric acid to form a poorly soluble stable complex which can precipitate in renal tubules and lead to kidney failure. 5 Instrumental methods for melamine analysis in food have been developed rapidly in response to the public health alarm: they include immunoassays, 6 capillary zone electrophoresis with diode array and mass spectrometry detection, 7,8 high performance liquid chromatography coupled with ultraviolet absorption 9,10 and with mass spectrometry, 11-15 gas chromatography/mass spectrometry 10,16 and ultra-performance liquid chromatography with tandem mass spectrometry. 17 However, all these methods require tedious sample preparation, for example, the US Food and Drug administration (FDA) has published a method for screening melamine in pet food using GC/MS, 18 which takes about 3 h for a single detection although by using parallel operations the time per sample can be decreased. The continuing need for rapid screening of melamine has led to the application of several of the new ambient ionization mass spectrometric techniques, specifically low temperature plasma (LTP), Based on a rectilinear ion trap (RIT) mass analyzer, 19 ) These ionization methods allow the direct mass spectrometric analysis of compounds present in condensed phase samples. In a prior short communication, we have reported LTP probe ionization for melamine screening using conventional benchtop mass spectrometers. 20 LTP is a particularly appropriate ionization method for use in conjunction with a miniature mass spectrometer, given the following characteristics: (1) direct sampling occurs without sample pretreatment (except for optional heating), (2) no solvents are used, (3) air can serve as the plasma support gas, (4) low power consumption ($3 W), (5) small size, and (6) rapid analysis. In the present paper, we report the characteristics of the LTP/miniature mass spectrometer combination for the detection and quantification of melamine. A modified discontinuous atmospheric pressure interface (DAPI) 47 was used to increase the ion transfer efficiency into the mass spectrometer. The interface includes a compact version of the LTP probe, a heater which focuses the heat and the plasma onto a 5 mm  5 mm surface area, and supplementary pumping to transfer the ions effectively into the ion trap. The LTP was used to desorb and ionize the analyte from a glass surface with thermal assistance (up to 200 C). Analysis speeds can reach the rate of two samples per minute. Results show that levels of melamine as low as 250 ng/mL (250 ppb) spiked into whole milk can be detected and that the linear dynamic range is 0.4-50 mg/mL. The detection limit is well below the US regulatory level of 1 ppm and the European level of 2.5 ppm. Experimental Chemical and reagents All the foods were randomly bought in local supermarkets and were used directly without further treatment. All chemicals, including melamine, cyanuric acid and methanol, were purchased from Sigma-Aldrich (USA) and used without purification. Synthetic urine was purchased from CST Technologies, Inc. (NY, USA). The deionized water used for preparing standard solutions was obtained using a Milli-Q purification system (Millipore, Bedford, MA, USA). Melamine in methanol and water (v:v 1:1) at a concentration of 1000 mg/mL served as stock solution. Spiked milk samples were made by diluting the melamine solution with whole milk using a dilution ratio of 1:20 (melamine solution:milk). For each measurement, 3 mL of solution was placed on a glass slide giving a sample spot of ca. 2 mm  2 mm, then the glass slide was placed directly under the heated LTP probe to execute the analysis. Fish meat was first ground, then 2 g of the fishpaste was mixed with selected amounts of melamine solution (500 mg/mL in methanol/water) to achieve different concentrations. The fishpaste was vortexed for 20 min to assure homogeneous mixing and allowed to stand for another 20 min before analysis (these steps were used in preparing a sample representative of contaminated fish, they are not needed for analysis). For each analysis, 5 mg fishpaste was used. All samples were prepared and measured at room temperature (15-25 C). LTP ionization source The LTP probe consists of a glass tube (o.d. 6.35 mm and i.d. 3.75 mm) with an axial grounded electrode (stainless steel; diameter, 1.57 mm) and an outer electrode (copper tape) wrapped onto the tube, as reported in a previous study. Miniature mass spectrometer and its ambient interface A previously described handheld rectilinear ion trap mass spectrometer (Mini 10.5) 25 was used for the experiments reported in this paper. To confirm the miniature mass spectrometer results, a parallel study was conducted using an LTQ (Thermo Fisher Scientific, Inc., San Jose, CA, USA). A miniature rough pump together with a miniature turbo pump was used to achieve an ultimate vacuum below 1  10 À5 Torr in the Mini 10.5. A twostage KNF Neuberger diaphragm pump (1091-N84.0-8.99) with a pumping speed of 5 L/min was used to provide a backing pressure below 2 Torr for the turbo pump. The latter was a 10 L/s Pfeiffer TPD 011 (Pfeiffer Vacuum Inc., Nashua, NH, USA) and it constituted the main vacuum pump of the system. All components of the Mini 10.5, including the electronics and vacuum systems, are assembled in an aluminium case, length 34 cm, width 22 cm and height 19 cm. The total weight of the instrument is 10 kg. A discontinuous DAPI 47 interface is used to transfer the ions created by the LTP source into the vacuum chamber of the Mini 10.5 for detection. The discontinuous interface acts as a mechanical switch, which opens the ion introduction channel briefly (10-30 ms) and then closes it during the subsequent periods of each scan cycle (ion cooling, mass analysis, ion clearance and reset). The pressure inside the vacuum chamber increases significantly (up to 10 mTorr) when the channel is open for ion (and accompanying air/sample vapor) introduction. It is appropriate to shut off all high voltages and maintain only a low RF voltage during this period. After ion introduction, the channel is closed to allow the pressure to decrease over a period of time (300-500 ms) until it reaches a value (normally 1 mTorr) that allows further ion manipulation and mass analysis. At this point, the high voltage is turned on and the RF is scanned to perform mass analysis. Each cycle takes around 1 s and all mass spectra were averaged over 3 cycles and are reported with background This journal is ª The Royal Society of Chemistry 2010 View Article Online subtraction. For this study an improved version of the interface (described in the next section) was employed. This optimized interface Results and discussion LTP and Mini 10.5 interface The LTP ambient ionization source can be directly combined with a benchtop mass spectrometer. The interface between LTP and Mini 10.5 was improved further in this study by using an extra pumping system (shown in This journal is ª The Royal Society of Chemistry 2010 Analyst, 2010, 135, 705-711 | 707 View Article Online Neuberger, Trenton, NJ, USA) was used to provide an air flow rate of 2.5 L/min toward the vacuum inlet. Ions created by the LTP were sucked into the quarter inch capillary (c1 in Direct detection of melamine in complex matrices With the LTP/Mini 10.5 described above Direct detection of melamine in milk. Soon after the 2008 melamine scandal, 2-4 several groups developed rapid melamine detection methods for complex samples using benchtop mass spectrometers operated with various ambient ionization methods, including LTP, 19,20 EESI, 21 DART 22 and DAPCI. 23 The first study to detect melamine using a miniature mass spectrometer (Mini 10.5) is presented in the present study. Organic milk spiked with melamine to a concentration of 5 mg/mL (sample dilution and operational details described in the Experimental section) gave a mass spectrum using the LTP/Mini 10.5 from which the presence of melamine could be detected 20 Direct detection of melamine in milk powder. Detection of melamine in milk powder could become a quality control activity in dairy plants. Due to the unique advantages of the LTP source, View Article Online i.e. no direct contact with the sample, low carrier gas flow rate and direct analyte desorption from the sample, the LTP/Mini 10.5 procedure can be used to detect melamine directly in milk powder at a concentration of 5 mg/g Direct detection of melamine in urine. If, unfortunately, the above food safety measures are unsuccessful and melaminecontaminated products do get into the food market, rapid and direct analysis of body fluid (such as urine) is important for clinical diagnosis. Given the complexity of the urine matrix, standard methods such as ESI and APCI are not suited to direct melamine detection. Although matrix assisted laser desorption ionization (MALDI) has recently been used to detect melamine in urine, 48 addition of R-cyano-4-hydroxycinnamic acid is still needed. The methods reported in this paper allow direct detection of melamine in urine using a portable mass spectrometer. As illustrated in Optimization and analytical performance Optimization experiments were conducted to decrease the LOD and increase the linear dynamic range of the LTP/Mini 10.5 combination 20 Similar results were obtained for the LTP/Mini 10.5 system and, based on the data shown in 25 The notch of the waveform for isolation of protonated melamine was set to cover 138-142 kHz corresponding to an isolation window of m/z 127 AE 2. The frequency of the AC for CID was set to 140 kHz to optimize the fragment ion abundance. The amplitudes of the AC for both isolation and activation were optimized and set at 6 V and 0.4 V Under these optimized conditions, the linear dynamic range for determination of melamine in whole milk is between 0.4 and 50 mg/mL with a LOD of 250 ng/mL (see Supplementary Materials ‡). The detection limit is far below the regulatory level in the US of 1 ppm or the European level of 2.5 mg/kg or 2.5 ppm. As noted in the European regulations, ''.the level of 2.5 mg/kg is the appropriate level to distinguish between the unavoidable background presence of melamine and unacceptable adulteration.''. 49 The analytical performance of the LTP/Mini 10.5 for all matrices tested in the present work is summarized i

Use of Medicare claims to rank hospitals by surgical site infection risk following coronary artery bypass graft surgery

ObjectiveTo evaluate whether longitudinal insurer claims data allow reliable identification of elevated hospital surgical site infection (SSI) rates.DesignWe conducted a retrospective cohort study of Medicare beneficiaries who underwent coronary artery bypass grafting (CABG) in US hospitals performing at least 80 procedures in 2005. Hospitals were assigned to deciles by using case mix-adjusted probabilities of having an SSI-related inpatient or outpatient claim code within 60 days of surgery. We then reviewed medical records of randomly selected patients to assess whether chart-confirmed SSI risk was higher in hospitals in the worst deciles compared with the best deciles.ParticipantsFee-for-service Medicare beneficiaries who underwent CABG in these hospitals in 2005.ResultsWe evaluated 114,673 patients who underwent CABG in 671 hospitals. In the best decile, 7.8% (958/12,307) of patients had an SSI-related code, compared with 24.8% (2,747/11,068) in the worst decile ([Formula: see text]). Medical record review confirmed SSI in 40% (388/980) of those with SSI-related codes. In the best decile, the chart-confirmed annual SSI rate was 3.2%, compared with 9.4% in the worst decile, with an adjusted odds ratio of SSI of 2.7 (confidence interval, 2.2-3.3; [Formula: see text]) for CABG performed in a worst-decile hospital compared with a best-decile hospital.ConclusionsClaims data can identify groups of hospitals with unusually high or low post-CABG SSI rates. Assessment of claims is more reproducible and efficient than current surveillance methods. This example of secondary use of routinely recorded electronic health information to assess quality of care can identify hospitals that may benefit from prevention programs

Re‐evaluation of phosphoric acid–phosphates – di‐, tri‐ and polyphosphates (E 338–341, E 343, E 450–452) as food additives and the safety of proposed extension of use

The Panel on Food Additives and Flavourings added to Food (FAF) provided a scientific opinion re‐evaluating the safety of phosphates (E 338–341, E 343, E 450–452) as food additives. The Panel considered that adequate exposure and toxicity data were available. Phosphates are authorised food additives in the EU in accordance with Annex II and III to Regulation (EC) No 1333/2008. Exposure to phosphates from the whole diet was estimated using mainly analytical data. The values ranged from 251 mg P/person per day in infants to 1,625 mg P/person per day for adults, and the high exposure (95th percentile) from 331 mg P/person per day in infants to 2,728 mg P/person per day for adults. Phosphate is essential for all living organisms, is absorbed at 80–90% as free orthophosphate excreted via the kidney. The Panel considered phosphates to be of low acute oral toxicity and there is no concern with respect to genotoxicity and carcinogenicity. No effects were reported in developmental toxicity studies. The Panel derived a group acceptable daily intake (ADI) for phosphates expressed as phosphorus of 40 mg/kg body weight (bw) per day and concluded that this ADI is protective for the human population. The Panel noted that in the estimated exposure scenario based on analytical data exposure estimates exceeded the proposed ADI for infants, toddlers and other children at the mean level, and for infants, toddlers, children and adolescents at the 95th percentile. The Panel also noted that phosphates exposure by food supplements exceeds the proposed ADI. The Panel concluded that the available data did not give rise to safety concerns in infants below 16 weeks of age consuming formula and food for medical purposes

Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m2. Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score ≤10 (3.63±0.55 versus 3.49±0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6±0.5 versus 3.5±0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score (p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function