12-hour Study Research Articles

Clinical validation of the novel fluorescent glomerular filtration rate tracer agent relmapirazin (MB-102)

The fluorescent compound relmapirazin has been rationally designed for use in point-of-care measurement of glomerular filtration rate (GFR), with attributes including negligible protein binding, negligible metabolites invivo, negligible tubular secretion, and excellent chemical and photo stability. Twenty-four nonclinical assays were performed in accordance with FDA requirements yielding negligible toxicology concerns. Here, a clinical study was performed to validate relmapirazin as a GFR tracer in patients by comparison to iohexol. This was evaluated in 120 adults at three clinical sites with eGFR values ranging from normal to Stage 4 chronic kidney disease. Relmapirazin and iohexol were administered intravenously in consecutive boluses to each subject and serial blood samples obtained over the subsequent 12 hours. Plasma concentrations were measured and the corresponding plasma GFR for each agent was determined using a standard two-compartment pharmacokinetic assessment. Urine from each subject was collected for the entire 12-hour study period to measure the amount of administered dose appearing in the urine. A near perfect linear regression correlation was observed between the GFRs measured by these two tracers (r2=0.99). Bland-Altman analysis confirmed agreement between these two measures of GFR (limits of agreement -7.0 to+5.6 mL/min; mean of -0.7 mL/min). The GFR determined by relmapirazin was independent of GFR stratification by chronic kidney disease stage, and importantly by race. The percent of the administered relmapirazin dose recovered in the urine was greater than or equal to that of iohexol with no reported severe adverse events. Thus, relmapirazin may be used as a GFR tracer agent in humans.

A randomized, crossover study to evaluate α-tocopherol bioavailability via a microemulsion gel or dry tablet delivery in healthy adults.

Vitamin E (α-tocopherol) is an essential micronutrient for human health and optimal physiological function. Inadequacy may be common due to a lack of bioavailability. The use of dietary lipids alongside other emulsification agents may elicit more robust serum concentrations of α-tocopherol via improved bioavailability. Therefore, the aim of the study was to examine oral bioavailability of two delivery methods of α-tocopherol, (1) a microemulsion gel formula composed of dietary lipids and other emulsification agents and (2) a dry solid tablet over 12 hours. Twelve participants (age = 37.3 ± 9.6 years; height = 173.4 ± 11.8 cm; body mass = 71.2 ± 10.0 kg) participated in a double-blind, randomized, crossover trial comparing two delivery methods both dosed at 288 mg of α-tocopherol. Serum α-tocopherol concentrations were assessed from blood donated by participants at pre-consumption, 2-, 4-, 8-, and 12-hour post-consumption. Study conditions were separated by a 7-day washout. The microemulsion gel formula delivery demonstrated significantly greater area under the curve (p < 0.001) and serum concentration maximums (p = 0.003) for serum α-tocopherol compared to the tablet delivery. No significant differences were detected between conditions for the time to reach concentration maximums (p = 0.375). We conclude that a mixture of dietary lipids and emulsification agents in the form of a microemulsion gel formula was able to significantly improve bioavailability of serum α-tocopherol compared to a tablet by yielding higher serum α-tocopherol maximum concentrations and area under the curve over a 12-hour study period despite dosage being matched.

Effect of Glutamine Administration After Cardiac Surgery on Kidney Damage in Patients at High Risk for Acute Kidney Injury: A Randomized Controlled Trial.

Acute kidney injury (AKI) is a common complication after cardiac surgery and is associated with increased morbidity and mortality. However, no specific treatment options are available, emphasizing the need for preventive measures. The aim of this study was to clarify the effect of glutamine on [TIMP2]*[IGFBP7] levels at the end of the intervention period. In a randomized clinical, double-blind pilot study, 64 eligible cardiac surgery patients at high risk for AKI identified by high urinary [TIMP2]*[IGFBP7] were randomized, and body weight-adapted intravenous glutamine or saline-control was administered continuously for 12 hours postoperatively. The primary outcome was urinary [TIMP2]*[IGFBP7] at the end of the 12-hour study period. Secondary outcomes included kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) at 12 hours, overall AKI rates at 72 hours, free days through day 28 of mechanical ventilation and vasoactive medication, renal recovery at day 90, requirement of renal replacement therapy and mortality each at days 30, 60, and 90, length of intensive care unit (ICU) and hospital stay, and major adverse kidney events consisting of mortality, dialysis dependency, and persistent renal dysfunction (serum creatinine ≥2× compared to baseline value) at day 90 (major adverse kidney event; MAKE 90 ). Sixty-four patients (mean age, 68.38 [standard deviation {SD} ± 10.48] years; 10 of 64 women) were enrolled and randomized. Patients received coronary artery bypass graft surgery (32/64), valve surgery (18/64), coronary artery bypass graft and valve surgery (6/64), or other procedures (8/64). Mean on-pump time was 68.38 (standard deviation ± 10.48) minutes. After glutamine administration, urinary [TIMP-2]*[IGFBP7] was significantly lower in the glutamine compared to the control group (primary end point, intervention: median, 0.18 [Q1, Q3; 0.09, 0.29], controls: median, 0.44 [Q1, Q3; 0.14, 0.79]; P = .01). In addition, [KIM-1] and [NGAL] were also significantly lower in the glutamine group. The overall AKI rate within 72 hours was not different among groups: (intervention 11/31 [35.5%] versus control 8/32 [25.0%]; P = .419; relative risk [RR], 0.86% [95% confidence interval {CI}, 0.62-1.20]). There were no differences regarding secondary end points. Glutamine significantly decreased markers of kidney damage in cardiac surgery patients at high risk for AKI. Future trials have to be performed to investigate whether the administration of glutamine might be able to reduce the occurrence of AKI after cardiac surgery.

Measurement of Heart Rate Using the Withings ScanWatch Device During Free-living Activities: Validation Study.

BackgroundWrist-worn devices that incorporate photoplethysmography (PPG) sensing represent an exciting means of measuring heart rate (HR). A number of studies have evaluated the accuracy of HR measurements produced by these devices in controlled laboratory environments. However, it is also important to establish the accuracy of measurements produced by these devices outside the laboratory, in real-world, consumer use conditions.ObjectiveThis study sought to examine the accuracy of HR measurements produced by the Withings ScanWatch during free-living activities.MethodsA sample of convenience of 7 participants volunteered (3 male and 4 female; mean age 64, SD 10 years; mean height 164, SD 4 cm; mean weight 77, SD 16 kg) to take part in this real-world validation study. Participants were instructed to wear the ScanWatch for a 12-hour period on their nondominant wrist as they went about their day-to-day activities. A Polar H10 heart rate sensor was used as the criterion measure of HR. Participants used a study diary to document activities undertaken during the 12-hour study period. These activities were classified according to the 11 following domains: desk work, eat or drink, exercise, gardening, household activities, self-care, shopping, sitting, sleep, travel, and walking. Validity was assessed using the Bland-Altman analysis, concordance correlation coefficient (CCC), and mean absolute percentage error (MAPE).ResultsAcross all activity domains, the ScanWatch measured HR with MAPE values <10%, except for the shopping activity domain (MAPE=10.8%). The activity domains that were more sedentary in nature (eg, desk work, eat or drink, and sitting) produced the most accurate HR measurements with a small mean bias and MAPE values <5%. Moderate to strong correlations (CCC=0.526-0.783) were observed between devices for all activity domains, except during the walking activity domain, which demonstrated a weak correlation (CCC=0.164) between devices.ConclusionsThe results of this study show that the ScanWatch measures HR with a degree of accuracy that is acceptable for general consumer use; however, it would not be suitable in circumstances where more accurate measurements of HR are required, such as in health care or in clinical trials. Overall, the ScanWatch was less accurate at measuring HR during ambulatory activities (eg, walking, gardening, and household activities) compared to more sedentary activities (eg, desk work, eat or drink, and sitting). Further larger-scale studies examining this device in different populations and during different activities are required.

How safe are paediatric emergency departments? A national prospective cohort study

BackgroundDespite the high number of children treated in emergency departments, patient safety risks in this setting are not well quantified. Our objective was to estimate the risk and type of...

Sparse Deconvolution of Pulsatile Growth Hormone Secretion in Adolescents.

Growth hormone (GH) is secreted by cells in the anterior pituitary on two time scales: discrete pulses over minutes that occur within a 24-hr pattern. Secretion reflects the balance of stimulatory and inhibitory inputs from the hypothalamus and is influenced by gonadal steroids, stress, nutrition, and sleep/wake states. We propose a novel approach for the analysis of GH data and use this approach to quantify (i) the timing, amplitude and the number of GH pulses and (ii) GH infusion, clearance and basal secretion (i.e., time invariant) rates, using serum GH sampled every 10 minutes during an 8-hour sleep study in 18 adolescents. In our method, we approximate hormonal secretory events by deconvolving GH data via a two-step coordinate descent approach. The first step utilizes a sparse-recovery approach to estimate the timing and amplitude of GH secretory events. The second step estimates physiological parameters. Our method identifies the timing and amplitude of GH pulses and system parameters from experimental and simulated data, with a median R2 of 0.93, among experimental data. Recovering GH pulses and model parameters using this approach may improve the quantification of GH parameters under different physiological and pathological conditions and the design and monitoring of interventions.

Asymptomatic Hyperinsulinemic Hypoglycemia and Grade 4 Intraventricular Hemorrhage in a Late Preterm Infant.

Hyperinsulinemic hypoglycemia (HH) has the potential to cause acute neurologic dysfunction and neurodevelopmental impairment. Parieto-occipital neuronal injuries have been reported in hypoglycemic infants, but intraparenchymal hemorrhage is rare. On day 5 of life, a late preterm infant was transferred to our care with recurrent asymptomatic hypoglycemia. Prior to arrival, plasma glucose levels were at a median of 1.25 mmol/L (22.5 mg/dL) in the first 6 hours of life, and he required a glucose infusion rate (GIR) of 22.6 mg/kg/min. Hyperinsulinism was confirmed in the presence of detectable insulin, low ketones, and fatty acid when hypoglycemic. A left grade 4 intraventricular hemorrhage (IVH) was noted in the cranial ultrasound scan during the workup for sepsis on the day of admission. However, magnetic resonance imaging of the brain on day 7 of life revealed extensive bilateral IVH. On day 9, he was initiated on diazoxide, and HH resolved within 48 to 72 hours, allowing increment of feeds while weaning GIR. Ventricular drain for post-hemorrhagic ventriculomegaly was advised but not performed. At 3 months, post-hemorrhagic ventriculomegaly was stable, and there were early signs of neurodevelopmental delay. After discontinuing diazoxide at 4 months of age, he passed an 8-hour fasting study confirming the resolution of HH. Severe hypoglycemia has been associated with cerebral hyperperfusion in preterm infants and potentially could cause IVH. Close monitoring and prompt intervention in preterm infants to prevent severe hypoglycemia are paramount. In addition to long-term neurodevelopmental follow-up, infants with recurrent hypoglycemia may benefit from neuroimaging and thereby early intervention if required.

NIR-responsive transdermal delivery of atenolol based on polyacrylamide-modified MoS2 nanoparticles

Transdermal drug delivery system (TDDS) is a successful non-invasive drug delivery system that shows several advantages. However, dose depletion effects remain a major challenge for sustained release TDDS. This study aimed to develop a polyacrylamide-modified MoS2 nanoparticles (CPAM-MoS2 NPs) based TDDS, which could control drug release and prolong the treatment time by light stimulation. In this work, the CPAM-MoS2 were produced by a facile hydrothermal method. The structure of CPAM-MoS2 NPs was detected by using FTIR, XRD and TEM, and the surface morphololgy of the NPs was observed by SEM. The colloid stability was tested by zeta potential and sedimentation volume ratio. Moreover, In vivo skin erythema study was conducted to explore the biocompatibility of CPAM-MoS2 NPs. As a result, the synthesisezed colloid-stable and skin-safe CPAM-MoS2 NPs possessed a high drug load efficiency of 87.2% and excellent photothermal conversion efficiency that was successfully applied in a TDDS with an enhancement ratio of 1.82. We measured its controlled release ability in an in vitro skin penetration test and, moreover, no drug depletion was observed during the 8-hour study in the light stimulation group. This paper describes the first use of CPAM-MoS2 NPs as a carrier for drugs in a TDDS.

Determining the relationship between hot flushes and LH pulses in menopausal women using mathematical modelling

BackgroundHypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurones regulate LH pulsatility. It is widely accepted that the menopausal hot flush (HF) consistently synchronizes with the LH pulse, implicating the hypothalamic KNDy neurones in generating LH pulsatility and HF. Using a modern immunoassay and mathematical modeling, we investigated if the HF and LH pulse were consistently synchronized in menopausal women.MethodsEleven menopausal women (51 to 62 years of age and experiencing ≥7 HF in 24 hours) participated in an 8-hour study. Subjects self-reported HF and underwent peripheral blood sampling every 10 minutes. LH pulsatility was determined using two mathematical models: blinded deconvolution analysis and Bayesian spectrum analysis. The probability that the LH pulse and HF event intervals matched was estimated using the interval distributions observed in our data.ResultsNinety-six HFs were self-reported, and 82 LH pulses were identified by blinded deconvolution analysis. Using both models, the probability that the two event intervals matched was low in the majority of participants (mean P = 0.24; P = 1 reflects perfect association).InterpretationOur data challenge the widely accepted dogma that HFs consistently synchronize with an LH pulse and therefore have clinically important therapeutic and mechanistic implications.

Sunscreen application to the face persists beyond 2 hours in indoor workers: an open-label trial

Background: The American Academy of Dermatology recommends reapplication of sunscreen every two hours for adequate sun protection when outdoor. However, the frequency of reapplication needed to achieve adequate protection in indoor workers remains unknown.Objective: To investigate the persistence of sunscreen applied once in the morning on the face of indoor workers throughout a normal 8-hour workday.Methods: This open-label trial included 20 healthy volunteers who work indoors. Volunteers applied 1 g of sunscreen (2 mg/cm2) mixed with 2% invisible blue fluorescent agent on the face in the morning. Photographs were taken by VISIA-CR booth in UV mode at 8 am and then every 2 hours thereafter until 4 pm with limited outdoor activity less than 1 hour. Six areas of the face were analyzed using digital image analysis software. The primary outcome was the total amount of sunscreen diminution during the 8-hour study period.Results: The amount of sunscreen decreased with mean peak reduction of 16.3% at 2 hours, and minimal reduction thereafter. Total sunscreen reduction was 28.2% at the end of the 8-hour day.Limitations: Small study population.Conclusion: For indoor workers who applied adequate amount of sunscreen once in the morning, reapplication of sunscreen may be unnecessary.

Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance.

ContextGlucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.ObjectiveTo determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes.DesignRandomized, double-blind, cross-over study.SettingCentre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom.PatientsEight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)].InterventionsTwo metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies.Main Outcome MeasuresStudy one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion.ResultsStudy one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60–480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0–240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0–360min (P = 0.006) were lower with lixisenatide than with placebo.ConclusionsLixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.

Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients.

Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid≥6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value<.05), which was faster in extensive (mean: 45.0L/hr) and intermediate (29.5L/hr) metabolizers than poor metabolizers (19.8L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.

Early goal-directed therapy using a physiological holistic view: the ANDROMEDA-SHOCK\u2014a randomized controlled trial

BackgroundSeptic shock is a highly lethal condition. Early recognition of tissue hypoperfusion and its reversion are key factors for limiting progression to multiple organ dysfunction and death. Lactate-targeted resuscitation is the gold-standard under current guidelines, although it has several pitfalls including that non-hypoxic sources of lactate might predominate in an unknown proportion of patients. Peripheral perfusion-targeted resuscitation might provide a real-time response to increases in flow that could lead to a more timely decision to stop resuscitation, thus avoiding fluid overload and the risks of over-resuscitation. This article reports the rationale, study design and analysis plan of the ANDROMEDA-SHOCK Study.MethodsANDROMEDA-SHOCK is a randomized controlled trial which aims to determine if a peripheral perfusion-targeted resuscitation is associated with lower 28-day mortality compared to a lactate-targeted resuscitation in patients with septic shock with less than 4 h of diagnosis. Both groups will be treated with the same sequential approach during the 8-hour study period pursuing normalization of capillary refill time versus normalization or a decrease of more than 20% of lactate every 2 h. The common protocol starts with fluid responsiveness assessment and fluid loading in responders, followed by a vasopressor and an inodilator test if necessary. The primary outcome is 28-day mortality, and the secondary outcomes are: free days of mechanical ventilation, renal replacement therapy and vasopressor support during the first 28 days after randomization; multiple organ dysfunction during the first 72 h after randomization; intensive care unit and hospital lengths of stay; and all-cause mortality at 90-day. A sample size of 422 patients was calculated to detect a 15% absolute reduction in mortality in the peripheral perfusion group with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle.ConclusionsIf peripheral perfusion-targeted resuscitation improves 28-day mortality, this could lead to simplified algorithms, assessing almost in real-time the reperfusion process, and pursuing more physiologically sound objectives. At the end, it might prevent the risk of over-resuscitation and lead to a better utilization of intensive care unit resources.Trial registration ClinicalTrials.gov Identifier: NCT03078712 (registered retrospectively March 13th, 2017)

Upper esophageal sphincter augmentation reduces pharyngeal reflux in nasogastric tube–fed patients

Aspiration of gastric refluxate is one of the most commonly observed complications among long-term nasogastric tube (NGT) fed patients. The upper esophageal sphincter (UES) pressure barrier is the main defense mechanism against pharyngeal reflux of gastric contents. Our objective was to investigate the efficacy and safety of the UES assist device (UES-AD) in preventing gastric reflux through the UES in long-term NGT-fed patients. Self-Controlled Case series. We studied 10 patients (mean age = 90.6 ± 3.4 years, four females) with dysphagia caused by stroke or dementia who were fed for 0.5 to 5 years (median = 3 years) by NGT. External pressures of 20 to 30 mm Hg were applied by using a handmade UES-AD, which was started 2 hours after the beginning of NGT infusion and was alternated between periods of 2 hours on and 2 hours off, for a total of 12 hours. Placement of the impedance sensors within the UES was guided by high-resolution manometry. Trans-UES and intraesophageal reflux events were recorded by using 24-hour combined pH-impedance measurements. No aspiration pneumonia events were noted in the period 1 month before or during the study in any of the cohort. Baseline UES pressure averaged 17.5 ± 9.4 mm Hg and was increased to 38.9 ± 11.9mm Hg after application of the UES-AD. Overall frequency of trans-UES reflux decreased significantly with the UES-AD compared to without (0.8 ± 0.9 vs. 3.3 ± 2.8, P < .05 for the 12-hour study period). There was no effect of the UES-AD on esophageal reflux events (7.4 ± 4.4 vs. 6.4 ± 3.0, P > .05). UES-AD significantly decreases the number of trans-UES reflux events and can potentially reduce the aspiration risk associated with NGT feeding. 4. Laryngoscope, 128:1310-1315, 2018.

Comparison of the diuretic effect of furosemide by different methods of administration in healthy dogs.

To compare the diuretic effects of subcutaneous (s.c.) administration of furosemide to conventional methods of administration including intravenous (i.v.), per os (p.o.), and constant rate infusion (CRI) in healthy dogs. Prospective, randomized, cross-over study. Veterinary university research facility. Seven healthy, adult mongrel dogs (3 males, 4 females). Each dog in the study was randomly assigned to receive a 2 mg/kg dose of furosemide via a single s.c., i.v., or p.o. dose at the beginning (time 0) of an 8-hour study, or via CRI during an 8-hour study period. Urine was collected by emptying the bladder using an indwelling catheter and blood samples were obtained via venipuncture at time 0 for baseline measurements and at 1, 2, 4, 6, and 8 hours into the study. Hourly urine output was calculated in all dogs for each study. Complete blood count, plasma total protein, blood urea nitrogen, creatinine, and renin concentration were measured for each sample. The s.c. administration of furosemide resulted in a urine output per hour (UOP/h) that peaked at 1 hour with UOP/h returning to baseline at 4 hours after injection. Following i.v. administration, UOP/h also peaked at 1 hour but returned more rapidly to baseline levels at 2 hours after injection. With p.o. administration, UOP/h reached a maximum UOP/h at 2 hours but time to return to baseline levels was prolonged to 6 hours after administration. With CRI administration, the time to the maximum UOP/h was delayed to 4 hours after injection but UOP/h was then maintained throughout the study period. Total urine output following s.c. administration of furosemide in healthy dogs was similar when compared to the i.v. and p.o. route. Subcutaneous route may be an effective means for administration of furosemide in dogs, particularly when i.v. access is difficult.

The ocular distribution of (14)C-labeled bromfenac ophthalmic solution 0.07% in a rabbit model.

PurposeTo evaluate the ocular distribution of an advanced formulation of bromfenac ophthalmic solution. Two studies were conducted in rabbits: 1) a 12-hour parallel-group study comparing the ocular distribution of 14C-bromfenac ophthalmic solution 0.07%, pH 7.8 with that of 14C-bromfenac ophthalmic solution 0.09%, pH 8.3, and 2) a 24-hour study evaluating the ocular distribution of 14C-bromfenac ophthalmic solution 0.07%, pH 7.8.MethodsIn the 12-hour study, rabbits were randomized to receive 50 μL of 14C-bromfenac 0.07%, pH 7.8 or 50 μL 14C-bromfenac 0.09%, pH 8.3 in one eye, whereas, in the 24-hour, study both eyes received 50 μL of 14C-bromfenac 0.07%, pH 7.8. Ocular tissues were collected at 1, 2, 4, 8, 12 (both studies) and 24 hours (second study only) following drug instillation, and tissue radioactivity was determined using liquid scintillation chromatography.ResultsMeasureable levels of bromfenac were observed in all ocular tissues, with the exception of vitreous humor, regardless of formulation. In the 12-hour study, high concentrations of 14C-bromfenac were found in the sclera, followed by the iris/ciliary body, aqueous humor, choroid, retina, and lens. There was no significant difference between the bromfenac 0.07%, pH 7.8 and bromfenac 0.09%, pH 8.3 formulations in any 14C-bromfenac tissue levels at any time point, with the exception of in sclera at 2 hours post-instillation (0.451 μg eq/g versus 0.302 μg eq/g, respectively, P<0.001). There was also no significant difference in the total amount of 14C-bromfenac in the tissues evaluated following instillation of the two formulations. In the 24-hour study evaluating bromfenac 0.07%, pH 7.8 only, high concentrations of 14C-bromfenac were found 1 hour post-instillation in the cornea (2.402 μg eq/g) and conjunctiva (1.049 μg eq/g), two tissues not evaluated in the 12-hour study. The rank order of 14C-bromfenac levels in the other ocular tissues was the same as that observed in the 12-hour study, with measureable amounts of 14C-bromfenac detected through 24 hours in all tissues with the exception of vitreous humor.ConclusionBromfenac ophthalmic solution 0.07%, pH 7.8 readily penetrated ocular tissues with levels similar to those of bromfenac ophthalmic solution 0.09%, pH 8.3.

Body positioning and medical therapy for infantile gastroesophageal reflux symptoms.

Proton-pump inhibitors (PPIs) reduce acid gastroesophageal reflux (GER) and esophageal acid exposure in infants; however, they do not reduce total GER or symptoms attributed to GER. Reflux is reduced in the left lateral position (LLP). We hypothesize that the effect of LLP in combination with acid suppression is most effective in reducing GER symptoms in infants. In this prospective sham-controlled trial, infants (0-6 months) with symptoms suggestive of gastroesophageal reflux disease were studied using 8-hour pH-impedance, cardiorespiratory and video monitoring, direct nurse observation, and a validated questionnaire. Infants demonstrating a positive GER symptom association were randomized to 1 of 4 groups; PPI + LLP, PPI + head of cot elevation (HE), antacid (AA) + LLP, or AA + HE. HE and AA were considered "sham" therapies. After 2 weeks the 8-hour studies were repeated on-therapy. Fifty-one patients were included (aged 13.6 [2-26] weeks). PPI + LLP was most effective in reducing GER episodes (69 [13] to 46 [10], P < 0.001) and esophageal acid exposure (median [interquartile range] 8.9% [3.1%-18.1%] to 1.1% [0%-4.4%], P = 0.02). No treatment group showed improvement in crying/irritability, although vomiting was reduced in AA + LLP (from 7 [2] to 2 [0] episodes P = 0.042). LLP compared with HE produced greater reduction in total GER (-21 [4] vs -10 [4], P = 0.056), regardless of acid-suppressive therapy. Acid exposure was reduced on PPI compared with AA (-6.8 [2.1] vs -0.9 [1.4]%, pH < 4, P = 0.043) regardless of positional intervention. A post-hoc analysis using automated analysis software revealed a significant reduction in crying symptoms in the PPI + LLP group (99 [65-103] to 62 [32-96] episodes, P = 0.018). "Symptomatic gastroesophageal reflux disease" implies disease causation for distressing infant symptoms. In infants with symptoms attributed to GER, LLP produced a significant reduction in total GER, but did not result in a significant improvement in symptoms other than vomiting; however, automated analysis appeared to identify infants with GER-associated crying symptoms who responded to positioning therapy. This is an important new insight for future research.

Treatment of allergic conjunctivitis with bepotastine besilate ophthalmic solution 1.5%.

PurposeTo examine the pooled per-protocol ocular end points from two conjunctival allergen challenge (CAC) clinical trials of the dual-action antihistamine bepotastine besilate ophthalmic solution (BBOS) 1.5%.MethodsTwo Phase III, placebo-controlled, double-masked, randomized clinical trials were conducted at a total of six separate centers using the CAC model of allergic conjunctivitis. The same study design was employed for both clinical trials, with subjects randomly assigned to either BBOS 1.5% (n=78) or placebo (n=79) treatment. Each subject received one eye drop of the test agent bilaterally at different study visits 15 minutes, 8 hours, or 16 hours prior to a CAC. Primary ocular end points included changes in ocular itching reported at 3, 5, and 7 minutes and conjunctival hyperemia assessed at 7, 15, and 20 minutes following each CAC. Secondary ocular end points included chemosis as well as episcleral and ciliary hyperemia judged by investigators, and tearing (scored as either absent or present) and eyelid swelling judged by subjects.ResultsA statistically significant reduction in ocular itching was observed for BBOS 1.5% treatment compared to placebo at all time points (P<0.0001), while measures for onset and 8-hour persistence of action also reached clinical significance (ie, ≥1.0 unit difference) at a majority of time points. In addition, a significant reduction in conjunctival hyperemia was achieved at a majority of time points during the onset of action CAC test. Secondary end points were also significantly improved compared to placebo, most prominently for reduced tearing at all study visits and reduced eyelid swelling at the onset of action and 8-hour study visits. Adverse events were generally mild and transient.ConclusionBBOS 1.5% rapidly reduced CAC-induced ocular itching with duration of effectiveness of at least 8 hours after dosing. Certain secondary signs of inflammation were also significantly reduced.

ABSTRACT 929

Background and aims: In Pakistan, no studies have identified factors associated with pediatric deaths in emergency settings. Aims: We sought to identify predictors of mortality in a public pediatric emergency department (ED) in Karachi, Pakistan. Methods: This was a prospective, observational study of patients presenting to the largest public pediatric ED in Pakistan during July 2013. All patients (>28 days) admitted to the ED during pre-determined 12-hour study periods over 28 consecutive days were enrolled. Guardians gave verbal consent for participation, as approved by Stanford University IRB. Trained research assistants used a standardized electronic questionnaire to collect data. Patients with phone access were followed up 2 and 14 days after ED visit. Multivariate regression was performed to identify predictors of mortality. Results: There were 878 patients enrolled. Median patient age was 2 years (28 days-13 years), with infants accounting for 30%. Thirty-two percent of patients were underweight. Diarrhea/vomiting (66%), fever (49%), respiratory complaints (26%), convulsions/seizures (15%), and abdominal problems (10%) were the most common presenting complaints. In patients able to be followed-up at 14-days (51%), the mortality rate was 12%. For the 50% (435/878) of patients with complete records and follow-up, predictors of mortality at 14-days included transport by ambulance (OR 8.98, 4.63-17.4) and presenting complaints of respiratory problem (OR 2.37, 1.15-4.86), fever (OR 0.46, 0.23-0.94), or seizure (OR 0.27, 0.07-0.97) [C-statistic=0.80]. Conclusions: In this study of Pakistani pediatric emergencies, a higher than expected mortality was observed. Transfer by ambulance and respiratory complaints were associated with increased likelihood of death.

Evaluating the Performance of a Novel Embedded Closed-loop System.

The objective was to assess the reliability of a novel automated closed-loop glucose control system developed within the AP@home consortium in adults with type 1 diabetes. Eight adults with type 1 diabetes on insulin pump therapy (3 men; ages 40.5 ± 14.3 years; HbA1c 8.2 ± 0.8%) participated in an open-label, single-center, single-arm, 12-hour overnight study performed at the clinical research facility. A standardized evening meal (80 g CHO) accompanied by prandial insulin boluses were given at 19:00 followed by an optional snack of 15 g at 22:00 without insulin bolus. Automated closed-loop glucose control was started at 19:00 and continued until 07:00 the next day. Basal insulin delivery (Accu-Chek Spirit, Roche) was automatically adjusted by Cambridge model predictive control algorithm, running on a purpose-built embedded device, based on real-time continuous glucose monitor readings (Dexcom G4 Platinum). Closed-loop system was operational as intended over 99% of the time. Overnight plasma glucose levels (22:00 to 07:00) were within the target range (3.9 to 8.0 mmol/l) for 75.4% (37.5, 92.9) of the time without any time spent in hypoglycemia (<3.9 mmol/l). Mean overnight glucose was 7.8 ± 1.3 mmol/l. For the entire 12-hour closed-loop period (19:00 until 07:00) plasma glucose levels were within the target range (3.9 to 10.0 mmol/l) for 84.4% (63.3, 100) of time. There were no adverse events noted during the trial. We observed a high degree of reliability of the automated closed-loop system. The time spent in target glucose level overnight was comparable to results of previously published studies. Further developments to miniaturize the system for home studies are warranted.