Search

Natural patterns of physical activity in youth are characterized by brief periods of exercise of varying intensity interspersed with rest. To better understand systemic physiologic response mechanisms in children and adolescents, we examined five responses [heart rate (HR), respiratory rate (RR), oxygen uptake (V̇O

OBJECTIVES/GOALS: Observational studies suggest unequal effects of COVID-19 on the population of the U.S. distinguished by race and ethnicity. Our primary research question: what are the demographic differences among patients identified with concurrent ischemic stroke and COVID-19 positivity? METHODS/STUDY POPULATION: The National Covid Cohort Collaboration (N3C) data was used to identify patients with concurrent COVID-19 and stroke, operationally defined as those with a COVID diagnosis and inpatient admission for ischemic stroke 1 week before or 6 weeks after their COVID diagnosis. The data was further age restricted (18-65 years) and a categorical variable was created representing payer plans (Medicaid, Medicare, Other insurance). Data on patients race/ethnicity, comorbidities, treatments administered (Remdesivir and ECMO) and insurance information was analyzed using various exploratory data methods and visualizations. Logistic regression was implemented to model the relationship between variables (dependent/independent) in the cohorts. Model complexity was analyzed using the F test of significance. RESULTS/ANTICIPATED RESULTS: Taken as a whole, the data contained over 7 billion rows and around 6.4 million persons (~ 2.15 million of whom were COVID+). The main cohort of individuals with concurrent COVID positivity and ischemic stroke made up around 0.29% of the original COVID+ group, and the payer plan sub-cohort consists of around 29.26% of our main cohort. Black/African American (AA) and the Hispanic/Latino any Race have younger distributions (median ~ 65 years), while the White Non-Hispanic group has the oldest distribution (median ~ 70 years). Black/AA had the highest average number of comorbidities per patient (4.49), compared to white non-Hispanic (3.39) and Asian non-Hispanic (2.59). In our analysis, Medicaid patients had lower odds of obtaining ECMO (p < .01), there was no significant difference in Remdesivir treatment. DISCUSSION/SIGNIFICANCE: We found the N3C data to be useful in studying a distinct group of patients, and exploring COVID-19 and ischemic stroke treatment across patients’ race/ethnicity identities and insurance status. Our exploratory analysis provides a foundation for further insight into demographic trends and discrepancies in apportionment of treatment.

The retention of ‘at risk’ students in secondary schools is a major challenge to inclusive education policy. Students with non-compliant behaviour at this level are typically dealt with by authoritarian and punitive disciplinary systems that frequently lead to exclusion from school. This paper reports on the successful establishment of a positive behaviour support system in a secondary school. School-wide systemic change was developed to support the inclusion of students at risk of failure and suspension for non-compliant behaviour. The programme led to the retention of all students in the identified cohort and improved academic performance for all the students. Classroom instructional patterns incorporating evidence-based strategies to engage students, goal setting and self management skills were introduced. Collaborative problem solving with students and teachers ensured intervention integrity. The outcome of the programme and extension at a systemic level for the whole school is briefly discussed.

With the implementation of Special Education 2000, a new policy on special education, New Zealand has moved to develop a world-class inclusive education system for students with mild to moderate learning and behavior needs. This article outlines a professional development program for a group of resource teachers who are implementing a major element of the policy. The authors report on the establishment of the training program through the collaboration of faculty from three universities. They also comment on the challenges to such a program, the ways in which these challenges were met through collaborative problem solving, and some outcomes to date.

The Resource Teachers Learning and Behaviour (RTLB) program is a unique special education development in New Zealand. The aim of this program is the creation of a nation-wide network of more than 700 RTLB operating as itinerant consulting teachers providing support in inclusive classrooms. The principles underlying the program are described and an outline provided of the curriculum and methods of delivery. The program also acknowledges the need to address the important bi-cultural elements of New Zealand society. The paper reports on RTLB demographic profiles and the initial responses of teachers to their training. Preliminary indices of program effectiveness are also presented. The paper indicates ways in which the RTLB initiative is likely to develop and notes issues within the New Zealand education system that will both strengthen and constrain the overall development of the program.

Clinical trials of antipyret.ic drugs in febrile children are difficult to conduct when exclusion criteria are so restrictive that a sufficient number of patients cannot be recruited to define efficacy for labeled use in the population. Recent use of an antipyretic drug is one such exclusion criterion that limits enrollment and consumes a great amount of triage time and effort. This paper examines the basis for this exclusion criterion, its impact on clinical trials undlerway in the Pediatric Pharmacology Research Unit (PPRU) Network, and alternatives that permit the exclusion of this criterion without compromising the study design or the outcome of data analysis.

A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmaxeffect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag,ka, β,T1/2β,AUC0–∞,Vd/F,andClp/F) were not different than those reported previously, except the APAPkawas significantly lower. The link component yieldedkeos of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr-1for APAP, IBU05, and IBU10, respectively: the SigmoidEmaxcomponent yieldedEC50s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmaxcomponent to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi(but not age) on the value of the slope function was found. There was no consistent effect of age orTempi, on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempiwas observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempiinteracted with β in a significant multiple linear relationship withAUC0–∞. The effects of IBU dose, age, andTempiare pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMaxeffect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempion the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Where does our time go? Can we be more efficient with our own time? How come we never have enough time to get the things done that we want to do? Why do our lives seem so hectic and fractured in time? Are we doing the things that are most important to us and our work in our time?

Intelsat General Corporation (IGC) presents a paper for the (AT&L)/SIO sponsored session on “Protected Communications Over Commercial Satellites” at MILCOM 2011 entitled “Commercially Hosted Resilient Communications” to describe the evolution of commercially provided satellite communications serving challenged and contested environments. This paper explores avenues for “Resilient SATCOM” technologies to be included aboard commercial missions as readily as Unprotected and Wideband SATCOM technologies. IGC surveys the viability of hosted military payloads with heritage to the FLTSAT EHF Package (FEP), Milstar, and Advanced EHF (AEHF) payloads. We will cite evidence of recent studies, advancements and successes in hosting full-featured standard military payloads on-board commercial spacecraft. IGC finds that a “Protected Tactical MILSATCOM” solution could be hosted to provide anti-jam, low probability of intercept / detection / exploitation (LPI / LPD / LPE) communications in both contested and benign operational environments without costly shielding and special hardening in design and construction of the space platform itself. IGC finds that the existing functionality of EHF SATCOM can be reconstituted using hosted payloads at considerable savings to the U.S. Government.

Technology Update Different artificial lift technologies have been used for decades to dewater coalbed methane (CBM) wells to reduce hydrostatic pressure and release the gas for production. Among the newest is the electric submersible pump (ESP) using progressive cavity pump (PCP) technology, known as an ESPCP (Fig. 1). Close coupling between a PCP and a submersible electric motor enable these units to run more quietly, pump more, and last longer. And because of their lower profile above ground, submersible pumps lend themselves to gas operations near residential areas and other locations where aesthetics and quiet operation are a priority. Dewatering CBM wells can be difficult because coal seams typically lie far below the groundwater level, often at depths greater than 2,000 ft. Conventional centrifugal water-well pumps and standard oilfield ESPs struggle at typical flow rates of wells of 250 B/D or less. To overcome this, some operators overspeed a centrifugal pump, which requires start and stop cycles to avoid overpumping. Such operation is inefficient and shortens pump and motor life. In addition, most centrifugal pumps that operate in this range tend to have small flow passages and become easily clogged. A different style of pump is required to operate these “low and slow” wells efficiently. The ESPCP, which combines the benefits of the ESP and the PCP (Fig. 2), meets this need. PCP Systems A PCP transfers fluid by advancing it through a sequence of fixed-shaped, discrete cavities, as the rotor is turned. This leads to the volumetric flow rate being directly proportional to the rate of rotation, and to low levels of shearing being applied to the pumped fluid. The individual pump cavities are tapered toward their ends and overlap in the axial direction with neighboring cavities so at any given instant, multiple cavities are open and discharging fluid. This makes for smooth fluid flow, with no pulsing action. Because the rotor is well sealed within the cavity walls, the pump is effective at low flow rates from significant depths. The pump’s lack of shearing action also makes it good for pumping fluids that contain fracturing sand, coal fines, or even large particles, typically present in CBM dewatering applications. Also typical are varying levels of gas and varying flow rates, which the PCP’s smooth and uniform operation is able to handle more easily. Additionally, the high pump efficiency helps to keep the power requirements modest at low flow rates. Franklin Electric has found that power levels for its ESPCP systems can be as low as 600 W to 3 kW to maintain desired water levels at depths of 900 ft to 1,300 ft. PCP systems have traditionally used aboveground motors with long drive shafts, but this can pose problems. The motors are noisy and if used near residential areas are often considered visually objectionable. If the well has a horizontal design, the drive shaft approach requires mechanical support such as bushings or bearings to negotiate the curve built into the well path. These will wear out, which increases operational costs.

A multiresidue method for the analysis of 168 pesticides in dried powdered ginseng has been developed using acetonitrile or acetone mixture (acetone/cyclohexane/ethyl acetate, 2:1:1 v/v/v) extraction, solid-phase extraction (SPE) cleanup with octyl-bonded silica (C(8)), graphitized carbon black/primary-secondary amine (GCB/PSA) sorbents and toluene, and capillary gas chromatography-mass spectrometry/selective ion monitoring (GC-MS/SIM) or -tandem mass spectrometry (GC-MS/MS). The geometric mean limits of quantitation (LOQs) were 53 and 6 microg/kg for the acetonitrile extraction and 48 and 7 microg/kg for the acetone-based extraction for GC-MS/SIM and GC-MS/MS, respectively. Mean percent recoveries and standard deviations from the ginseng fortified at 25, 100, and 500 microg/kg using GC-MS/SIM were 87 +/- 10, 88 +/- 8, and 86 +/- 10% from acetonitrile extracts and 88 +/- 13, 88 +/- 12, and 88 +/- 14% from acetone mixture extracts, respectively. The mean percent recoveries from the ginseng at the 25, 100, and 500 microg/kg levels using GC-MS/MS were 83 +/- 19, 90 +/- 13, and 89 +/- 11% from acetonitrile extracts and 98 +/- 20, 91 +/- 13, and 88 +/- 14% from acetone extracts, respectively. Twelve dried ginseng products were found to contain one or more of the following pesticides and their metabolites: BHCs (benzene hexachlorides, alpha-, beta-, gamma-, and delta-), chlorothalonil, chlorpyrifos, DDT (dichlorodiphenyl trichloroethane), dacthal, diazinon, iprodione, quintozene, and procymidone ranging from1 to4000 microg/kg. No significant differences were found between the two extraction solvents, and GC-MS/MS was found to be more specific and sensitive than GC-MS/SIM. The procedures described were shown to be effective in screening, identifying, confirming, and quantitating pesticides in commercial ginseng products.

A multiresidue method for the analysis of pesticides in fresh produce has been developed using salt-out acetonitrile extraction, solid-phase dispersive cleanup with octadecyl-bonded silica (C(18)), and graphitized carbon black/primary-secondary amine (GCB/PSA) sorbents and toluene, followed by capillary gas chromatography-mass spectrometry in selected ion monitoring mode (GC-MS/SIM) or -tandem mass spectrometry (GC-MS/MS). Quantitation was determined from calibration curves using matrix-matched standards ranging from 3.3 to 6667 ng/mL with r(2) > 0.99, and geometric mean limits of quantitation were typically 8.4 and 3.4 microg/kg for GC-MS/SIM and GC-MS/MS, respectively. Identification was determined by using target and qualifier ions and qualifier-to-target ratios for GC-MS/SIM and two ion transitions for GC-MS/MS. Fortification studies (10, 25, 100, and 500 microg/kg) were performed on 167 organohalogen, organophosphorus, and pyrethroid pesticides in 10 different commodities (apple, broccoli, carrot, onion, orange, pea, peach, potato, spinach, and tomato). The mean percent recoveries were 90 +/- 14, 87 +/- 14, 89 +/- 14, and 92 +/- 14% for GC-MS/SIM and 95 +/- 22, 93 +/- 14, 93 +/- 13, and 97 +/- 13% for GC-MS/MS at 10, 25, 100, and 500 microg/kg, respectively. GC-MS/MS was shown to be more effective than GC-MS/SIM due to its specificity and sensitivity in detecting pesticides in fresh produce samples. The method, based on concepts from the multiresidue procedure used by the Canadian Food Inspection Agency and QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe), was shown to be efficient in screening, identifying, and quantitating pesticides in fresh produce samples.

Ibuprofen was evaluated as an antipyretic agent in 178 children (aged 3 months to 12 years) to compare dosage (5 vs 10 mg/kg), establish absolute efficacy (with a placebo control group), determine relative efficacy (ibuprofen vs acetaminophen), evaluate maximum efficacy, and identify potential confounding variables. Ibuprofen 5 mg/kg was minimally effective in children less than 6 years of age who had an initial temperature of at least 38.8 degrees C (101.9 degrees F). Ibuprofen 10 mg/kg was more effective for febrile children. The area under the curve for temperature (or change in temperature) captured the net effect of each drug and provided the best estimate for efficacy comparison during a defined period. A linear correlation between initial temperature and measures of efficacy was observed. A twofold increase in efficacy was observed for children with an initial temperature less than 38.8 degrees C. A similar effect was noted for each treatment group. Age was also found to have confounding effects on antipyretic response. A complex interaction between antipyretic response, initial temperature, and age raises questions about the pharmacodynamics of the antipyretic response. We conclude that the most important variable in antipyretic study design is initial temperature. The influence of initial temperature on the magnitude of the response to an antipyretic drug is a previously unappreciated finding with potential impact on pharmacodynamic investigations of antipyretic medications. We describe this finding as nonlinear pharmacodynamics.

Current acetaminophen (APAP) formulations approved for antipyretic use in children require up to five doses/day, which compromise compliance and risk breakthrough fever over 4 hours after dosing. A total of 112 evaluable febrile children received oral APAP-equivalent doses of either one dose of APAP controlled release (CR) as sprinkles on applesauce or one dose q 4 hours x 2 of APAP immediate-release (IR) elixir in an 8-hour, double-blind, double-dummy, randomized, multicenter study. Prior or concurrent antibiotic use did not significantly affect either the magnitude or the pattern of temperature reduction during the 8-hour observation period. Significantly greater aural temperature reductions were found with APAP-CR than with APAP-IR at 4 and 5 hours. However, the 8-hour AUCs of temperature reduction were not significantly different between treatments. Pharmacokinetic/pharmacodynamic modeling of APAP was performed in 8 patients with values in both treatments similar to previous results, except for expected differences in AUC0-infinity. Similar 8-hour temperature reduction for APAP-CR (one dose) and APAP-IR (two doses) demonstrates the efficacy of APAP-CR as an antipyretic in children 2 to 11 years of age. A decrease in the number of APAP daily doses and the prolonged antipyretic effect of APAP-CR may assist those who care for febrile children at home.

The purpose of this paper is to trace the development of the role of Resource Teachers Learning and Behaviour (RTLB) from its genesis in the establishment of the Guidance and Learning Units in 1975, through the establishment of support teams and Resource Teacher Special Needs to its present form. This development is placed in the context of two paradigm shifts that have impacted on special education practice and policy in New Zealand over the last 25 years. The somewhat halting progress of special education is explained by the multi-paradigmatic nature of the social sciences and the consequent clashes of opinion and tensions that result from it. National guidelines have made schools responsible for the learning of all children. These guidelines addressed issues of equity, rights, values and devolved accountability and consequently included those students with special teaching needs who had previously been considered separately. These guidelines therefore enabled changes in special education to take place. The paper goes on to outline the rationale and structure of the training programme for RTLB and discusses some of the tensions still remaining in the implementation of the role.

Hospital administrators are regularly faced with having to cut patient services. Such decisions are essentially questions of distributive justice, and administrators may welcome some guidance. We begin with a key idea from the most influential theory of justice of our times, that of John Rawls, and generate from it a series of test questions against which the ethical dimensions of allocation decisions can be judged.

The developing rat is hypersensitive to aminoglycoside ototoxicity during the period of anatomical and functional development of the cochlea. Toxicity is expressed only after a few days of treatment when kanamycin is given during the most sensitive period for production of ototoxicity (postnatal days 11-20). In contrast, when the drug is administered after the 20th postnatal day, the same dose and duration of treatment do not produce an ototoxic effect. Only after prolonged treatment (e.g., > or = 20 days) is there an observed effect. We characterized the pharmacokinetics of kanamycin in the serum of 12- and 25-day-old rats and observed a greater than 2.5-fold increase in elimination half-life in the 12- versus 25-day-old rat. The longer duration half-life of kanamycin in younger rats may explain the hypersensitivity of immature mammals to aminoglycoside ototoxicity.

The objective of the program was to architect a vehicle health management (VHM) system for space systems avionics that assures system readiness for launch vehicles and for space-based dormant vehicles. The platforms which were studied and considered for application of VHM for guidance, navigation and control (GN&C) included the Advanced Manned Launch System (AMLS), the Horizontal Landing-20/Personnel Launch System (HL-20/PLS), the Assured Crew Return Vehicle (ACRV) and the Extended Duration Orbiter (EDO). This set was selected because dormancy and/or availability requirements are driving the designs of these future systems.

Conflicting reports raise a question about decreased plasma clearance (Cl p ) of theophylline in man during viral infections. Thus a dilemma exists concerning requisite dose adjustments. We examined this issue by retrospectively evaluating theophylline Cl p in children infected with respiratory syncytial virus (RSV). Two pharmacokinetic approaches were applied to a one-compartment open model to fit theophylline concentrations during 83 hospitalizations of 76 children, 6 to 48 months of age, who received intravenous theophylline therapy and were tested for RSV infection. Iterative linear regression analyses of all theophylline data were used to estimate apparent volume of distribution, elimination rate constant, plasma half-life, and Cl p in 39 of the hospitalizations. When insufficient data were available to distinguish apparent volume of distribution and elimination rate constant (n=44), steady-state estimates of Cl p were calculated. An age-matched and percentile body weight-matched cohort design presented RSV as the primary covariate. Theophylline Cl p was similar in 29 matched RSV-infected and -uninfected pairs (1.32±0.14 and 1.25±0.05 ml/kg perminute, respectively), as were other pharmacokinetic values. Unexpectedly, a significant, inverse linear relationship was found for Cl p and percentile body weight. Additionally, children born prematurely and hospitalized in the neonatal intensive care unit had significantly higher theophylline Cl p ; this did not affect findings regarding RSV infection. Theophylline Cl p was not decreased in RSV-infected children. Current theophylline dosing recommendations for young children infected with RSV should not be altered, but careful monitoring of plasma theophylline levels should be continued.

The study was undertaken to determine whether affiliative loss might play a role in the development of insulin-dependent diabetes by increasing the percentage of helper-inducer T cells when diabetics were reminded of the loss. It was found that diabetics who had experienced the recent death of a loved one showed a marked increase in helper cells, in contrast to diabetics who had not experienced a recent death, after both groups viewed a film about a happy, but doomed, love affair. The diabetics who had experienced a recent death also showed more affiliative distress after viewing the film. This increase in distress was associated with a physiological sign of increased activation, namely, increased plasma cortisol output, which in turn was associated with gains in helper-cell percentages. This suggests that frequent reminders of severe affiliative disturbances during the pre-onset histories of such diabetics may result in physiological activation, which leads to periodical recruitment of helper cells, which could augment the immune attack on the insulin-producing cells in the pancreas. None of these results was obtained with controls, which suggests that the diabetics were unusually sensitive to affiliative distress.

The Paria-Hackberry Wilderness Study Area, in central Kane County, southern Utah, is region of generally flat-lying, gently folded Jurassic and Cretaceous sedimentary rocks bonded on the east by the east-dipping limb of the East Kaibab Monocline and cut by sheer-walled, narrow canyons. The area selected for study by the U.S. Bureau of Land Management totaled 94,642 acres (148 square miles); because of uncertainty as to final boundaries, the U.S. Geological Survey studies an additional contiguous 41,180 acres (64 square miles). No identified resources of metals or nonmetallic minerals are present in the study area. An unsuccessful attempt to recover flour from the Chinle Formation was made in the early part of the century at the now-abandoned townsite of Paria. The mineral resource potential for all metals, including gold, uranium, barium, silver, strontium, arsenic, antimony, mercury, copper, manganese, cadmium, and zinc, is low for the entire Paria-Hackberry Wilderness Study Area. The likelihood of occurrence of decorative-use gypsum and of sand and gravel is moderate in limited areas of the northern part of the wilderness study are and, for sand and gravel, in a few small occurrences along the Paria River valley. A moderate energy resource potential is assessed for oil andmore » gas and a low potential for geothermal energy, for the entire study area. There is no energy resource potential for coal.« less

Although numerous studies have shown that cochlear impairment exists in audiogenic-seizure (AGS)-susceptible mice, there is only one report of cochlear potentials obtained from AGS-susceptible rats. To investigate the hypothesis that cochlear impairment also exists in AGS rats, cochlear microphonics (CM) and the primary afferent activity of the auditory division of the eighth cranial nerve (N1) were studied in AGS rats. AGS rats were obtained from the Veterans Administration Medical Center (Shreveport, La.) colony of Sprague Dawley derived animals, and control rats were obtained from Sprague Dawley, Inc. Two school bells ringing simultaneously were used to produce a sound of approximately 115 dB (AGS test stimulus). Exposure to the AGS test stimulus was once per week for three consecutive weeks. Chloramphenicol was used to treat the frequent otitis media found in the colony of AGS rats. Two categories of AGS-susceptible and control rats were studied: (1) rats exposed to the AGS test stimulus and chloramphenicol regimen; and (2) rats not receiving these treatments. All rats were anesthetized with i.p. Dial-Urethane and prepared for cochlear round window recording. Cochlear microphonics were recorded in response to a click stimulus. A significant decrease in cochlear sensitivity was seen in both groups of AGS rats when compared to appropriate controls as reflected by a 25-35 dB shift in all CM and N1 input-output functions. These results support the hypothesis that a functional cochlear impairment exists in the AGS rat.

Twenty-seven cats were recorded from the scala media of the cochlea in order to evaluate the reduction in the positive endocochlear dc potential (EP) produced by iv bumetanide and to compare these changes to the bumetanide-induced N1 depression observed previously. A linear relationship does exist between the dose of bumetanide administered and the resultant mV reduction of the EP. The equation for the regression line of this dose-response to bumetanide is y (maximal reduction of EP) = 259.5 + 92.8 × (log mmol/kg iv bumetanide). The maximal reduction of EP occurring within 1 min after the larger doses of bumetanide correlates well with changes in N1 previously observed after similar doses. When multiple linear regression analysis is performed, the amount of N1 depression produced by a particular dose of bumetanide is found to be linearly related to the amount of EP reduction produced by that dose of bumetanide. These data indicate that the acute ototoxicity produced by this “loop” diuretic is due to its effect on EP.

Ototoxicity limited the use of the antitubercular drug, streptomycin, and there are many other drugs with similar damaging side-effects. Cochlear toxicity represents one form of ototoxicity, and studies may include analyses of behavioral, anatomical, electrophysiological and biochemical changes. However, each parameter has drawbacks and limitations, and in this review Charles Henley and Don Brown discuss why a combined electrophysiological and anatomical approach represents the most effective method of assessing risk of ototoxicity.

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post-partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half-life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3-5 days post-partum) the FB concentration in breast milk was less than 0.050 micrograms/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 micrograms/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post-partum period.

Many antimicrobial medications may be administered to paediatric patients with a degree of impunity because they are relatively non-toxic and have a wide therapeutic margin. However, because of different pharmacokinetics from those in adults, the potential for toxicity exists with the use of some of these agents. Drug absorption in paediatric patients, either orally or parenterally, is generally similar to that in adults, except among neonates and, particularly, premature neonates. Similarly, in neonates, drug distribution is altered, plasma protein binding is decreased and hepatic metabolism and renal excretory capacity are limited by physiological immaturity. Thus, in neonates, only drugs that have pharmacokinetically derived dosage schedules should be used, and therapeutic monitoring of plasma drug concentrations is recommended during therapy with aminoglycosides, vancomycin and chloramphenicol. In older infants and children, the pharmacokinetics of antimicrobial drugs generally approximate those in adults, and recommended dosages have been determined relative to bodyweight. Therapeutic monitoring of plasma drug concentrations may be important in certain patients, such as those with major organ failure, and may be useful in cases of suspected noncompliance. Additional pharmacokinetic considerations concerning antimicrobial medication and paediatric patients are the extent to which drug therapy penetrates the cerebrospinal fluid in meningitis, and the potential for and implications of exposure of infants to antimicrobial medications excreted in breast milk.

The organ of Corti of Genetically Epilepsy Prone Rats was examined anatomically and electrophysiologically using scanning electron microscopy (SEM) and electrophysiological recording of alternating current cochlear potentials (ACCP) and N1, a volume conductor recording of the primary auditory afferent action potentials. ACCPs for GEPRs with low intensity seizures (Acoustic Response Score (ARS) = 2 or 3) and high intensity seizures (ARS = 9) showed similar impairment in cochlear function. Approximately a 25-35 dB shift in input-output functions was present in GEPRs as compared to controls. SEM revealed several types of possible genetic abnormalities which explain the deficits in cochlear function and could serve as the basis for seizure predisposition in these animals.

In response to "Aspirin and Reye Syndrome" by the Committee on Infectious Diseases of the American Academy of Pediatrics (p 810), we offer comments which are restricted to our analysis of existing epidemiologic study data, portions of which were provided to us by the Ohio, Michigan, and Arizona investigators. This commentary should not be construed as our approval or disapproval of aspirin use in children. Rather, it summarizes our specific disagreements with the interpretation of the state epidemiologic data that were the basis of the report by the Committee on Infectious Diseases. We have found that an unassessed confounding variable of large magnitude is common to the state studies.

The need for clinical pharmacology in research and education, drug development, and health care delivery is well known. However, a current profile of those working in the field is not available. The ACCP authorized a survey of clinical pharmacologists to provide such a profile. Members of the ACCP or ASCPT were solicited by mail with a self-assessment questionnaire. A response rate of 37% was obtained. Demographic findings agree well with a previous study2 limited to those with the M.D. Our results reveal that most clinical pharmacologists are between 30-59 years of age, have an MD, PhD or PharmD degree; most of those with MDs list their primary specialty as internal medicine, pediatrics, psychiatry, or anesthesiology. They affiliate with the respective departments (including pharmacology) in academia or hold positions in industry or government, but few are in clinical therapeutics per se. About 20% of those with only a MD or PharmD degree cite employment in health care delivery. However, a higher percentage of these respondents work in research and education rather than in drug development or health care delivery. For those with only a PhD, more work in drug development and research and education than in health care delivery. The highest proportion of respondents with any doctoral degree work in the Northeast. The average income is a function of rank, doctoral degree, specialty, department appointment, and type and location of employer. The profile of a typical clinical pharmacologist is presented. An analysis of clinical pharmacology manpower from several perspectives reveals a marked deficit, but the field itself is professionally and economically attractive. Lack of a well defined career track in academia and a poorly defined clinical role for MD clinical pharmacologists are proposed as reasons limiting entry of trainees. These and other results of the survey support an increased emphasis on training programs. Clinical pharmacologist involvement in health care delivery and drug development must be increased if the safe and effective use of new drugs is to be realized. Nine assessments and initiatives are formulated to accomplish this goal within the next decade.

Comparisons were made of the effects of various doses of intravenous bumetanide and furosemide on the primary auditory afferent activity (N1) and cochlear microphonics (CM) of beagles. The dose-response relationships of the N1 depressions to bumetanide and furosemide are parallel; those of the CM depressions are also parallel but have a much shallower slope than those of the N1 depressions. With both drugs, N1 depression occurs at lower doses than does CM depression. The N1 depression produced by a particular dose of bumetanide or furosemide bore a linear relationship to the CM depression produced. This finding supports the postulate that the cochlear site and mechanism of ototoxic action of the loop diuretics are directed at an earlier step of the cochlear transduction process than N1. Using N1 depression as the gross electrophysiologic index of ototoxicity, the acute ototoxic potency of bumetanide in beagles is approximately 6.5 times that of furosemide, whereas its diuretic potency is 40 to 60 times that of furosemide. Therefore, when clinical dosages of the two drugs are considered, the relative acute ototoxic potency of bumetanide in the beagle is 0.11 to 0.16 that of furosemide. This range is identical to the relative ototoxic potency of 0.11 to 0.16 previously obtained in the cat. Serum concentrations of bumetanide and furosemide increased linearly with the doses of the two drugs, except for the highest dose given (100 mg/kg for both drugs). The serum concentrations at that dose of both drugs are less than the mathematically predicted values. Histologic (light-microscopic) examination of the cochleas did not reveal any significant pathology.

Inherent difficulties of opportunistic approaches have contributed to the existing paucity of information about drug excretion in human breast milk. This situation prevails for new drugs and also for post marketing surveillance of drugs. Most anecdotal or purely descriptive studies have offered too little understanding about fundamental mechanisms which in turn allow accurate quantitative estimations of the milk/plasma (M/P) drug concentration ratio after single and/or repeated doses or even during a dosing interval. Few studies have sufficient numbers of women to address this M/P ratio, or even amount of drug in milk, with regard to interindividual variation. The practical importance of an accurate, widely applicable but drug specific M/P ratio is recognized because it captures the net effect of maternal dose, dose interval, and drug disposition to give a ratio for calculation of dose delivered to the infant via breast milk.

We have emphasized the variance of the M/P ratio with time after dosing (1). This variance is kinetically determined. Accordingly, variance in the M/P ratio may be confounded by factors altering the kinetic profile of drug concentration in the fluid of reference i.e., blood or milk. These factors include dose, route and duration of administration. We have evaluated each of these for their contribution to the temporal variance of the M/P ratio (2). These pharmacological manipulations were performed by using the goat as an animal model and with acetaminophen (APAP) as the test drug. Acetaminophen was chosen because it has a short elimination half-life and can be administered by either the oral or intravenous route in the goat.

A single-point estimate of the milk to plasma (M/P) drug ratio presupposes an invariant ratio. This may lead to erroneous conclusions about the amount of drug excreted in breast milk. A variance of the M/P ratio with regard to time has been shown for acetaminophen under standardized biologic conditions in the lactating goat. This ratio is potentially confounded by such factors as route of administration, dose amount and duration of exposure to the drug. Each factor was evaluated by computer simulations of the M/P ratio and by derivation of a ratio from empirical data in the goat. Route of administration was found to influence both the pattern and magnitude of the M/P ratio after acetaminophen dosing in the goat. Similar, but less, effects were found for duration of dosing. Dose itself did not influence the ratio. A temporal basis exists for each confounding factor. We thus propose that the M/P ratio is fundamentally variant with time under a standard set of biologic conditions. The contributing variance of confounding factors must be assessed if drug in milk dosing of the infant is to be accurately evaluated by use of the M/P ratio.