Estimating the potential cost of a high dose immune tolerance induction (ITI) therapy relative to the cost of a combined therapy of a low dose ITI therapy with bypassing agent prophylaxis.

INTRODUCTION: The International Immune Tolerance Study (I-ITI) demonstrated comparable success rates between low (FVIII 50 IU/kg/TIW) and high dose (FVIII 200 IU/kg/day) regimens. While costlier, the high dose ITI regimen achieved shorter time-to-treatment success with fewer bleeding episodes compared to the low dose ITI regimen. Adding bypassing agent prophylaxis (BAP) to a low dose ITI regimen may reduce bleeding while still being less costly than high dose ITI. AIM AND METHODS: An economic model was developed to compare high dose ITI to low dose ITI with BAP. All model inputs were derived from clinical trials. The I-ITI study indicated a median time to negative inhibitor titre of 4.6 and 9.2 months and average number of bleeds/patient of 4.2 and 9.9 for the high and low dose regimens respectively. Based on the BAP trials, aPCC (85 U/kg/TIW) and rFVIIa (90 µg/kg/day) achieved a 62% and 45% reduction in bleeding frequency respectively. Cost analysis was from a US third party payer perspective and limited to drug costs. One-way, two-way and probabilistic sensitivity analyses were performed. RESULTS: Costs of low dose ITI with aPCC prophylaxis until negative inhibitor titre is achieved was 24.0% less compared to high dose ITI. Low dose ITI with rFVIIa prophylaxis cost 46.5% more compared to high dose ITI. Model results were robust in the majority of the sensitivity analyses. CONCLUSION: A low dose ITI regimen with aPCC prophylaxis may be cost saving compared to a high dose ITI regimen with the potential to reduce morbidity by lowering the risk for breakthrough bleeds.

Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII (hFVIII). OBI-1 is an investigational, B-domain deleted, recombinant FVIII, porcine sequence, with low cross-reactivity to anti-hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI-1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg(-1) , OBI-1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI-1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti-porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI-1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI-1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients.

Solid-phase synthesis of 2,4-diaminoquinazoline libraries.

A series of libraries containing the 2,4-diaminoquinazoline ring system were prepared, starting from polymer-bound amines. The key steps included reaction of the support-bound amine with 6,7-dimethoxy-2,4-dichloroquinazoline, followed by displacement of the second chlorine with an amine and subsequent TFA-mediated cleavage of the product from the support. When a symmetrical or unsymmetrical diamine was used in the displacement step, the free amine could be acylated with an activated acid to generate another set of compounds. The optimization of conditions for the reductive amination and displacement steps will be discussed as well as the final choice of resin for library production. In addition, quality control methods for library analysis is also described.

Comparison of length of stay for asthma by hospital type.

OBJECTIVE: To determine whether length of stay (LOS) for asthma admissions at a local university-affiliated children's hospital (UACH) is similar to that of community hospitals within the same county. METHODS: A retrospective analysis was performed using computerized hospital abstract records from 1989 through 1994. The study population was children 1 to 18 years old whose first or only hospitalization for a primary diagnosis of asthma occurred during the study period at either the UACH or one of the 17 community hospitals in King County, WA, that admit pediatric patients (n = 2491). Transfers and patients with chronic obstructive asthma or secondary diagnoses such as cystic fibrosis were not included in the study. Asthma patients were compared by sociodemographic and health risk characteristics such as age, sex, insurance status, and a comorbidity severity score. Differences between the two hospital populations were tested by chi2 and t tests. The effect of hospitalization at the UACH or the community hospitals on LOS was determined using analysis of covariance after adjusting for the sociodemographic and health risk covariates. RESULTS: Sixty-two percent (62%) of the asthma patients in the study population were discharged from the UACH. Compared with patients discharged from the community hospitals, the UACH patients were significantly younger, more often male, used public insurance, and resided in areas with lower median household incomes. The severity of comorbidities was not different between the two hospital groups. Overall, adjusted mean LOS was not significantly longer at the UACH (2.1 days) than at the community hospitals (2.0 days); however, adjusted mean LOS for specific subgroups, most notably poor children and those with public insurance, was significantly longer at the UACH. CONCLUSION: LOS for first or only asthma hospitalizations during 1989 through 1994 at the UACH was similar to local community hospitals within the same county. Specific subgroups of children were hospitalized for a longer period at the UACH, but children with private insurance and from areas with higher median household incomes had similar LOS, and presumably costs, at the UACH and the community hospitals.

The safety of newborn early discharge. The Washington State experience.

CONTEXT: While early discharge of newborns following routine vaginal delivery has become common practice, its safety has not been firmly established. OBJECTIVE: To assess the risk for rehospitalization following newborn early discharge. DESIGN: Population-based, case-control study. SETTING: Washington State linked birth certificate and hospital discharge abstracts covering 310578 live births from 1991 through 1994. PATIENTS: Case patients were 2029 newborns rehospitalized in the first month of life. Control subjects were 8657 randomly selected newborns not rehospitalized and frequency matched to case patients on year of birth. Cesarean deliveries, multiple births, and births at less than 36 weeks' gestation were not included. MAIN OUTCOME MEASURE: Stratified analyses and logistic regression were performed to assess the risk for rehospitalization within a month of birth after early discharge (<30 hours after birth) compared with later discharge (30-78 hours after birth). RESULTS: Seventeen percent of newborns were discharged early. Newborns discharged early were more likely to be rehospitalized within 7 days (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.47), 14 days (OR, 1.16; 95% CI, 1.03-1.32), and 28 days (OR, 1.12; 95% CI, 1.00-1.25) of discharge than newborns sent home later. Subgroups at increased risk for rehospitalization following early discharge included newborns born to primigravidas (OR,1.25; 95% CI, 1.07-1.45), mothers younger than 18 years (OR, 1.22; 95% CI, 0.79-1.91), and mothers with premature rupture of membranes (OR, 1.41; 95% CI, 0.85-2.36). Early discharge was also associated with an increased risk of readmission for jaundice, dehydration, and sepsis. CONCLUSION: Newborns discharged home early (<30 hours after birth) are at increased risk for rehospitalization during the first month of life.

Pediatric home health care in King County, Washington.

BACKGROUND: Pediatric home health care is one of the fastest growing segments of our health care system. However, our knowledge of the extent and quality of the services provided in this field is generally limited. Despite this shortcoming, pediatric health care providers are increasingly expected to participate in the home health care of their patients. OBJECTIVE: To describe the agencies and services that constitute pediatric home health care in a large metropolitan setting. METHODS: During the summer of 1995, home health care agencies in King County, WA, were surveyed if they had provided any pediatric services within the preceding 6 months. The agencies were queried about their characteristics and services provided, as well as referral and reimbursement sources. Survey data were supplemented by interviews with agency and state health personnel. RESULTS: Fourteen (88%) of the 16 agencies providing pediatric home health care services completed the survey. Agencies were predominantly for-profit, free-standing, and in business fewer than 10 years. Although there were uniform licensing requirements for agencies, no pediatric-specific regulations existed. In addition, many agencies lacked internal methods to ensure the provision of quality pediatric care. Eighty percent of all pediatric home health care services were provided by only 5 agencies. For intermittent (acute) services, agencies served approximately 450 children per month. The average number of visits per child was two, with 40% receiving only one visit. Services included skilled nursing (60%), infusion (27%), and respiratory therapy (9%). Maintenance (chronic) home health care services, for 156 chronically ill children, were provided almost exclusively by skilled nursing for an average of 9 hours per patient per day. The majority of referrals to agencies (75%) originated from health care providers, although a small number came from insurance companies or individual families. Reimbursement for intermittent care services was divided among commercial insurance (35%), captitated contracts (35%), and Medicaid (20%). In contrast, 90% of reimbursement for the chronically ill was from Medicaid. CONCLUSIONS: In King County, WA, pediatric home health care is predominantly an unregulated, for-profit industry, with most agencies having little actual experience in pediatric home health care. In addition, the unique features of pediatric home health care necessitate both a greater understanding of this field and the consideration of more specific guidelines.

Training generalist physicians: structural elements of the curriculum.

To train more generalist physicians, structural changes must be made along the continuum of medical education. Future generalists require in-depth exposure to primary care practice, with substantive experience in the longitudinal management of patient panels and the opportunity to work with successful generalist role models. Clinical training and course work must incorporate a wide range of skills and disciplines, including areas now under-emphasized, such as epidemiology, health services, and psychosocial medicine. Recommendations for structural changes to increase the generalist focus of medical education include: 1) the development within institutions of central authorities, involving departments of internal medicine, family medicine, and pediatrics, in joint efforts to foster all aspects of generalist training, including recruitment, curriculum development, community linkages, innovative approaches to training, and recognition and support for successful generalist teachers; 2) commitment of a minimum of 50% of clinical training to ambulatory care settings at both medical school and residency levels; 3) required longitudinal care experiences for all medical students and a 20% or greater time commitment to longitudinal care for internal medicine, pediatrics, and family medicine residents; and 4) increased numbers of generalist faculty and enhanced teaching skills among faculty in the outpatient environment, to guarantee increased exposure of medical students and residents to generalist role models.

Efficacy of cough suppressants in children.

To test the hypothesis that codeine and dextromethorphan are effective in alleviating the symptoms of acute cough, we conducted a randomized, controlled trial. Eligible patients were children 18 months to 12 years of age, seen in private pediatric practices, with significant night cough of less than 14 days' duration. Study patients were randomly selected to receive codeine, dextromethorphan, or placebo at bedtime for 3 consecutive nights. Outcomes were assessed by the use of a parent questionnaire rating the severity of symptoms at the initiation of therapy, and after each night of the study. Every patient had a cough score (range 0 to 4) and composite symptom score (range 0 to 9) computed for each day of the study. One hundred forty-one doses of study medication were evaluated in 49 patients, including 13 children receiving placebo, 19 dextromethorphan, and 17 codeine. Mean cough and composite symptom scores decreased in each of the three treatment groups on each day of the study; there were no significant differences. Regression analysis, with reduction in cough score as the outcome of interest, showed that neither dextromethorphan nor codeine was significantly more effective than placebo (p = 0.41 and 0.70, respectively). Reduction in cough score was positively correlated with the severity of cough at the start of treatment (p = 0.007). Our data suggest that, in the doses used, neither codeine nor dextromethorphan is superior to placebo in treating night cough in children.

Measurement of gestational cocaine exposure: sensitivity of infants' hair, meconium, and urine.

We studied the sensitivity of testing the newborn infant's hair, meconium, and urine in detecting gestational cocaine exposure. The infants were born to 59 women who were interviewed to determine their use of cocaine during pregnancy and whose hair was analyzed for the presence of cocaine. Regression analysis was used to evaluate the relationship between cocaine in newborn hair and in maternal hair. Radioimmunoassay of infants' hair and gas chromatography-mass spectrometry of meconium were more sensitive than immunoassay of urine (p less than 0.02), which failed to identify 60% of cocaine-exposed infants. The quantity of benzoylecgonine in the newborn infant's hair correlated best with the proximal-segment maternal hair, representing the last 12 weeks of antepartum hair growth (R = less than R less than 0.83). Approximately half (52%) of the variation in infants' hair was explained by variation in the proximal maternal hair segment. Correlation (R = 0.77) and explained variation (59%) improved slightly when premature infants (n = 9) were excluded. We conclude that analysis of the newborn infant's hair by radioimmunoassay or of meconium by gas chromatography-mass spectrometry is more sensitive than analysis by immunoassay of urine, and can detect fetal cocaine exposure that occurred during the last two trimesters of pregnancy.

Ten-year study of pediatric drownings and near-drownings in King County, Washington: lessons in injury prevention.

The factors associated with submersion events among less than 20-year-old persons that occurred in King County from 1974 to 1983 were studied to focus prevention efforts. Near-drowning (n = 103) and drowning (n = 96) victims were identified from medical examiners' reports, paramedics' reports, and hospital discharge registers. Annual incidence was 5.5; the mortality rate was 2.6 per 100,000 children. Although preschool-aged children had the largest incidence (12.8), followed by older adolescents (4.9), adolescents had the largest case fatality rate, 77%. Lake and river victims had the largest incidence, mortality, and case fatality rate; swimming pools, the smallest case fatality rate (25%). A total of 89% of all victims had absent or no supervision; victims supervised by lifeguards had a 42% case fatality rate. Prior seizures were part of the history of 7.5% of all victims; 25% of fatal submersions by adolescents were associated with alcohol. Bathtub submersions were associated with child abuse in three of 16 preschool-aged children and epilepsy in four of five older children. Certain age groups and sites combined had the greatest incidence: preschool-aged children in swimming pools, infants in bathtubs, teenagers in lakes and rivers. Incidence decreased in public and semipublic pools coincident with fencing regulations. These findings suggest prevention strategies: extending fencing requirements to private pools, discouraging alcohol consumption during water sports, changing bathing practices of epileptics, and improving lifeguard efficacy.

Umbilical cord separation in the normal newborn.

During a 13-month period, 363 infants were followed up through the first six weeks to determine the effect of perinatal factors (birth weight, gestational age, type of delivery, and pregnancy and neonatal complications) on umbilical cord separation. Also, breast-feedings and umbilical cord care were studied. Except for cesarean section deliveries, study infants were similar to all infants (N = 1474) admitted to the same nursery during the study period. Cord separation occurred from days three to 45, with a mean of 13.9 days. Infants born by cesarean section were found to have an increased interval for cord separation when compared with infants born vaginally (mean +/- SD, 15.9 +/- 5.0 days vs 12.9 +/- 4.2 days). In this study, delays in separation of the umbilical cord beyond 3 weeks of age was not associated with an increased risk of infection.

Fever as a predictor of infection in burned children.

Although children with burns often develop fevers, we have found no reports characterizing the course and duration of these fevers. To evaluate the predictive value of fever as an indicator of infection in burned children, we reviewed the hospital charts of all 223 children admitted to a regional burn center in the years 1979 through 1982. The highest temperature reading for each 8-hour period of the child's hospitalization was recorded. The highest mean temperature in burned children occurred at 38 to 96 hours after the burn injury; the peak temperatures appeared at the same time, regardless of whether the child had an infection. All of the 23 children with infections (100%) and 145 of the 200 without infections (73%) had a recorded temperature reading of 38.2 degrees C or higher within 2 weeks after their burn injury. When children less than 4 years, or children with more than 20% total body surface area burns were considered alone, the presence of a temperature greater than 38.2 degrees C was not significant in differentiating those with infections. Fever is not a specific predictor of infection in burned children; in children less than 4 years of age and in children with more than 20% burns, fever has no predictive value for the presence of infection. The physical examination is a reliable source of information about wound infection, sepsis, or other childhood infections, and should be the primary tool used in making the diagnosis of infection in burned children.

Pediatric patients in a regional burn center.

Because scald burns are reported to be the leading cause of burn injuries to children, little is written about other etiologies of burn injury in the pediatric literature. To test the hypothesis that burns from other etiologies are more serious and require longer hospitalizations than scald burns, a retrospective chart review was undertaken. The charts of all patients less than 16 years of age who were admitted to Harborview Medical Center Burn Unit in the years 1979 to 1984 were reviewed. Four hundred sixty-four children were admitted to the regional burn center during that time. We found that children under four years of age are at greatest risk for being hospitalized for thermal injury, that the burn most commonly occurs inside the home between 6 PM and midnight, and that scalds are the most common etiology for thermal injuries in children (54%). However, 46% of the burns resulting in admission to our burn center were from etiologies other than scald injury. There was no significant correlation between etiology of the burns and length of hospital stay, rate of infection, or need for excision and grafting. Thermal injuries to children from any etiology are serious; pediatric health care providers should be aware that children may be burned in a variety of ways and should direct some of their well-child visit time to the topic of burn prevention in the home.

The status of research in ambulatory pediatrics.

To investigate the status of clinical research in ambulatory pediatrics and to characterize those environments that produce the most research activities and receive funding for research, a questionnaire survey was undertaken of all ambulatory pediatrics programs in the United States and Canada (N = 143). Our response rate was 68%. We found that divisions of ambulatory pediatrics that conduct clinical research have more faculty with formal research training, faculty with more time devoted to research endeavors, a designated research coordinator, research funding, and regular research seminars. Divisions of ambulatory pediatrics that have funding for research have more faculty with formal research training, fellows, a designated research coordinator, and regular research seminars. Funding for research is a more influential factor in producing clinical research than the number of faculty members in the division. The most frequently mentioned barrier to doing research was lack of time. Divisions of ambulatory pediatrics must continue to stress formal research training, faculty time set aside for research, and skills in grant writing if they hope to compete for academic recognition in the years ahead.

Multiple pulmonary complications in a patient with Stevens-Johnson syndrome.

Since first described in 1922, Stevens-Johnson syndrome has been associated frequently with pneumonia of many etiologies. This "mucosal respiratory syndrome," first reported by Stanyon and Warner in 1945, is associated with "early" pneumonia which resolves 2 to 3 weeks after onset of the rash. In our patient, pneumonia began 10 days after rash onset and was nearly resolved by day 20. The unique feature of this case was the onset of late pulmonary complications 25 days after the appearance of the exanthem, manifesting as acute noninfectious interstitial disease with superimposed airway obstruction.

Pediatric residents' attitudes and cognitive knowledge, and faculty ratings.

We compared pediatric residents' psychosocial attitude, personality, and in-training examination (American Board of Pediatrics) scores with faculty evaluations of the residents' clinical performance (clinical skills, medical knowledge, interpersonal skills and relationship with other staff) in inpatient, outpatient, and intensive care settings. We found no relationship between psychosocial attitudes and the in-training examination scores or among aggregate faculty ratings, attitudes, and examination scores, but faculty ratings grouped by setting yielded more discriminating results. On inpatient rotations, cognitive knowledge (as reflected by in-training examination scores) was positively correlated with faculty ratings. On intensive care and outpatient rotations, knowledge did not correlate with faculty ratings. Residents' attitudes favoring a psychosocial approach to medical practice were associated with positive evaluations on outpatient rotations but with negative evaluations on intensive care rotations. Psychosocial attitudes seemed to be determined by the social orientation of the resident's personality styles. Our results emphasize the importance of clinical setting to faculty rating and suggest that valued resident characteristics vary by setting. These findings have significant implications for both improving the clinical evaluation of residents and creating a better understanding of the interaction of personality, attitude, and cognitive variables in rated clinical performance.

The Frey syndrome: a simple, effective treatment.

The benign but socially embarrassing problem of gustatory sweating and flushing (Frey syndrome) has been studied in the past in search of a simple but effective treatment. Twenty-two patients participated in clinical trials of glycopyrrolate on an investigational basis, 17 of which have been followed up for four to five years. Double-blind comparisons of the efficacy and side effects of topical scopolamine (solution and cream) and glycopyrrolate (roll-on lotion, solution, and cream) are also presented. The use of 1% glycopyrrolate roll-on lotion and cream were associated with an average of three days of complete control of gustatory sweating and a remarkably low incidence of side effects.