Susan G. Marshall

Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis

BACKGROUND AND METHODS We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization. RESULTS The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group. CONCLUSIONS In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.

Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders

Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources.

From concept to culture: the WWAMI program at the University of Washington School of Medicine.

Shortages of primary care physicians have historically affected rural areas more severely than urban and suburban areas. In 1970, the University of Washington School of Medicine (UWSOM) administrators and faculty initiated a four-state, community-based program to increase the number of generalist physicians throughout a predominantly rural and underserved region in the U.S. Northwest. The program developed regional medical education for three neighboring states that lacked their own medical schools, and encouraged physicians in training to practice in the region. Now serving five Northwest states (Washington, Wyoming, Alaska, Montana, and Idaho), the WWAMI program has solidified and expanded throughout its 30-year history. Factors important to success include widespread participation in and ownership of the program by the participating physicians, faculty, institutions, legislatures, and associations; partnership among constituents; educational equivalency among training sites; and development of an educational continuum with recruitment and/or training at multiple levels, including K-12, undergraduate, graduate training, residency, and practice. The programs positive influences on the UWSOM have included historically early attention to primary care and community-based clinical training and development of an ethic of closely monitored innovation. The use of new information technologies promises to further expand the ability to organize and offer medical education in the WWAMI region.

An oral health curriculum for medical students at the University of Washington.

Oral health disparities are a major public health problem, according to the U.S. Surgeon General. Physicians could help prevent oral disease, but lack the knowledge to do so. To create an oral health curriculum for medical students at the University of Washington School of Medicine, the authors (beginning in 2003) (1) reviewed current evidence of medical education and physician training in oral health, (2) developed oral health learning objectives and competencies appropriate for medical students, and (3) identified current oral health content in the undergraduate curriculum and opportunities for including additional material. The authors identified very few Medline articles on medical student education and training in oral health. The United States Medical Licensing Examination Steps 2 and 3 require specific clinical knowledge and skills in oral and dental disorders, but other national curriculum databases and the Web site of the Liaison Committee on Medical Education devote no significant attention to oral health. To develop learning objectives, the authors reviewed major oral health reports, online oral health educational resources, and consulted with dental faculty. The curriculum was assessed by interviewing key medical school faculty and analyzing course descriptions, and was found to be deficient in oral health content. The authors developed five learning themes: dental public health, caries, periodontal disease, oral cancer, and oral–systemic interactions, and recommend the inclusion of corresponding competencies in targeted courses through a spiral curriculum. Current progress, the timeline for curriculum changes at the University of Washington, and the ethical values and attitudinal shifts needed to support this effort are discussed.

A New Oral Health Elective for Medical Students at the University of Washington

Background: Oral health is an important but inadequately addressed area in medical school curricula. Primary care practitioners are in an ideal position to help prevent oral disease but lack the knowledge to do so. Purposes: We developed an oral health elective that targeted 1st- and 2nd-year medical students as part of a previously described oral health initiative and oral health curriculum. Methods: To promote interprofessional collaboration, we utilized medical–dental faculty teams for lectures and hands-on peer instruction by dental students for clinical skills. Results: Evaluations revealed positive shifts in attitudes toward oral health and significant gains in oral health knowledge and self-confidence. Students rated the course highly and advocated for further integration of oral health into required medical curricula. Conclusions: We describe the elective including curriculum development, course evaluation results, and steps for implementing a successful oral health elective into medical education. We highlight interprofessional collaboration and constituency building among medical and dental faculty and administrators.

Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors

Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators are also emphasized. Pediatr Pulmonol. 2015; 50:S3–S13.

Induction of eustachian tube dysfunction with histamine nasal provocation

Abstract This study assessed changes in nasal airway resistance and nasal airway power as well as eustachian tube function after histamine nasal provocation in 12 atopic subjects and 10 nonatopic subjects. Results demonstrated that subjects could not be placed in the atopic or nonatopic group on the basis of prechallenge nasal resistance and power measurements. Atopic subjects demonstrated a statistically significant difference in nasal airway power after histamine provocation ( p p

Therapeutic range cromolyn dose-response inhibition and complete obliteration of SO2-induced bronchoconstriction in atopic adolescents

Eight atopic adolescent subjects with exercise-induced bronchospasm were studied to determine whether cromolyn sodium could inhibit or block sulfur dioxide (SO2)-induced bronchoconstriction. Cromolyn or placebo were administered by turboinhaler 20 minutes before 10 minutes of SO2 exposure at 1.0 ppm during continuous moderate exercise on a treadmill. The exercise level that was chosen did not in itself produce bronchoconstriction. The cromolyn doses were 0 (placebo), 20, 40, and 60 mg. Pulmonary functions (FEV1, and total respiratory resistance) were measured before and after drug administration and after exposure. SO2 exposure after placebo produced significant bronchoconstriction. Pretreatment with 20 mg of cromolyn did not change the SO2 response, 40 mg significantly inhibited the response, and 60 mg completely abolished the pulmonary function changes. These results demonstrate for the first time a dose-response inhibition of SO2-induced bronchoconstriction in atopic subjects within a clinically acceptable dosage range and complete obliteration of SO2 sensitivity in this group with 60 mg of cromolyn pretreatment.

The effects of albuterol on sulfur dioxide-induced bronchoconstriction in allergic adolescents

Ten allergic subjects with exercise-induced bronchospasm were studied to determine whether albuterol could prevent sulfur dioxide (SO2)-induced bronchoconstriction. Albuterol or placebo (180 micrograms) were administered by metered-dose inhaler 20 minutes before a 10-minute exposure to SO2 or clean air during moderate exercise on a treadmill at an exercise level that by itself did not produce exercise-induced bronchospasm. Pulmonary functions (FEV1 and total respiratory resistance [RT]) were measured before the drug, after the drug, and after exposure to SO2 or clean air. Albuterol treatment produced significant bronchodilation and also prevented SO2-induced bronchoconstriction. Following SO2 inhalation after placebo, FEV1 decreased 15% (p less than 0.02) and RT increased 50% (p less than 0.03). Following SO2 inhalation after albuterol treatment, neither FEV1 or RT changed significantly. We conclude that albuterol, a beta 2-agonist, inhibits SO2-induced bronchoconstriction. This result suggests that the adrenergic nervous system or mast cell degranulation are involved in SO2-induced bronchoconstriction.

A follow-up study of the characteristics of dean's letters.

Purpose To assess the content and quality of deans letters since the publication of guidelines recommended by the Association of American Medical Colleges (AAMC) in 1989. Method In 1998, the deans letter writers at all 124 U.S. medical schools were surveyed. The questionnaire incorporated items from two previous surveys (1981 and 1992). In addition, samples of deans letters (n = 451) from all U.S. medical schools for the graduating class of 1998 were rated based on the AAMCs guidelines. Results The response rate of the 1998 survey (66%) was lower than those of the two previous surveys (87% for 1992 and 85% for 1981). Schools that prepared letters that followed the AAMCs guidelines were somewhat more likely to have responded. According to the letter writers in 1998, close to 300,000 letters (approximately 1,050,000 pages total) were sent to residency directors, at an estimated cost of