Second Sets of Tympanostomy Tubes Extrude Sooner.

INTRODUCTION: Some clinicians believe second sets of tympanostomy tubes extrude more quickly than first sets. STUDY DESIGN: Retrospective case-control series. METHODS: We identified children who were examined 12 months after placement of their second set of tympanostomy tubes and compared them to a similar number of children who were examined 12 months after their first set of tympanostomy tubes. Extrusion was determined by otoscopy, otomicroscopy, and/or tympanometry. RESULTS: One hundred eighteen children had 12-month follow-up data available after their first set of tubes, 54 had 12-month follow-up data available for their second set, and 56 had 12-month follow-up data after their first and second sets. A total of 568 tubes were observed. Looking at each tube, second set tubes were significantly more likely to be extruded at 12 months (48%) compared to first set (28%) (P < .001). Patient age was not associated with extrusion rate. For patients who had 12-month follow-up for both their first and second set of tubes, there was no correlation between extrusion of first and second set tubes. CONCLUSION: Second set tympanostomy tubes are significantly less likely to remain functional 12 months after placement than first sets, independent of patient age at placement and independent of whether the child's first tubes extruded by 12 months. Given the short duration of second tube function, delaying second set placement until the fall might be a better choice for some children. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:222-224, 2022.

In RRP, serologic response to HPV is frequently absent and slow to develop.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is characterized by repeated formation of papillomas in the respiratory tract and is caused by human papillomavirus (HPV) types 6 and 11. Women with genital HPV infection are slow to develop weak humoral immunity, but respond robustly to the HPV vaccine. We wondered if people with RRP had a similar immune response. METHODS: A convenience cross-sectional sample of patients with RRP were recruited into one of four groups: 1) adults and adolescents with active RRP, 2) children with active RRP, 3) RRP patients who had undergone HPV vaccination prior to enrollment and, 4) people with RRP who were in remission. Anti-HPV6 and HPV11 serology was determined by cLIA on a single blood draw. RESULTS: Of the 70 subjects enrolled, 36, 16, 8, and 10, were in groups 1, 2, 3, and 4, respectively. 47% of participants aged >11 years and 81% aged ≤11 years possessed no antibodies against HPV6 or HPV11 (ie. double seronegative). 61% of patients in remission were double seronegative. All participants who had received HPV vaccine previously were seropositive to at least one of these low risk HPV types (ie none of them were double seronegative). Among patients who had active RRP and never had HPV vaccination (n = 52) there was an association between duration of symptoms and seropositivity. Of those who were seropositive, the geometric mean duration of symptoms was 11 years compared to 4.7 years for those who were seronegative (p = 0.001). CONCLUSION: People with RRP are capable of developing a humoral response to HPV6 and HPV11. That response appears to be robust when initiated by the HPV vaccine, but either nonexistent or slow to develop in response to infection. Most in remission do not have demonstrable antibody levels against HPV6 or HPV11.

Age at diagnosis, but not HPV type, is strongly associated with clinical course in recurrent respiratory papillomatosis.

BACKGROUND: Recurrent Respiratory Papillomatosis (RRP) is a rare disease characterized by the growth of papillomas in the airway and especially the larynx. The clinical course is highly variable among individuals and there is poor understanding of the factors that drive an aggressive vs an indolent course. METHODS: A convenience cohort of 339 affected subjects with papillomas positive for only HPV6 or HPV11 and clinical course data available for 1 year or more, from a large multicenter international study were included. Exploratory data analysis was conducted followed by inferential analyses with frequentist and Bayesian statistics. RESULTS: We examined 339 subjects: 82% were diagnosed prior to the age of 18 years, 65% were infected with HPV6, and 69% had an aggressive clinical course. When comparing age at diagnosis with clinical course, the probability of aggressiveness is high for children under five years of age then drops rapidly. For patients diagnosed after the age of 10 years, an indolent course is more common. After accounting for confounding between HPV11 and young age, HPV type was minimally associated with aggressiveness. Fast and Frugal Trees (FFTs) were utilized to determine which algorithms yield the highest accuracy to classify patients as having an indolent or aggressive clinical course and consistently created a branch for diagnostic age at ~5 years old. There was no reliable strong association between clinical course and socioeconomic or parental factors. CONCLUSION: In the largest cohort of its type, we have identified a critical age at diagnosis which demarcates a more aggressive from less aggressive clinical course.

Deletion of genes involved in the ketogluconate metabolism, Entner-Doudoroff pathway, and glucose dehydrogenase increase local and invasive virulence phenotypes in Streptococcus pneumoniae.

Streptococcus pneumoniae displays increased resistance to antibiotic therapy following biofilm formation. A genome-wide search revealed that SP 0320 and SP 0675 (respectively annotated as 5-keto-D-gluconate-5-reductase and glucose dehydrogenase) contain the highest degree of homology to CsgA of Myxococcus xanthus, a signaling factor that promotes cell aggregation and biofilm formation. Single and double SP 0320 and SP 0675 knockout mutants were created in strain BS72; however, no differences were observed in the biofilm-forming phenotypes of mutants compared to the wild type strain. Using the chinchilla model of otitis media and invasive disease, all three mutants exhibited greatly increased virulence compared to the wild type strain (increased pus formation, tympanic membrane rupture, mortality rates). The SP 0320 gene is located in an operon with SP 0317, SP 0318 and SP 0319, which we bioinformatically annotated as being part of the Entner-Doudoroff pathway. Deletion of SP 0317 also resulted in increased mortality in chinchillas; however, mutations in SP 0318 and SP 0319 did not alter the virulence of bacteria compared to the wild type strain. Complementing the SP 0317, SP 0320 and SP 0675 mutant strains reversed the virulence phenotype. We prepared recombinant SP 0317, SP 0318, SP 0320 and SP 0675 proteins and confirmed their functions. These data reveal that disruption of genes involved in the degradation of ketogluconate, the Entner-Doudoroff pathway, and glucose dehydrogenase significantly increase the virulence of bacteria in vivo; two hypothetical models involving virulence triggered by reduced in carbon-flux through the glycolytic pathways are presented.

Safety of preoperative ibuprofen in pediatric tonsillectomy.

OBJECTIVE: Oral ibuprofen is believed to be safe and effective after pediatric adenotonsillectomy. There has been little study of its use as a preoperative analgesic. We attempt to document its safety in this setting. STUDY DESIGN: Individual case control study. METHODS: Children who underwent tonsillectomy or adenotonsillectomy from January 2013 to December 2015 did not receive preoperative ibuprofen. Those who underwent tonsillectomy or adenotonsillectomy from January 2016 to December 2017 received oral ibuprofen 7 mg/kg preoperatively. Pre- and postoperative records were reviewed. Intraoperative bleeding > 50 mL or early postoperative bleeding requiring surgical control were outcome measures. Delayed bleeding events were also recorded. RESULTS: A total of 217 children met inclusion criteria. Of those, 112 patients did not receive preoperative ibuprofen, and 105 patients did receive preoperative ibuprofen. Mean age was 8.7 years (range: 1-18) in the control/non-ibuprofen cohort and 8.3 years (range: 1-18) in the ibuprofen cohort. No child experienced significant intraoperative or early postoperative bleeding in the non-ibuprofen (95% confidence interval [CI] 0-0.027) or in the ibuprofen cohort (95% CI 0- 0.029). Delayed bleeding rates were similar in both groups. CONCLUSION: In this series, children treated with preoperative ibuprofen did not experience increased bleeding during or soon after tonsillectomy compared to controls. Pain control was not studied in these patients. These favorable safety data argue for a future prospective randomized study of preoperative ibuprofen's effectiveness in reducing pain and opioid requirement after pediatric tonsillectomy. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:2415-2418, 2018.

To P or Not to P: Backing Bayesian Statistics.

In biomedical research, it is imperative to differentiate chance variation from truth before we generalize what we see in a sample of subjects to the wider population. For decades, we have relied on null hypothesis significance testing, where we calculate P values for our data to decide whether to reject a null hypothesis. This methodology is subject to substantial misinterpretation and errant conclusions. Instead of working backward by calculating the probability of our data if the null hypothesis were true, Bayesian statistics allow us instead to work forward, calculating the probability of our hypothesis given the available data. This methodology gives us a mathematical means of incorporating our "prior probabilities" from previous study data (if any) to produce new "posterior probabilities." Bayesian statistics tell us how confidently we should believe what we believe. It is time to embrace and encourage their use in our otolaryngology research.

Hydroxyapatite cement cranioplasty following translabyrinthine approach: Long-term study of 369 cases.

OBJECTIVE: To report the authors' experience with hydroxyapatite cement (HAC) cranioplasty and analyze the material's long-term safety and efficacy in repairing translabyrinthine skull-base defects by examining adverse events, specifically cerebrospinal fluid (CSF) leaks and surgical site infections. STUDY DESIGN: Retrospective case-control study (primary study arm); prospective cross-sectional study of patients not examined within the last 5 years (secondary arm). SETTING: tertiary-care neurotology private practice and academic practice (two centers). METHODS: Hydroxyapatite cement implanted following translabyrinthine approach, with or without fat graft, was included. Combined approaches were excluded. Implant-associated adverse events were defined as 1) CSF leaks requiring reoperation or spinal drainage, and (2) infections requiring reoperation. Patients not examined within 5 years were interviewed by telephone to update their condition. Incidence of adverse events was compared to published data for translabyrinthine cranioplasty using fat graft alone. Implant survival analysis was performed. RESULTS: The study cohort included 369 HAC implants in the same number of patients. There were seven CSF leaks and seven infections. Combined (n = 14) incidence of adverse events was 3.8% (2.09%, 6.28%). Compared to fat graft alone, the adverse events associated with HAC were fewer (P < 0.001). Up to 15 years (5,475 days), HAC cement maintained 95% adverse event-free survival. There were no cases of meningitis. CONCLUSION: Cranioplasty using HAC with autologous fat following translabyrinthine skull-base surgery is safer and more effective than fat graft alone, up to 15 years after surgery. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2120-2125, 2017.

Estimating the additive benefit of surgical excision to stereotactic radiosurgery in the management of metastatic brain disease.

BACKGROUND: There are limited data on the benefits of surgical tumor resection plus stereotactic radiosurgery (SRS) in comparison with SRS alone for patients with oligometastatic brain disease. OBJECTIVE: To determine the benefit of adding resection to SRS. METHODS: We reviewed 162 consecutive patients with oligometastatic brain disease, who underwent surgical tumor resection and SRS boost (n = 49) or SRS alone (n = 113). Patients receiving prior whole brain radiation therapy were excluded. Factors related to patient survival and time-to-local recurrence (TTLR) were determined by Cox regression. The effect of complete resection + SRS boost on survival was further explored by propensity score matching. RESULTS: The average age of the cohort was 65.3 years, it was 49.4% female, and included 260 brain tumors, of which 119 tumors were single. Seventy-three brain tumors recurred (28%). TTLR was related to radiation-sensitive pathology (hazards ratio [HR] = 0.34, P = .001), treatment volume (HR = 1.078/mL, P = .002), and complete tumor resection (HR = 0.37, P = .015). Factors related to survival were age (HR = 1.21/decade, P = .037), Eastern Cooperative Oncology Group performance score (HR = 1.9, P = .001), and complete surgical resection (HR = 0.55, P = .01). Propensity score matched analysis of complete surgical resection + SRS boost (n = 40) vs SRS alone (n = 80) yielded nearly identical survival results (HR = 0.52, P = .030) compared with the initial unmatched sample. Incomplete tumor resection had both median survival and TTLR equivalent to SRS alone. CONCLUSION: Complete surgical resection + SRS boost is associated with improved survival and reduced likelihood of local tumor recurrence in comparison with SRS alone. Incomplete resection did not improve survival or TTLR compared with SRS alone.

Current trends in perioperative antibiotic use: a survey of otolaryngologists.

This study describes the patterns of perioperative antimicrobial use by otolaryngologists during common otolaryngologic surgical procedures. Through the American Academy of Otolaryngology--Head and Neck Surgery Infectious Diseases Committee, a survey was developed to assess the current practice patterns regarding the use of perioperative antibiotics in otolaryngology. A total of 6903 surveys were sent out; 458 were fully or partially completed, and a total of 442 responses were included in the final analysis. Most physicians reported routinely prescribing antibiotics either preoperatively or postoperatively for 12 of the 17 procedures included in the questionnaire despite providers agreeing that there is not enough evidence to support their use. The most common procedure for which antibiotics were prescribed was laryngectomy (91.1%). Antibiotic use is a common practice during the perioperative period for otolaryngologic procedures; however, there is a discrepancy between utilization and evidence of benefit.

In vivo capsular switch in Streptococcus pneumoniae--analysis by whole genome sequencing.

Two multidrug resistant strains of Streptococcus pneumoniae - SV35-T23 (capsular type 23F) and SV36-T3 (capsular type 3) were recovered from the nasopharynx of two adult patients during an outbreak of pneumococcal disease in a New York hospital in 1996. Both strains belonged to the pandemic lineage PMEN1 but they differed strikingly in virulence when tested in the mouse model of IP infection: as few as 1000 CFU of SV36 killed all mice within 24 hours after inoculation while SV35-T23 was avirulent.Whole genome sequencing (WGS) of the two isolates was performed (i) to test if these two isolates belonging to the same clonal type and recovered from an identical epidemiological scenario only differed in their capsular genes? and (ii) to test if the vast difference in virulence between the strains was mostly - or exclusively - due to the type III capsule. WGS demonstrated extensive differences between the two isolates including over 2500 single nucleotide polymorphisms in core genes and also differences in 36 genetic determinants: 25 of which were unique to SV35-T23 and 11 unique to strain SV36-T3. Nineteen of these differences were capsular genes and 9 bacteriocin genes.Using genetic transformation in the laboratory, the capsular region of SV35-T23 was replaced by the type 3 capsular genes from SV36-T3 to generate the recombinant SV35-T3* which was as virulent as the parental strain SV36-T3* in the murine model and the type 3 capsule was the major virulence factor in the chinchilla model as well. On the other hand, a careful comparison of strains SV36-T3 and the laboratory constructed SV35-T3* in the chinchilla model suggested that some additional determinants present in SV36 but not in the laboratory recombinant may also contribute to the progression of middle ear disease. The nature of this determinants remains to be identified.

Microdebrider tonsillectomy associated with more intraoperative blood loss than electrocautery.

OBJECTIVE: To describe and compare the intraoperative blood loss in children who underwent tonsillectomy and/or adenoidectomy during a transition from using electrocautery to a microdebrider. METHODS: Retrospective case series of a single pediatric otolaryngologist at an urban general hospital. Patients aged 2-20 years who had tonsillectomy, adenoidectomy, or adenotonsillectomy over a 12 month period were included. Tonsillectomy was performed by microdebrider or electrocautery and adenoidectomy was performed by microdebrider, curette, or suction electrocautery. Total intraoperative blood loss was measured and compared between surgical techniques. RESULTS: Of the 148 patients, 109 had tonsillectomy with or without adenoidectomy and 39 had adenoidectomy alone. The mean blood loss was 47 ml or 1.8 ± 1.6 ml/kg and the maximum blood loss was 11 ml/kg. Adenoid curette and adenoid microdebrider yielded similar blood loss but were associated with more bleeding than suction electrocautery (P<0.05). Microdebrider tonsillectomy yielded more blood loss than electrocautery tonsillectomy (mean of 2.6 ± 2.2 ml/kg versus 1.2 ± 1.2 ml/kg, P=0.0002). Eighteen percent of adenotonsillectomy patients lost greater than 5% of calculated circulating blood volume (95% CI, 9.8-26). Linear regression models did not show an association between the amount of blood loss and patient age, clinical indication, or the surgeon's experience with the microdebrider (P>0.05). CONCLUSIONS: Microdebrider tonsillectomy is associated with more intraoperative bleeding than electrocautery tonsillectomy. Approximately twice as much blood was lost with the microdebrider, but the absolute increase was insignificant from a hemodynamic perspective.

Differences in genotype and virulence among four multidrug-resistant Streptococcus pneumoniae isolates belonging to the PMEN1 clone.

We report on the comparative genomics and characterization of the virulence phenotypes of four S. pneumoniae strains that belong to the multidrug resistant clone PMEN1 (Spain(23F) ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinants.

More than a surgical mission--pediatric Otolaryngology in Ethiopia.

OBJECTIVES: Improving the quality of pediatric healthcare in the developing world poses some formidable challenges. Surgical missions aim to improve the lot of individual children, but do little to alter the wellness of the majority. METHODS: Members of the American Society of Pediatric Otolaryngology (ASPO) are working in coordination with existing programs--universities, mission hospitals and non-governmental organizations--with a focus on public health and education of local physicians. RESULTS: We have completed our first four visits to Ethiopia, teaching, performing surgery and building relationships. CONCLUSIONS: We hope that by moving from the traditional surgical mission format to a long-term, integrated educational effort we can enhance otolaryngic care for children in Sub-Saharan Africa.

Age of child, more than HPV type, is associated with clinical course in recurrent respiratory papillomatosis.

BACKGROUND: RRP is a devastating disease in which papillomas in the airway cause hoarseness and breathing difficulty. The disease is caused by human papillomavirus (HPV) 6 or 11 and is very variable. Patients undergo multiple surgeries to maintain a patent airway and in order to communicate vocally. Several small studies have been published in which most have noted that HPV 11 is associated with a more aggressive course. METHODOLOGY/PRINCIPAL FINDINGS: Papilloma biopsies were taken from patients undergoing surgical treatment of RRP and were subjected to HPV typing. 118 patients with juvenile-onset RRP with at least 1 year of clinical data and infected with a single HPV type were analyzed. HPV 11 was encountered in 40% of the patients. By our definition, most of the patients in the sample (81%) had run an aggressive course. The odds of a patient with HPV 11 running an aggressive course were 3.9 times higher than that of patients with HPV 6 (Fisher's exact p = 0.017). However, clinical course was more closely associated with age of the patient (at diagnosis and at the time of the current surgery) than with HPV type. Patients with HPV 11 were diagnosed at a younger age (2.4y) than were those with HPV 6 (3.4y) (p = 0.014). Both by multiple linear regression and by multiple logistic regression HPV type was only weakly associated with metrics of disease course when simultaneously accounting for age. CONCLUSIONS/SIGNIFICANCE ABSTRACT: The course of RRP is variable and a quarter of the variability can be accounted for by the age of the patient. HPV 11 is more closely associated with a younger age at diagnosis than it is associated with an aggressive clinical course. These data suggest that there are factors other than HPV type and age of the patient that determine disease course.

Strain-specific virulence phenotypes of Streptococcus pneumoniae assessed using the Chinchilla laniger model of otitis media.

BACKGROUND: Streptococcus pneumoniae [Sp] infection is associated with local and systemic disease. Our current understanding of the differential contributions of genetic strain variation, serotype, and host response to disease phenotype is incomplete. Using the chinchilla model of otitis media [OM] we investigated the disease phenotype generated by the laboratory strain TIGR4 and each of thirteen clinical strains (BS68-75, BS290, BS291, BS293, BS436 and BS437); eleven of the thirteen strains have been genomically sequenced. METHODOLOGY/PRINCIPAL FINDINGS: For each strain 100 colony forming units were injected bilaterally into the tympanic bullae of 6 young adult chinchillas under general anesthesia. All animals were examined daily for local and systemic disease by a blinded observer. Pneumatic otoscopy was used to evaluate local disease, and behavioral assessments served as the measure of systemic disease. Virulence scoring was performed using a 4-point scale to assess four clinical parameters [severity and rapidity of local disease onset; and severity and rapidity of systemic disease onset] during a 10-day evaluation period. Highly significant variation was observed among the strains in their ability to cause disease and moribundity. CONCLUSIONS/SIGNIFICANCE: As expected, there was a significant correlation between the rapidity of systemic disease onset and severity of systemic disease; however, there was little correlation between the severity of otoscopic changes and severity of systemic disease. Importantly, it was observed that different strains of the same serotype produced as broad an array of disease phenotypes as did strains of different serotypes. We attribute these phenotypic differences among the strains to the high degree of genomic plasticity that we have previously documented.

Virulence phenotypes of low-passage clinical isolates of nontypeable Haemophilus influenzae assessed using the chinchilla laniger model of otitis media.

BACKGROUND: The nontypeable Haemophilus influenzae (NTHi) are associated with a spectrum of respiratory mucosal infections including: acute otitis media (AOM); chronic otitis media with effusion (COME); otorrhea; locally invasive diseases such as mastoiditis; as well as a range of systemic disease states, suggesting a wide range of virulence phenotypes. Genomic studies have demonstrated that each clinical strain contains a unique genic distribution from a population-based supragenome, the distributed genome hypothesis. These diverse clinical and genotypic findings suggest that each NTHi strain possesses a unique set of virulence factors that contributes to the course of the disease. RESULTS: The local and systemic virulence patterns of ten genomically characterized low-passage clinical NTHi strains (PittAA - PittJJ) obtained from children with COME or otorrhea were stratified using the chinchilla model of otitis media (OM). Each isolate was used to bilaterally inoculate six animals and thereafter clinical assessments were carried out daily for 8 days by blinded observers. There was no statistical difference in the time it took for any of the 10 NTHi strains to induce otologic (local) disease with respect to any or all of the other strains, however the differences in time to maximal local disease and the severity of local disease were both significant between the strains. Parameters of systemic disease indicated that the strains were not all equivalent: time to development of the systemic disease, maximal systemic scores and mortality were all statistically different among the strains. PittGG induced 100% mortality while PittBB, PittCC, and PittEE produced no mortality. Overall Pitt GG, PittII, and Pitt FF produced the most rapid and most severe local and systemic disease. A post hoc determination of the clinical origins of the 10 NTHi strains revealed that these three strains were of otorrheic origin, whereas the other 7 were from patients with COME. CONCLUSION: Collectively these data suggest that the chinchilla OM model is useful for discriminating between otorrheic and COME NTHi strains as to their disease-producing potential in humans, and combined with whole genome analyses, point the way towards identifying classes of virulence genes.

Human susceptibility to viral infection: the search for HIV-protective alleles among Africans by means of genome-wide studies.

Human immunodeficiency virus (HIV) infection represents a major global health problem, with HIV now recognized as the fourth leading cause of death on a worldwide basis. One approach to developing effective anti- HIV interventions is to identify and understand the molecular mechanisms by which natural genetic variations provide protection from infection or disease progression. This approach can be used to identify human gene alleles that confer resistance or increased susceptibility to HIV infection. To date, however, this approach has been underutilized in the African population and all HIV-resistance alleles that have been described have been identified by evaluating candidate genes. This limited approach is based upon a researcher's assumption that those genes that will provide the host with a benefit can be predicted, a priori, but it does not provide for a large scale systematic screen of all possible candidate genes. Nonetheless, this method has met with some success in identifying HIV-resistance genes, mostly among the white population. The lack of a comprehensive genetic approach, both in terms of the populations studied and the percentage of the genome investigated, likely explains why all of the HIV-restriction alleles identified to date fall within two gene families, and why no resistance genes have been identified among black Africans. It is likely, as with any complex trait, that most protective alleles will provide only partial HIV resistance. Thus, HIV resistance in most persons likely arises through a QTL (quantitative trait loci) mechanism meaning that protection is a polygenic trait. This feature coupled with interpopulation genetic heterogeneity makes the candidate gene mapping approach a daunting task. A comprehensive genome-wide case-control allelic association study in the African population will maximize our chances of identifying new targets for the development of new therapeutics that have the promise of benefiting all persons infected with HIV.

Unique challenges of obtaining regulatory approval for a multicenter protocol to study the genetics of RRP and suggested remedies.

OBJECTIVE: Investigations that seek to generalize findings or to understand uncommon diseases must be conducted at multiple centers. This study describes the process of obtaining regulatory approval for a minimal risk genetic study in a multi-center setting as undertaken by the Recurrent Respiratory Papillomatosis (RRP) Task Force. STUDY DESIGN AND SETTING: Sequential cohort of American children's hospitals. A single protocol was submitted to each Institutional Review Board (IRB). RESULTS: Documentation was prepared for 14 IRBs over 2.5 years. The median time between enlistment and approval at the first 8 sites was 15 months. Institutions varied considerably in their requirements and in the issues that were raised. Protocols were submitted sequentially and accumulated experience was used in the preparation of applications to subsequent IRBs. Nevertheless, there was no correlation between the accumulated experience and the number of issues that were raised. CONCLUSION: Despite uniform federal standards, all local IRBs required unique and individualized submissions. For multicenter studies, investigators should seriously consider the establishment of cooperative authorization agreements. On a simpler level, a standardized format for applications needs to be adopted nationwide. EBM RATING: B-3b.