Identification and confirmation via in situ hybridization of Merkel cell polyomavirus in rare cases of posttransplant cutaneous T-cell lymphoma.

BACKGROUND: Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens. METHODS: Alignment of off-target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus-Clip. RESULTS: Four cases of post-cardiac-transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T-cell lymphoma (PTCL) were positive in off-target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes. CONCLUSIONS: Our findings raise the question of whether MCPyV may play a role in rare cases of T-lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting.

Trichodysplasia Spinulosa Polyomavirus Endothelial Infection, California, USA.

We describe 3 patients in California, USA, with trichodysplasia spinulosa polyomavirus (TSPyV) infection of endothelium after steroid administration. We detected TSPyV RNA in tissue specimens by in situ hybridization, which revealed localization to endothelial cells. These cases suggest that diseases associated with endothelial inflammation could be associated with TSPyV infection.

Genome-wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies. METHODS: We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data. RESULTS: We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10-13 ) and rs1411478 in STX6 (P = 3.45 × 10-10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP. CONCLUSIONS: Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society.

Cleft palate: a clinical review.

Orofacial clefts, including cleft palates (CP), are one of the most common birth defects. CP have a multiplicity of effects on the individual and society in terms of economic costs, loss of productivity, psychosocial effects, and increased morbidity and mortality at all stages of life. Embryological development of the palate is well delineated, with developments in the last decade regarding the biomolecular processes involved. Etiology is complex, involving a number of genetic and environmental factors. Various techniques can be employed for the repair of CP, depending on whether the cleft is of the primary or secondary palate, the width of the cleft, whether lengthening of the palate is necessary, and with regard to concerns of disruption of midfacial growth. All surgical techniques have the goals of restoring functional speech, swallowing, and aesthetics. A multidisciplinary team is necessary for the long-term pre- and postoperative care of CP patients to handle complications, associated anomalies, and to optimize function and quality of life.

The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

PURPOSE: Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants. METHODS: Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data. RESULTS: We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable. CONCLUSION: Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.

p53 immunohistochemistry as an ancillary tool for rapid assessment of residual disease in TP53-mutated acute myeloid leukemia and myelodysplastic syndromes.

OBJECTIVES: Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53-mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC. METHODS: We retrospectively identified 28 pre- and posttherapy bone marrow biopsy specimens from 9 patients with TP53+ AML/MDS and a p53 overexpressor phenotype by IHC (strong 3+ staining at initial diagnosis). Next-generation sequencing and/or MRD-FC results were collected for each specimen. RESULTS: Using a threshold of more than ten 2-3+ cells in any one 400× field, p53 IHC detected residual disease with a sensitivity of 94% and a specificity of 89%. The threshold used in this study showed a high degree of concordance among 6 blinded pathologists (Fleiss κ = 0.97). CONCLUSIONS: Our study suggests that p53 IHC can be used as a rapid tool (within 24 hours) to aid in the detection of residual disease that may complement MRD-FC or NGS in cases in which the flow cytometry immunophenotype is equivocal and/or the bone marrow aspirate is suboptimal.

Plastids are major regulators of light signaling in Arabidopsis.

We previously provided evidence that plastid signaling regulates the downstream components of a light signaling network and that this signal integration coordinates chloroplast biogenesis with both the light environment and development by regulating gene expression. We tested these ideas by analyzing light- and plastid-regulated transcriptomes in Arabidopsis (Arabidopsis thaliana). We found that the enrichment of Gene Ontology terms in these transcriptomes is consistent with the integration of light and plastid signaling (1) down-regulating photosynthesis and inducing both repair and stress tolerance in dysfunctional chloroplasts and (2) helping coordinate processes such as growth, the circadian rhythm, and stress responses with the degree of chloroplast function. We then tested whether factors that contribute to this signal integration are also regulated by light and plastid signals by characterizing T-DNA insertion alleles of genes that are regulated by light and plastid signaling and that encode proteins that are annotated as contributing to signaling, transcription, or no known function. We found that a high proportion of these mutant alleles induce chloroplast biogenesis during deetiolation. We quantified the expression of four photosynthesis-related genes in seven of these enhanced deetiolation (end) mutants and found that photosynthesis-related gene expression is attenuated. This attenuation is particularly striking for Photosystem II subunit S expression. We conclude that the integration of light and plastid signaling regulates a number of END genes that help optimize chloroplast function and that at least some END genes affect photosynthesis-related gene expression.

Two cases of mycosis fungoides with large cell transformation with KMT2A rearrangements.

Cutaneous T-cell lymphomas (CTCL) are a clinically and molecularly heterogeneous class of lymphomas of the skin-homing T cell, and their genetic profiles are not fully characterized. Previously, rearrangements of the Lysine Methyltransferase 2A (KMT2A) gene have been identified as driver mutations only in acute leukemias. KMT2A plays a role in epigenetic regulation, and cancers with such rearrangements are responsive to epigenetic therapy including hypomethylating agents. Here, we report two cases of CTCL with novel genetic profiles. KMT2A rearrangements were identified in two aggressive cases of mycosis fungoides with large cell transformation. A KMT2A::DSCAML1 gene rearrangement was seen in Case 1, while a KMT2A::MAPRE1 fusion was identified in Case 2. These cases demonstrate that KMT2A rearrangements can be found in primary CTCLs rather than solely acute leukemias, illustrating the importance of correlating molecular findings with clinical and histologic features in diagnosis. Additionally, this finding suggests that the subset of CTCLs driven by aberrancy of the KMT2A pathway may be responsive to therapy with hypomethylating agents or menin inhibitors, as seen in acute leukemias.

Percent Agreement Between Immunohistochemistry and Next-Generation Sequencing in Testing Patients for Mismatch Repair Deficiency.

The presence of mismatch repair deficiency is frequently assessed in gastrointestinal and gynecologic neoplasms by surgical pathologists using immunohistochemical methods. Targeted next-generation sequencing (NGS) covering some genes in the mismatch repair complex is used with increasing frequency, however, the percent positive and negative agreement of immunohistochemical methods and NGS of mismatch repair genes is not well-described in the literature. We sought to compare performance of immunohistochemistry (IHC) and NGS of mismatch repair genes on our institutional targeted panel. We evaluated the concordance of immunohistochemical and panel-based gene sequencing methods in a retrospective cohort study of patients evaluated at our center with both immunohistochemical and panel-based sequencing. Our NGS panel covers only MLH1 and MSH2, whereas our immunohistochemical panel assesses for expression of MLH1, PMS2, MSH2, and MSH6. We identified 68 unique patients with both immunohistochemical evaluation of mismatch repair protein expression and NGS panel sequencing, of which 67 were suitable for analysis given the patterns of immunohistochemical loss of expression observed. The percent positive agreement for NGS with IHC was 50%, albeit with very rare positive cases (n=2/4). Percent negative agreement was also high at 100% (n=63/63). One case with loss of MLH1, PMS2, and MSH6 expression by IHC and no pathogenic variants by NGS exhibited MLH1 promoter hypermethylation. Percent negative agreement between immunohistochemical and NGS gene sequencing is high, although firm conclusions regarding percent positive agreement between NGS and IHC are limited by low numbers of positive cases in our cohort. In general, we consider the findings to support continued use of immunohistochemical methods to screen for the presence of mismatch repair deficiency and consider additional testing by NGS likely to add little diagnostic value in the context of intact immunohistochemical expression of mismatch repair proteins.

Socioeconomic Status and Rurality Among Patients With Head and Neck Cancer.

OBJECTIVE: Describe the relationship among rurality, socioeconomic status (SES), and patient/tumor characteristics in patients presenting with head and neck cancer. STUDY DESIGN: Retrospective single-institution study. SETTING: Academic tertiary-level medical center. METHODS: Patients with head and neck cancer presenting between 2011 and 2015 were included. Stage at presentation, insurance status, and demographic characteristics were collected. Rurality was measured through Rural-Urban Continuum Codes. SES was measured by SES index scores of the Agency for Healthcare Research and Quality, which incorporate multiple components of SES. Associations among rurality, SES, and patient/tumor characteristics were assessed with univariate and multivariable statistics. All P values were calculated via 2-sided hypotheses. The threshold for statistical significance was set at P < .05. Statistical analyses were conducted with Stata/SE 14 (StataCorp). RESULTS: The study included 266 patients diagnosed with head and neck cancer between 2011 and 2015. Rural residence was associated with lower SES (P < .001). T and N stages were associated with rurality (P = .036 and .050, respectively). Higher educational status was associated with oropharyngeal cancer (P = .005). CONCLUSIONS: Rurality and SES have distinct impacts on patients with head and neck cancer. Specifically, rurality is associated with tumor stage among patients with head and neck cancer. Knowledge of disparities among patients with rural residency may help target interventions to facilitate earlier diagnosis.

Performance Characteristics of Mutational Signature Analysis in Targeted Panel Sequencing.

CONTEXT.­: Mutational signatures have been described in the literature and a few centers have implemented pipelines for clinical reporting. OBJECTIVE.­: To describe the performance of a mutational signature caller with clinical samples sequenced on a targeted next-generation sequencing panel with a small genomic footprint. DESIGN.­: One thousand six hundred eighty-two clinical samples were analyzed for the presence of mutational signatures using deconstructSigs on variant calls with at least 20 variant reads. RESULTS.­: Signature 10 (associated with POLe mutation) achieved separation of cases and controls in hypermutated samples. Signatures 4 (associated with tobacco smoking) and 7 (associated with ultraviolet radiation) as an indicator of pulmonary or cutaneous primary sites showed moderate sensitivity and high specificity at optimal cutpoints. Mutational signatures in malignancies with unknown primaries were somewhat consistent with the clinically suspected primary site, with an apparent dose-response relationship between the number of variants analyzed and the ability of mutational signature analysis to correctly suggest a primary site. CONCLUSIONS.­: Mutational signatures represent an opportunity for orthogonal testing of primary site, which may be particularly useful in supporting cutaneous or pulmonary sites in poorly differentiated neoplasms. Tobacco smoking, ultraviolet radiation, and POLe mutational signatures are the most appropriate signatures for implementation. Even relatively small numbers of variants appear capable of supporting a clinically suspected primary.

Plasma as an alternative COVID-19 diagnostic specimen in a hospitalized patient negative for SARS-CoV-2 by nasopharyngeal swab.

We present the case of an inpatient with pneumonia and repeatedly negative nasopharyngeal SARS-CoV-2 testing. In such challenging cases, alternative diagnostic options include lower respiratory tract and plasma SARS-CoV-2 RNA testing, of which the latter may be particularly useful where bronchoscopy is deferred due to clinical factors or transmission risk.

Is Merkel Cell Carcinoma of Lymph Node Actually Metastatic Cutaneous Merkel Cell Carcinoma?

OBJECTIVES: The possibility of a so-called primary lymph node neuroendocrine carcinoma has been described in the literature. Here we evaluate cases fitting such a diagnosis and find that the cases demonstrate a convincing and pervasive pattern consistent with metastatic Merkel cell carcinoma. METHODS: Six cases of primary lymph node Merkel cell carcinoma and one case of metastatic neuroendocrine carcinoma at a bony site, all with unknown primary, were sequenced using a combination of whole-exome and targeted panel methods. Sequencing results were analyzed for the presence of an ultraviolet (UV) mutational signature or off-target detection of Merkel cell polyomavirus (MCPyV). RESULTS: Four of six primary lymph node cases were positive for a UV mutational signature, with the remaining two cases positive for off-target alignment of MCPyV. One case of neuroendocrine carcinoma occurring at a bony site was also positive for a UV mutational signature. CONCLUSIONS: We find no evidence to corroborate the existence of so-called primary Merkel cell carcinoma of lymph node.

Fibroblast levels are increased in chronic rhinosinusitis with nasal polyps and are associated with worse subjective disease severity.

BACKGROUND: Fibroblasts are implicated in tissue remodeling and recruitment of inflammatory cells in chronic rhinosinusitis (CRS). Populations of fibroblasts remain unquantified in CRS subtypes. The objectives of this study were to measure fibroblast populations in subtypes of CRS, and to investigate the association between fibroblasts and disease severity. METHODS: Patients undergoing endoscopic sinus surgery (ESS) for CRS were prospectively enrolled from January 2011 to December 2014. Control subjects included patients undergoing endoscopic surgery for non-inflammatory conditions such as cerebrospinal fluid leak repair or non-hormone-secreting pituitary tumors. Patients completed 22-item Sino-Nasal Outcome Test (SNOT-22) questionnaires prior to surgery. Blood and tissue biopsies were taken during surgery. Percent of sinonasal fibroblasts was determined via flow cytometry by selecting fibroblast-specific protein (FSP)-positive and Mucin 1 (MUC1)-negative cells. RESULTS: A total of 69 patients were enrolled: control (n = 24), CRS without nasal polyps (CRSsNP) (n = 13), CRS with nasal polyps (CRSwNP) (n = 22), and allergic fungal rhinosinusitis (AFRS) (n = 10). Patients with CRSwNP had significantly more fibroblasts than both control (p < 0.001) and CRSsNP (p < 0.01). Patients with AFRS had the most fibroblasts when compared to control (p < 0.0001), CRSsNP (p < 0.0001), and CRSwNP (p < 0.05). Atopy and asthma were not associated with increased fibroblasts in CRSwNP (p = 0.21, p = 0.26, respectively). Increased fibroblasts correlated with subjective disease severity as measured by SNOT-22 for CRSwNP (p = 0.003) and AFRS (p = 0.048). CONCLUSION: Sinonasal fibroblasts are increased in CRSwNP and AFRS compared to control and CRSsNP. Increased fibroblasts correlated with worse quality of life in CRSwNP and AFRS.

Predictors of 30-day morbidity and mortality in transnasal microscopic pituitary tumor excision.

BACKGROUND: There is a lack of population-based, multi-institutional analyses of factors associated with morbidity and mortality following pituitary tumor excision. METHODS: The American College of Surgeons National Surgical Quality Improvement Project files were used to compile information on patients that had undergone transnasal microscopic pituitary tumor resection from 2006 to 2012. Patient demographics, comorbidities, operative characteristics, and morbidity and mortality in the 30 days following surgery were included. Multivariate logistic regression was used for categorical variables and multivariate linear regression was used for continuous variables to evaluate factors leading to adverse events. RESULTS: A total of 658 patients were included, of which 58 (8.81%) experienced a complication, reoperation or death in the 30 days following surgery. The most common complications were reoperation (3.37%), followed by unplanned reintubation (1.99%), urinary tract infection (1.68%), and transfusion (1.68%). Predictors of any complication, reoperation, or death include preoperative sepsis (odds ratio [OR] = 7.596) and lower preoperative serum albumin (OR = 6.667). Younger age predicted surgical complications (OR = 1.105). Predictors of medical complications include higher body mass index (OR = 1.112), chronic steroid use (OR = 6.568), preoperative sepsis (OR = 15.297), and lower preoperative serum hematocrit (OR = 1.225). Predictors of increased total length of hospital stay were older age (ß = 0.146), higher body mass index (ß = 0.188), chronic steroid use (ß = 0.142), preoperative sepsis (ß = 0.489), and lower preoperative serum albumin (ß = -0.213). CONCLUSION: Although adverse events following pituitary tumor excision are low, awareness of factors associated with morbidity and mortality in the early postoperative period may allow for improved patient monitoring and outcomes.

Protecting the airway and the physician: Aspects of litigation arising from tracheotomy.

BACKGROUND: In recent decades, medical malpractice costs have increased and have led to a change in the way physicians practice medicine. Tracheotomies are cases in which complications have a high risk of morbidity and mortality and the potential for litigation. METHODS: The Westlaw legal database was used to gather data on 43 jury verdicts and settlements from 1987 to 2013. Various factors included outcome, defendant specialty, and the reason for litigation. RESULTS: Median settlements were $500,000 and median verdict awards were $2,000,000. Postoperative negligence was alleged most often (81%) followed by intraoperative negligence (27.9%) and permanent injury (18.6%). Otolaryngologists were named as defendants most often (25.6%), with nurses named second most often. Pediatric cases had significantly higher awards and were more often named in favor of the plaintiff. CONCLUSION: An awareness of tracheotomy malpractice litigation has the potential to both help physicians avoid future litigation and improve patient safety.

Multi-institutional study of risk factors for perioperative morbidity following transnasal endoscopic pituitary adenoma surgery.

BACKGROUND: The goal of this study was to identify preoperative risk factors associated with increased perioperative morbidity after endoscopic pituitary surgery. METHODS: A retrospective review of patients undergoing endoscopic pituitary adenoma surgery between 2002 and 2014 at 6 international centers was performed. Standard demographic and comorbidity data, as well as information regarding tumor extent and treatment were collected. Logistic regression was used to examine risk factors for the following 30-day outcomes: systemic complications, intracranial complications, postoperative cerebrospinal fluid (CSF) leaks, length of hospital stay, readmission, and reoperation. RESULTS: Data was collected on 982 patients with a mean age of 52 years. The median body mass index (BMI) for all patients was 30.9 kg/m(2) with 56% female. The median hospital stay was 5 days and 23.8% of patients suffered a postoperative adverse event. Systemic complications occurred in 3.2% of patients and intraventricular extension was a risk factor (odds ratio [OR] 8.9). Intracranial complications occurred in 7.3% of patients and risk factors included previous radiation (OR 8.6) and intraventricular extension (OR 7.9). Reoperation occurred in 6.5% of patients and intraventricular extension (OR 7.3) and age (<40 years, OR 3.5; 40 to 64 years, OR 3.2) were risk factors. Postoperative CSF leaks occurred in 5.5% of patients and risk factors included female gender (OR 2.4), BMI ≥ 30 (OR 2.1), age (<40 years, OR 5.3; 40 to 64 years, OR, 7.9), and intraventricular extension (OR, 9.5). CONCLUSION: Postoperative endoscopic pituitary adenoma surgery complications are associated with tumors with intraventricular extension, preoperative radiation, as well as common patient comorbidities. Identification of these factors may permit implementation of strategies to reduce postoperative complications.

Vitamin D for the treatment of respiratory diseases: is it the end or just the beginning?

A large number of human, animal and in vitro studies have suggested that vitamin D3 (VD3) plays a critical role in inflammatory airway diseases such as asthma, chronic rhinosinusitis, and allergic rhinitis. VD3 acts upon a broad range of immune cells involved in the pathogenesis of these diseases including T-cells, dendritic cells (DCs), macrophages, and B-cells. In addition, VD3 can also regulate the functions of a number of non-immune cells including epithelial cells, fibroblasts, and smooth muscle cells. Given that VD3 has known effects on the immune system, it seems logical that supplementation with VD3 would prove efficacious in the treatment of these three diseases. While many studies, most of which are observational, have suggested that VD3 deficiency is associated with more severe disease, VD3 supplementation trials in humans have resulted in varied outcomes in terms of efficacy. In this review article we will discuss the role of VD3 in these three commonly associated respiratory diseases. We will explore the literature describing associations of VD3 deficiency with patient outcomes, cells in the respiratory microenvironment susceptible to VD3 regulation, conflicting results of VD3 supplementation trials, and potential gaps in our knowledge that may be limiting the widespread use of VD3 for the treatment of respiratory diseases such asthma, chronic rhinosinusitis and allergic rhinitis. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Hockey-related facial injuries: a population-based analysis.

OBJECTIVES/HYPOTHESIS: Recognition of the potentially severe sequelae arising from inadequate facial protection has facilitated sustained efforts to increase the use of protective visors in recent decades. Our objective was to characterize nationwide trends among patients presenting to emergency departments (ED) for facial injuries sustained while playing ice hockey. METHODS: The National Electronic Injury Surveillance System was searched for hockey-related facial injuries, with analysis for incidence; age and gender; and specific injury diagnoses, mechanisms, and facial locations. RESULTS: There were an estimated 93,444 ED visits for hockey-related facial injuries from 2003 to 2012. The number of annual ED visits declined by 43.8% from 2003 to 2012. A total of 90.6% of patients were male; and the peak age of injury was 17 years. Lacerations were the most common form of facial injury (81.5% of patients) across all age groups. Contusions/abrasions and fractures followed in frequency, with fractures increasing with advancing age. CONCLUSIONS: The overall incidence of ED visits due to facial injuries from ice hockey has significantly decreased over the last decade, concurrent with increased societal use of facial protective equipment. Nonetheless, facial hockey injuries facilitate a significant number of ED visits among both adults and children; thus, the knowledge of demographic-specific trends described in this analysis is relevant for physicians involved in the management of facial trauma. These findings reinforce the need to educate individuals who play hockey about the importance of appropriate facial protection.

Recent randomized controlled trials in otolaryngology.

OBJECTIVE: To assess recent trends in the prevalence and quality of reporting of randomized controlled trials (RCTs) in 4 otolaryngology journals. STUDY DESIGN: Methodology and reporting analysis. SETTING: Randomized controlled trials in 4 otolaryngology journals. SUBJECTS AND METHODS: All RCTs published from 2011 to 2013 in 4 major otolaryngology journals were examined for characteristics of study design, quality of design and reporting, and funding. RESULTS: Of 5279 articles published in 4 leading otolaryngology journals from 2011 to 2013, 189 (3.3%) were RCTs. The majority of RCTs were clinical studies (86%), with the largest proportion consisting of sinonasal topics (31%). Most interventions were medical (46%), followed by surgical (38%) and mixed (16%). In terms of quality, randomization method was reported in 54% of RCTs, blinding in 33%, and adverse events in 65%. Intention-to-treat analysis was used in 32%; P values were reported in 87% and confidence intervals in 10%. Research funding was most often absent or not reported (55%), followed by not-for-profit (25%). CONCLUSIONS: Based on review of 4 otolaryngology journals, RCTs are still a small proportion of all published studies in the field of otolaryngology. There seem to be trends toward improvement in quality of design and reporting of RCTs, although many quality features remain suboptimal. Practitioners both designing and interpreting RCTs should critically evaluate RCTs for quality.