Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-offunction DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed highresolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-leftright dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.Keywords: left-right dynein; primary ciliary dyskinesia; normal ciliary ultrastructure; immunofluorescence microscopy; transmission electron microscopy Clinical RelevanceConventional transmission electron microscopy (TEM) is not diagnostic for approximately 30% of primary ciliary dyskinesia (PCD) cases because they have normal ciliary ultrastructure; DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its molecular characterization in human respiratory cilia is completely lacking. We show that DNAH11 distinctly localizes to the proximal region of respiratory cilia, independently of all previously described factors governing dynein arm assembly. TEM tomography detects a partial reduction of outer dynein arms in only the proximal region of DNAH11-deficient cilia. This helps explain why DNAH11 mutations result in normal ciliary ultrastructure and hyperkinetic ciliary beating and suggests a novel mode of axonemal assembly in respiratory cilia.

Background Heart failure (HF) inpatient mortality prediction models can help clinicians make treatment decisions and researchers conduct observational studies. Published models have not been validated in external populations, however. Methods and Results We compared the performance of seven models that predict inpatient mortality in patients hospitalized with acute decompensated heart failure (ADHF): Four HF-specific mortality prediction models developed from three clinical databases (Acute Decompensated HF National Registry [ADHERE], Enhanced Feedback for Effective Cardiac Treatment [EFFECT] Study, Get with the Guidelines-HF [GWTG-HF] Registry); two administrative HF mortality prediction models (Premier, Premier+); and a model that uses clinical data but is not specific for HF (Laboratory-Based Acute Physiology Score [LAPS2]). Using a multi-hospital electronic health record-derived (EHR) dataset (HealthFacts [Cerner Corp], 2010–2012), we identified patients ≥18 years admitted with HF. Of 13,163 eligible patients, median age was 74 years; half were women; and 27% were black. In-hospital mortality was 4.3%. Model predicted mortality ranges varied: Premier+ (0.8–23.1%), LAPS2 (0.7–19.0%), ADHERE (1.2–17.4%), EFFECT (1.0–12.8%), GWTC-Eapen (1.2–13.8%), and GWTG-Peterson (1.1–12.8%). The LAPS2 and Premier models outperformed the clinical models (c-statistics: LAPS2 0.80 [95% CI: 0.78–0.82], Premier models 0.81 [95% CI: 0.79–0.83]) and 0.76 [95% CI: 0.74–0.78]; clinical models 0.68–0.70). Conclusions Four clinically-derived inpatient HF mortality models exhibited similar performance, with c-statistics near 0.70. Three other models, one developed in EHR data and two developed in administrative data, also were predictive, with c-statistics from 0.76–0.80. Because every model performed acceptably, the decision to use a given model should depend on practical concerns and intended use.

For stable angina, the benefits of percutaneous coronary intervention (PCI) are limited to symptom relief, but patients often believe that PCI prevents myocardial infarction (MI). Whether presenting accurate information about the benefits of PCI would dispel these beliefs remains unknown. We hypothesized that explanatory information would be more effective for influencing volunteers' beliefs. OBJECTIVE To assess the effect of explicit and explanatory information on participants' beliefs about PCI and their willingness to choose it. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized trial in 2012 among adults older than 50 years living in the general community. We recruited participants using the Internet. INTERVENTIONS Participants read 1 of 3 scenarios in which they experienced class I angina and were referred to a cardiologist. The cardiologist provided no information about the effects of PCI on MI risk, a specific statement that PCI does not reduce MI risk, or an explanation of why PCI does not reduce MI risk. MAIN OUTCOMES AND MEASURES Participants' beliefs about the benefit of PCI and choice of PCI and medication. RESULTS A total of 1257 participants (90.0%) completed the survey; 54.5% chose PCI. Compared with those receiving explicit and explanatory information, those receiving no information were most likely to believe that PCI prevents MI (71.0% vs 38.7% vs 30.6%, respectively; P < .001), most likely to choose PCI (69.4% vs 48.7% vs 45.7%, respectively; P < .001), and least likely to agree to medication therapy (83.1% vs 87.4% vs 92.3%, respectively; P < .001). Across the entire sample, the decision to have PCI was strongly correlated with the belief that PCI would prevent MI (odds ratio, 5.82 [95% CI, 4.13-8.26]) and that the participant would feel less worried (odds ratio, 5.36 [95% CI, 3.87-7.45]), but was not associated with how much participants were limited by symptoms. CONCLUSIONS AND RELEVANCE In the setting of mild, stable angina, most people assume PCI prevents MI and are likely to choose it. Explicit information can partially overcome that bias and influence decision making. Explanatory information was the most effective intervention in overcoming this bias.