Heparin Does Not Regulate Circulating Human PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) in a General Population-Brief Report.

BACKGROUND: PCSK9 (proprotein convertase subtilisin-kexin type 9) chaperones the hepatic LDLR (low-density lipoprotein receptor) for lysosomal degradation, elevating serum LDL (low-density lipoprotein) cholesterol and promoting atherosclerotic heart disease. Though the major effect on the hepatic LDLR comes from secreted PCSK9, the details of PCSK9 reuptake into the hepatocyte remain unclear. In both tissue culture and animal models, HSPGs (heparan sulfate proteoglycans) on hepatocytes act as co-receptors to promote PCSK9 reuptake. We hypothesized that if this PCSK9:HSPG interaction is important in humans, disrupting it with unfractionated heparin (UFH) would acutely displace PCSK9 from the liver and increase plasma PCSK9. METHODS: We obtained remnant plasma samples from 160 subjects undergoing cardiac catheterization before and after administration of intravenous UFH. PCSK9 levels were determined using a commercial enzyme-linked immunosorbent assay. RESULTS: Median plasma PCSK9 was 113 ng/mL prior to UFH and 119 ng/mL afterward. This difference was not significant (P=0.83 [95% CI, -6.23 to 6.31 ng/mL]). Equivalence testing provided 95% confidence that UFH would not raise plasma PCSK9 by > 4.7%. Among all subgroups, only subjects with the lowest baseline PCSK9 concentrations exhibited a response to UFH (8.8% increase, adj. P=0.044). A modest correlation was observed between baseline plasma PCSK9 and the change in plasma PCSK9 due to UFH (RS=-0.3634; P<0.0001). CONCLUSIONS: Administration of UFH does not result in a clinically meaningful effect on circulating PCSK9 among an unselected population of humans. The results cast doubt on the clinical utility of disrupting the PCSK9:HSPG interaction as a general therapeutic strategy for PCSK9 inhibition. However, the observations suggest that in selected populations, disrupting the PCSK9:HSPG interaction could still affect PCSK9 reuptake and offer a therapeutic benefit.

Development and application of an electronic synoptic report for reporting and management of low-dose computed tomography lung cancer screening examination.

BACKGROUND: Interpretation of Low Dose CT scans and protocol driven management of findings is a key aspect of lung cancer screening program performance. Reliable and reproducible methods are needed to communicate radiologists' interpretation to the screening program or clinicians driving management decision. METHODS: We performed an audit of a subset of dictated reports from the PANCAN study to assess for omissions. We developed an electronic synoptic reporting tool for radiologists embedded in a clinical documentation system software. The tool was then used for reporting as part of the Alberta Lung Cancer Screening Study and McGill University Health Centre Pilot Lung Cancer Screening Program. RESULTS: Fifty reports were audited for completeness. At least one omission was noted in 30 (70%) of reports, with a major omission (missing lobe, size, type of nodule in report or actionable incidental finding in recommendation section of report) in 24 (48%). Details of the reporting template and functionality such as automated nodule cancer risk assessment, Lung-RADS category assignment, auto-generated narrative type report as well as personalize participant results letter is provided. A description of the system's performance in its application in 2815 CT reports is then summarized. CONCLUSIONS: We found that narrative type radiologist reports for lung cancer screening CT examinations frequently lacked specific discrete data elements required for management. We demonstrate the successful implementation of a radiology synoptic reporting system for use in lung cancer screening, and the use of this information to drive program management and communications.

High-Throughput Synthesis, Analysis, and Optimization of Injectable Hydrogels for Protein Delivery.

The development of in situ-gelling hydrogels that can enable prolonged protein release is increasingly important due to the emergence of a growing number of protein-based therapeutics. Herein, we describe a high-throughput strategy to fabricate, characterize, and subsequently optimize hydrazone-cross-linked in situ-gelling hydrogels for protein delivery. Hydrogels are fabricated using an automated high-throughput robot to mix a variety of thermoresponsive, nonthermoresponsive, charged, neutral, naturally sourced, and synthetic polymers functionalized with hydrazide or aldehyde groups, generating in situ-gelling hydrogels with well-defined compositions within a 96-well plate. High-throughput characterization strategies are subsequently developed to enable on-plate analysis of hydrogel swelling, mechanics, degradation, transparency, and protein (ovalbumin) release kinetics that yield results consistent with those collected using traditional bulk hydrogel analysis techniques. Dynamic regression and latent variable modeling are then applied to fit performance statistics to the collected data set; subsequently, numerical optimization is used to identify mixtures of precursor polymers that exhibit targeted combinations of minimal burst release, maximum total protein release, minimum release rate, and maximum transparency (the latter of particular relevance for ophthalmic protein delivery applications). Given the rapid throughput of the protocols developed (i.e., 126 hydrogels can be synthesized and screened in quadruplicate within hours), this approach offers particular promise for accelerating the identification of injectable hydrogel compositions relevant for both protein delivery as well as other biomedical applications for which clearly predefined materials properties are required.

Combined medical-interventional approaches for the management of complex fungal balls: a case series as a viable alternative in non-surgical patients.

Intracavitary pulmonary aspergilloma is a persistent and life-threatening infection that carries a mortality rate of up to 15%. It occurs when Aspergillus species gain entry to an existing lung cavity. In the absence of definitive treatment, patients may succumb to severe complications such as massive hemoptysis, cachexia, or secondary infections. Aspergillomas often show limited response to antifungal medications, mainly due to insufficient drug concentrations within the cavities. Surgery is frequently the preferred treatment option, but it poses significant risks, and many individuals are ineligible due to underlying health issues. We present the most extensive non-surgical fungal ball cohort to date, managed using an innovative multimodal strategy that combines antifungal therapy before and after bronchoscopic debulking. This was a cross-sectional observational study. For those who cannot undergo surgery, our medical center has pioneered a multimodal approach to aspergilloma resection. This approach combines bronchoscopic endoscopy with antifungal therapy and has been applied successfully to more than 18 patients that are presented in this series. The median age of the cohort was 58 years (range: 32-73), with an equal sex distribution. The mean percent predicted FEV1 was 65.3%. The mean follow-up duration was 3.6 years (range: 0.5-10 years). The cohort receiving antifungals systematically prior to debridement showed a reduction of the pre-existing cavity (40.38 mm versus 34.02 mm, p = 0.021). Across the 18 patients during the follow-up period, 94% remained recurrence-free (defined by symptoms and radiology). Our study fills a critical knowledge gap regarding the significance of initiating antifungal treatment before bronchoscopic debulking and presents a viable approach in these cases for which there is a current unmet therapeutic need.

The use of both medical and interventional methods to treat difficult fungal masses: A collection of cases showing efficacy for patients who can't undergo surgeryIntracavitary pulmonary aspergilloma is a serious and potentially deadly infection with a death rate of up to 15%. It happens when certain types of fungi invade existing lung cavities. Without proper treatment, patients may experience severe complications like heavy bleeding from the lungs, weight loss, or other infections. Traditional antifungal medications often don't work well because they can't reach high enough concentrations in the cavities. Surgery is usually the best option, but it's risky and not possible for many due to other health problems. Our study introduces a new way to treat aspergilloma without surgery. We've treated a significant number of patients using a combination of antifungal drugs and a procedure called bronchoscopic debulking. This involves removing the fungal growth using a thin tube inserted through the airways. Our research involved observing 18 patients treated this way. They were mostly middle-aged, with equal numbers of men and women. Their lung function was moderately impaired, and we followed them for an average of 3.6 years. We found that giving antifungal drugs before the debulking procedure helped reduce the size of the cavities. After treatment, almost all patients remained free of symptoms and signs of recurrence. This study highlights the importance of starting antifungal therapy before bronchoscopic debulking and offers a promising option for patients who can't have surgery.

Procedural success and long-term outcomes of aspiration thrombectomy for the treatment of stent thrombosis.

BACKGROUND: Stent thrombosis (ST) is associated with a significant burden of coronary thrombus and potential microvascular obstruction. Aspiration thrombectomy may decrease the extent of microvascular obstruction in patients with acute myocardial infarction but its role in the treatment of ST is uncertain. The present study sought to evaluate the association between aspiration thrombectomy, procedural success and long-term outcomes among patients presenting with ST. METHODS: In a multicenter cohort of patients with definite ST, procedural success, long-term mortality, and major adverse cardiovascular events (death, stroke, re-infarction, revascularization) were ascertained. Propensity weighting was used to determine the association between aspiration thrombectomy and long-term outcomes. RESULTS: A total of 205 patients with ST were identified. Among these, 115 (56%) patients underwent adjunctive aspiration thrombectomy during percutaneous coronary intervention. Patients undergoing aspiration thrombectomy were more likely to present with ST-elevation myocardial infarction (75% vs. 52%, P < 0.003) and require hemodynamic support (19% vs. 10%, P = 0.07). Aspiration thrombectomy was associated with improved procedural outcomes including postprocedural TIMI 3 flow, resulting in higher angiographic and procedural success (each 96% vs. 83%, P < 0.001). Despite improved angiographic outcomes, the use of aspiration thrombectomy was not associated with a difference in long-term mortality (adjusted HR 0.99, 95% CI 0.44-2.24) or major adverse cardiovascular events (adjusted HR 1.06, 95% CI 0.45-2.48). CONCLUSIONS: Aspiration thrombectomy is associated with improved coronary flow and procedural success but is not associated with improved long-term outcomes among patients undergoing percutaneous intervention for definite ST. CLINICAL TRIAL REGISTRATION: NCT00931502 (http://www.clinicaltrials.gov/ct2/show/NCT00931502)

Angiographically confirmed stent thrombosis in contemporary practice: insights from intravascular ultrasound.

OBJECTIVE: We hypothesized that patients presenting with stent thrombosis (ST) have a high prevalence of stent underexpansion and malapposition when assessed by intravascular ultrasound (IVUS). BACKGROUND: IVUS can provide mechanistic insight into mechanical factors, including stent underexpansion, malapposition, and fracture that may predispose to ST. METHODS: All consecutive cases of angiographically confirmed ST from a multicenter registry (from 2005 to 2010) were reviewed. All IVUS images were reviewed off-line for the presence of stent underexpansion, malapposition, and fracture. Kaplan-Meier analysis was used to determine whether use of IVUS at the time of ST was associated with long-term mortality and major adverse cardiovascular events. RESULTS: IVUS was performed in 32 of 173 subjects with ST (18%). Stent underexpansion was present in 82% of cases and in all cases of early ST, with a mean stent expansion of 0.7 ± 0.23 by MUSIC criteria. Stent malapposition was most frequently observed in very late ST (40%). In-hospital mortality was similar between subjects who had IVUS performed at the time of ST when compared with the non-IVUS group (3.2% vs. 4.3%, P = 0.8). Subjects who had IVUS performed at the time of ST had lower rates of mortality (HR 0.4, 95% CI 0.1-1.6, P =0.2) and major adverse cardiovascular events (HR 0.5, 95% CI 0.2-1.4, P =0.2) at follow-up, but these values were not statistically significant. CONCLUSIONS: There is a high prevalence of stent underexpansion in early ST, while the prevalence of malapposition is higher in very late ST. Use of IVUS during treatment for ST may identify mechanisms underlying the development of ST.

Atrioesophageal Fistula Rates Before and After Adoption of Active Esophageal Cooling During Atrial Fibrillation Ablation.

BACKGROUND: Active esophageal cooling reduces the incidence of endoscopically identified severe esophageal lesions during radiofrequency (RF) catheter ablation of the left atrium for the treatment of atrial fibrillation. A formal analysis of the atrioesophageal fistula (AEF) rate with active esophageal cooling has not previously been performed. OBJECTIVES: The authors aimed to compare AEF rates before and after the adoption of active esophageal cooling. METHODS: This institutional review board (IRB)-approved study was a prospective analysis of retrospective data, designed before collecting and analyzing the real-world data. The number of AEFs occurring in equivalent time frames before and after adoption of cooling using a dedicated esophageal cooling device (ensoETM, Attune Medical) were quantified across 25 prespecified hospital systems. AEF rates were then compared using generalized estimating equations robust to cluster correlation. RESULTS: A total of 14,224 patients received active esophageal cooling during RF ablation across the 25 hospital systems, which included a total of 30 separate hospitals. In the time frames before adoption of active cooling, a total of 10,962 patients received primarily luminal esophageal temperature (LET) monitoring during their RF ablations. In the preadoption cohort, a total of 16 AEFs occurred, for an AEF rate of 0.146%, in line with other published estimates for procedures using LET monitoring. In the postadoption cohort, no AEFs were found in the prespecified sites, yielding an AEF rate of 0% (P < 0.0001). CONCLUSIONS: Adoption of active esophageal cooling during RF ablation of the left atrium for the treatment of atrial fibrillation was associated with a significant reduction in AEF rate.

Contemporary clinical characteristics, treatment, and outcomes of angiographically confirmed coronary stent thrombosis: results from a multicenter California registry.

OBJECTIVES: To describe the contemporary treatment and outcomes for patients with angiographically confirmed (definite) stent thrombosis (ST). BACKGROUND: Limited data are available on contemporary treatment patterns and outcomes of patients with ST in the United States. METHODS: In this multicenter California registry, consecutive cases of definite ST over 5 years were identified. Clinical characteristics, in-hospital outcomes, and long-term survival are reported. RESULTS: One hundred and sixty five consecutive episodes of ST were identified in 153 patients from January 2005 to February 2010. The distribution of acute (≤24 hr), subacute (24 hr to 30 days), late (30 days to 1 year), and very late (≥1 year) ST was 3.9%, 21.8%, 17.6%, and 50.3%, respectively. Only 41.2% of patients were on dual antiplatelet therapy at the time of presentation, while 22.4% of patients were on none. Of the 61.4% of patients treated with restenting, 71.1% of them received a drug-eluting stent. Procedural success was 88.1%, and in-hospital death, stroke, and CABG occurred in 5.5%, 0.6%, and 6.1% of subjects, respectively. All-cause mortality at 1 year was 14.3%. Although female gender, diabetes mellitus (DM), bifurcation disease, ejection fraction <40%, and cardiogenic shock at the time of presentation were associated with an increased risk of in-hospital mortality, only DM (P = 0.047) and bifurcation disease (P = 0.027) remained independent predictors of in-hospital death. CONCLUSION: In-hospital mortality from definite ST is lower than previously reported, but long-term mortality remains high. DM and bifurcation disease, but not type of percutaneous therapy, are independently associated with in-hospital mortality.

Can preoperative computed tomography of the chest predict completeness of the major pulmonary fissure at surgery?

BACKGROUND: An incomplete major pulmonary fissure can make anatomic lung resection technically more difficult and may increase the risk of complications, such as prolonged postoperative air leak. The objective of this study was to determine if preoperative computed tomography (CT) of the chest could accurately predict the completeness of the major pulmonary fissure observed at the time of surgery. METHODS: From October 2008 to June 2009, patients at a single university institution were enrolled if they underwent surgery for a pulmonary nodule, mass or known cancer. At the time of surgery, completeness of the major pulmonary fissure was graded 1 if pulmonary lobes were entirely separate, 2 if the visceral cleft was complete with an exposed pulmonary artery at the base with some parenchyma fusion, 3 if the visceral cleft was only evident for part of the fissure without a visible pulmonary artery and 4 if the fissure was absent. The preoperative CT scan of each patient was graded by a single, blinded chest radiologist using the same scale. We used the Pearson χ2 test with 2-tailed significance to test the independence of the operative and radiologic grading. RESULTS: In 48% (29 of 61) of patients, the radiologic and operative grading were the same. Of those graded differently, 94% (30 of 32) were within 1 grade. Despite this agreement, we observed no statistically significant correlation between the operative and radiologic grading (p = 0.24). CONCLUSION: The major fissure can often be well-visualized on a preoperative CT scan, but preoperative CT cannot accurately predict the completeness of the major pulmonary fissure discovered at surgery.

Pregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection.

Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.

Effects of pimobendan in cats with hypertrophic cardiomyopathy and recent congestive heart failure: Results of a prospective, double-blind, randomized, nonpivotal, exploratory field study.

BACKGROUND: The benefits of pimobendan in the treatment of congestive heart failure (CHF) in cats with hypertrophic cardiomyopathy (HCM) have not been evaluated prospectively. HYPOTHESIS/OBJECTIVES: To investigate the effects of pimobendan in cats with HCM and recent CHF and to identify possible endpoints for a pivotal study. We hypothesized that pimobendan would be well-tolerated and associated with improved outcome. ANIMALS: Eighty-three cats with HCM and recently controlled CHF: 30 with and 53 without left ventricular outflow tract obstruction. METHODS: Prospective randomized placebo-controlled double-blind multicenter nonpivotal field study. Cats received either pimobendan (0.30 mg/kg q12h, n = 43), placebo (n = 39), or no medication (n = 1) together with furosemide (<10 mg/kg/d) with or without clopidogrel. The primary endpoint was a successful outcome (ie, completing the 180-day study period without a dose escalation of furosemide). RESULTS: The proportion of cats in the full analysis set population with a successful outcome was not different between treatment groups (P = .75). For nonobstructive cats, the success rate was 32% in pimobendan-treated cats versus 18.2% in the placebo group (odds ratio [OR], 2.12; 95% confidence interval [CI], 0.54-8.34). For obstructive cats, the success rate was 28.6% and 60% in the pimobendan and placebo groups, respectively (OR, 0.27; 95% CI, 0.06-1.26). No difference was found between treatments for the secondary endpoints of time to furosemide dose escalation or death (P = .89). Results were similar in the per-protocol sets. Adverse events in both treatment groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: In this study of cats with HCM and recent CHF, no benefit of pimobendan on 180-day outcome was identified.

Cooling or Warming the Esophagus to Reduce Esophageal Injury During Left Atrial Ablation in the Treatment of Atrial Fibrillation.

Ablation of the left atrium using either radiofrequency (RF) or cryothermal energy is an effective treatment for atrial fibrillation (AF) and is the most frequent type of cardiac ablation procedure performed. Although generally safe, collateral injury to surrounding structures, particularly the esophagus, remains a concern. Cooling or warming the esophagus to counteract the heat from RF ablation, or the cold from cryoablation, is a method that is used to reduce thermal esophageal injury, and there are increasing data to support this approach. This protocol describes the use of a commercially available esophageal temperature management device to cool or warm the esophagus to reduce esophageal injury during left atrial ablation. The temperature management device is powered by standard water-blanket heat exchangers, and is shaped like a standard orogastric tube placed for gastric suctioning and decompression. Water circulates through the device in a closed-loop circuit, transferring heat across the silicone walls of the device, through the esophageal wall. Placement of the device is analogous to the placement of a typical orogastric tube, and temperature is adjusted via the external heat-exchanger console.

Congenital anomalies of coronary arteries: role in the pathogenesis of sudden cardiac death.

After hypertrophic cardiomyopathy, coronary artery anomalies of origin from the wrong sinus of Valsalva are the second most common cause of sudden death on the athletic field in the USA. Although the right coronary artery arising from the left coronary sinus (ARCA) is four times as common as the left coronary artery arising from the anterior sinus (ALCA), it is the latter that is by far the more common cause of sudden death with or shortly after vigorous physical activity. Of the four types of ALCA, the interarterial type, where the left coronary artery passes anteriorly between the aorta and the right ventricular outflow tract, is the only type that places the patient at risk of sudden death. Another feature of this syndrome is the fact that sudden death occurs associated with or shortly after vigorous exercise and is very unusual after the patient is > 35 years of age. The mechanism by which there is sudden occlusion of the interarterial coronary artery is at present unknown, although there are a number of hypotheses involving the oblique passage of the vessel as it leaves the aorta. Sudden death is probably rare considering the number of people who have these anomalies. Symptoms premonitory to a fatal event such as exertional syncope, chest pain, or palpitations are probably common in patients at risk, and surgical correction is indicated in symptomatic patients at any age. In older asymptomatic patients, surgery is not recommended, since the incidence of sudden death in this age group is extremely small. In asymptomatic young patients, a stress test, preferably with radioisotope myocardial perfusion imaging or stress echocardiogram, should be done and surgical correction performed in those with ischemia provoked in the appropriate myocardial region. Since there is evidence that in patients who have survived a potentially fatal event, it is rare to be able to provoke ischemia with equal or greater exercise than had precipitated the malignant arrhythmia, the decision to surgically correct an asymptomatic young patient, serendipitously found to have ALCA, who has a negative exercise test, is debatable. Any decision for surgery in such patients should be made only after a full discussion of the risks pro and con surgery with the patient and the patient's family.

Radiation dose from initial trauma assessment and resuscitation: review of the literature.

BACKGROUND: Trauma care benefits from the use of imaging technologies. Trauma patients and trauma team members are exposed to radiation during the continuum of care. Knowledge of exposure amounts and effects are important for trauma team members. METHODS: We performed a review of the published literature; keywords included "trauma," "patients," "trauma team members," "wounds," "injuries," "radiation," "exposure," "dose" and "computed tomography" (CT). We also reviewed the Board on Radiation Effects Research (BEIR VII) report, published in 2005 and 2006. RESULTS: We found no randomized controlled trials or studies. Relevant studies demonstrated that CT accounts for the single largest radiation exposure in trauma patients. Exposure to 100 mSv could result in a solid organ cancer or leukemia in 1 of 100 people. Trauma team members do not exceed the acceptable occupation radiation exposure determined by the National Council of Radiation Protection and Management. Modern imaging technologies such as 16- and 64-slice CT scanners may decrease radiation exposure. CONCLUSION: Multiple injured trauma patients receive a substantial dose of radiation. Radiation exposure is cumulative. The low individual risk of cancer becomes a greater public health issue when multiplied by a large number of examinations. Though CT scans are an invaluable resource and are becoming more easily accessible, they should not replace careful clinical examination and should be used only in appropriate patients.

Echocardiographic determination of pulmonary arterial capacitance.

A growing body of evidence has demonstrated that pulmonary arterial capacitance (PAC) is the strongest hemodynamic predictor of clinical outcomes across a wide spectrum of cardiovascular disease, including pulmonary hypertension and heart failure. We hypothesized that a ratio of right ventricular stroke volume (RVOT VTI) to the associated peak arterial systolic pressure (PASP) could function as a reliable non-invasive surrogate for PAC. We performed a prospective study of patients undergoing simultaneous transthoracic echocardiography and right heart catheterization (RHC) for various clinical indications. Measurements of the RVOT VTI/PASP ratio from echocardiographic measurements were compared against PAC calculated from RHC measurements. Correlation coefficients and Bland-Altman analysis compared the RVOT VTI/PASP ratio with PAC. Forty-five subjects were enrolled, 38% were female and mean age was 54 years (SD 13 years). The reason for referral to RHC was most commonly post-heart transplant surveillance (40%), followed by heart failure (22%), and pulmonary hypertension (18%). Pre-capillary pulmonary hypertension was present in 18%, isolated post-capillary pulmonary hypertension was present in 13%, and combined pre-and post-capillary pulmonary hypertension was present in 29%. The RVOT VTI/PASP ratio was obtainable in the majority of patients (78%), and Pearson's correlation demonstrated moderately-strong association between PAC and the RVOT VTI/PASP ratio, r = 0.75 (P < 0.001). Bland-Altman analysis demonstrated good agreement between measurements without suggestion of systematic bias and a mean difference in standardized units of - 0.133. In a diverse population of patients and hemodynamic profiles, we validated that the ratio of RVOT VTI/PASP to be a reliably-obtained non-invasive marker associated with PAC.

Application of Lung-Screening Reporting and Data System Versus Pan-Canadian Early Detection of Lung Cancer Nodule Risk Calculation in the Alberta Lung Cancer Screening Study.

BACKGROUND: False-positive scans and resultant needless early recalls can increase harms and reduce cost-effectiveness of low-dose CT (LDCT) lung cancer screening. How LDCT scans are interpreted and classified may impact these metrics. METHODS: The Pan-Canadian Early Detection of Lung Cancer risk calculator was used to determine nodule risk of malignancy on baseline screening LDCTs in the Alberta Lung Cancer Screening Study, which were then classified according to Nodule Risk Classification (NRC) categories and ACR Lung Screening Reporting and Data System (Lung-RADS). Test performance characteristics and early recall rates were compared for each approach. RESULTS: In all, 775 baseline screens were analyzed. After a mean of 763 days (±203) of follow-up, lung cancer was detected in 22 participants (2.8%). No statistically significant differences in sensitivity, specificity, or area under the receiver operator characteristic curve occurred between the NRC and Lung-RADS nodule management approaches. Early recall rates were 9.2% and 9.3% for NRC and Lung-RADS, with the NRC unnecessarily recalling some ground glass nodules, and the Lung-RADS recalling many smaller solid nodules with low risk of malignancy. CONCLUSION: Performances of both the NRC and Lung-RADS in this cohort were very good with a trend to higher sensitivity for the NRC. Early recall rates were less than 10% with each approach, significantly lower than rates using the National Lung Screening Trial cutoffs. Further reductions in early recall rates without compromising sensitivity could be achieved by increasing the NRC threshold to 20% for ground glass nodules or by applying the nodule risk calculator with a 5% threshold to 6- to 10-mm solid nodules under Lung-RADS.

Comparison of pharmacodynamic variables following oral versus transdermal administration of atenolol to healthy cats.

OBJECTIVE: To describe the disposition of and pharmacodynamic response to atenolol when administered as a novel transdermal gel formulation to healthy cats. ANIMALS: 7 healthy neutered male client-owned cats. PROCEDURES: Atenolol was administered either orally as a quarter of a 25-mg tablet or as an equal dose by transdermal gel. Following 1 week of treatment, an ECG and blood pressure measurements were performed and blood samples were collected for determination of plasma atenolol concentration at 2 and 12 hours after administration. RESULTS: 2 hours after oral administration, 6 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 579 +/- 212 ng/mL. Two hours following transdermal administration, only 2 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 177 +/- 123 ng/mL. The difference in concentration between treatments was significant. Trough plasma atenolol concentrations of 258 +/- 142 ng/mL and 62.4 +/- 17 ng/mL were achieved 12 hours after oral and transdermal administration, respectively. A negative correlation was found between heart rate and plasma atenolol concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.

Clinical Features of English Bulldogs with Presumed Arrhythmogenic Right Ventricular Cardiomyopathy: 31 Cases (2001-2013).

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden death in people and boxer dogs that has recently been described in English bulldogs. The objective of this retrospective study was to describe the clinical characteristics of English bulldogs with presumed ARVC. The medical records were searched for English bulldogs examined between 2001 and 2013 with a clinical diagnosis of ARVC. The average age of the 31 dogs identified was 9.2 ± 1.6 yr (range 7-13 yr). Males were overrepresented by a factor of 2.9 to 1. At initial presentation, 5 dogs had subclinical arrhythmia, 10 dogs had clinical signs attributable to arrhythmia, and 16 dogs had congestive heart failure. Eighteen dogs (58%) had ventricular tachycardia and five (16%) also had supraventricular arrhythmias. Four dogs experienced sudden death, 2 dogs died from congestive heart failure, 11 dogs were euthanized for cardiac causes, and 2 dogs died or were euthanized for noncardiac causes. Kaplan-Meier analysis showed a median survival time of 8.3 mo. This is the first study to describe the clinical characteristics of a population of English bulldogs with presumed ARVC. Further studies are needed to better characterize the clinical features of the disease in this breed.

The effects of rate and irregularity on sympathetic nerve activity in human subjects.

BACKGROUND: We have recently shown that atrial fibrillation is associated with an increase in sympathetic nerve activity (SNA) compared with sinus rhythm. It remains unclear, however, whether these findings are true at various rates and whether the magnitude of sympathoexcitation is related to the degree of irregularity. OBJECTIVE: To determine the role of irregularity in mediating the SNA changes at various pacing rates. Univariate analysis showed that as the irregularity increased, SBP increased (r = 0.44, P < .001) but that MAP and DBP did not change significantly. METHODS: Using custom-made software, atrioventricular sequential pacing with predetermined rates (100, 120, and 140 bpm) and irregularities (standard deviation = 0%, 5%, 15%, and 25% of mean cycle length) was performed in 23 patients referred for electrophysiologic evaluation. Pacing at each rate/irregularity was performed for 2 minutes, with 2 minutes of recovery in between. Systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), central venous pressure (CVP), and SNA were measured at baseline and during pacing. RESULTS: Univariate analysis showed that as the irregularity increased, SBP increased (r = 0.44, P < .001 but that MAP and DBP did not change significantly. A significant correlation was found between the pacing irregularity and SNA, with greater sympathoexcitation noted at greater degrees of irregularity (r = 0.2, P = .04). A five-variable linear model using DBP, MAP, CVP, and degree of pacing irregularity to predict SNA was highly statistically significant (r = 0.46, P < .001). After controlling for hemodynamic changes, for every 1% increase in irregularity, there was a 6.1% increase in SNA. CONCLUSION: We have shown that greater degrees of irregularity cause greater sympathoexcitation and that the effects of irregular pacing on SNA are independent of the hemodynamic changes.