Search

CASE DESCRIPTION An 8-month-old 41.2-kg (90.6-lb) sexually intact male Dogue de Bordeaux with urinary incontinence and signs of nausea was referred for further evaluation and treatment of bilateral hydronephrosis, hydroureter, and ectopic ureters. CLINICAL FINDINGS Clinicopathologic analyses revealed urine specific gravity and serum concentrations of urea nitrogen and creatinine within reference limits. Abdominal ultrasonography and CT revealed unilateral abdominal cryptorchidism, ureters that bilaterally passed dorsal to and appeared compressed by the external iliac arteries (retroiliac ureters), and bilateral hydronephrosis, hydroureter, and ectopic ureters. On CT, minimal uptake of contrast medium by the right kidney indicated either a lack of renal function or ureteral obstruction. TREATMENT AND OUTCOME The dog underwent exploratory laparotomy, right ureteronephrectomy, left neoureterocystostomy, bilateral castration, and incisional gastropexy without complication and was discharged 2 days postoperatively. Eleven days after surgery, the dog had improved but continued urinary incontinence, improved left hydronephrosis and hydroureter, and serum concentrations of urea nitrogen and creatinine within reference limits. At 24 months after surgery, the dog was reportedly clinically normal, other than having persistent urinary incontinence. CLINICAL RELEVANCE To our knowledge, this was the first report of a dog with retroiliac ureters and compression-induced ureteral obstruction with secondary hydroureter and hydronephrosis. Retroiliac ureters should be considered as a differential diagnosis in young dogs with ureteral obstruction. Our findings indicated that a good outcome was possible for a dog with retroiliac ureters treated surgically; however, the presence of additional congenital anomalies should be considered and may alter the prognosis in dogs with retroiliac ureters.

Radiographic assessment of heart size is important for clinical management of dogs with cardiovascular disease (CVDz). We sought to compare the ability of vertebral heart size (VHS), vertebral left atrial size (VLAS), and radiologists' assessment of left atrial size (RadLAE) to predict echocardiographic left atrial size (EchoLAE), an important marker of left heart disease severity. We also compared the ability of VHS and VLAS to predict echocardiographic criteria for ACVIM stage B2 (EchoB2) in dogs with myxomatous mitral valve disease (MMVD). This prospective observational study enrolled 183 dogs with known or suspected CVDz that had an echocardiographic examination and thoracic radiographs obtained within 24 h. Compared to increased VHS, VLAS 2.3 was a more accurate predictor of EchoLAE (P = .002). VLAS 2.3 and RadLAE (both P .0001) were independently associated with EchoLAE but VHS was not (P = .45). Optimal cutoffs for VLAS and VHS to predict EchoLAE were 2.3 vertebrae (sensitivity [Sn] = 90.3%, specificity [Sp] = 73.6%) and 11.1 vertebrae (Sn = 75.8%, Sp = 76.0%), respectively. Diagnostic accuracy of VLAS (AUC 0.84, 95% CI 0.73-0.92) and VHS (AUC 0.78, 95% CI 0.66-0.88) to predict EchoB2 in dogs with subclinical MMVD (n = 64) were not significantly different (P = .17). Results demonstrate that VLAS and RadLAE were superior indicators of EchoLAE compared to VHS in dogs with known or suspected CVDz. Both VLAS and VHS are useful predictors of EchoB2 in dogs with subclinical MMVD. When echocardiography is unavailable, VLAS represents a useful radiographic measurement to aid clinical management of dogs with known or suspected CVDz.

AIM To compare the safety and efficacy of bexagliflozin administered as monotherapy at three dosage strengths over a 12-week period to patients with type 2 diabetes who were either naive to pharmacotherapy or were previously prescribed one oral hypoglycaemic agent and underwent a 6-week period of medication abstinence. METHODS Adults with type 2 diabetes (n = 292) having an HbA1c of between 7.0% and 8.5% were randomized to receive one of three dosage strengths of bexagliflozin (5, 10 or 20 mg) or placebo. The primary endpoint was the change from baseline to week 12 in the %HbA1c. Secondary endpoints included the changes from baseline in fasting plasma glucose (FPG), systolic blood pressure and diastolic blood pressure, body mass and fraction of patients achieving an HbA1c of

AIM To explore the safety and effectiveness of extended exposure to bexagliflozin as a monotherapy for type 2 diabetes. METHODS Adults with diabetes (n = 288) from the USA, Colombia and Mexico were randomized 1:1 to receive bexagliflozin (20 mg) or placebo for 96 weeks. The primary endpoint was the placebo-adjusted change in HbA1c at 24 weeks. Dosing was continued an additional 72 weeks to assess safety and the durability of the treatment effect. Secondary endpoints measured changes from baseline in body mass and systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 24, and the change, over study duration, in HbA1c. RESULTS: The placebo-adjusted change in HbA1c from baseline to week 24 was -0.79% (-8.6 mmol/mol) [95%CI -0.53, -1.06 (-5.8, -11.6), P

AIM To compare the relative safety and effectiveness of bexagliflozin and sitagliptin as adjuncts to metformin for the treatment of adults with type 2 diabetes. METHODS Participants (n = 386) were randomized to receive bexagliflozin (20 mg) or sitagliptin (100 mg) in addition to their existing doses of metformin. The primary endpoint was the non-inferiority of bexagliflozin to sitagliptin for change in HbA1c from baseline to week 24. Changes from baseline to week 24 in fasting plasma glucose (FPG), body mass (in subjects with baseline body mass index ≥25 kg m-2 ) and systolic blood pressure (SBP) were secondary endpoints. RESULTS The mean change from baseline to week 24 in HbA1c was -0.74 (95% CI -0.86%, -0.62%) in the bexagliflozin arm and -0.82% (95% CI -0.93%, -0.71%) in the sitagliptin arm, establishing non-inferiority. The changes from baseline FPG, body mass and SBP were -1.82 mmol L-1 , -3.35 kg and -4.23 mmHg in the bexagliflozin arm and -1.45 mmol L-1 , -0.81 kg and -1.90 mmHg in the sitagliptin arm, respectively. These differences were significant for the first two measures (one-sided P = 0.0123, P

Magnetic resonance imaging is the primary method used to diagnose canine glial cell neoplasia and noninfectious inflammatory meningoencephalitis. Subjective differentiation of these diseases can be difficult due to overlapping imaging characteristics. This study utilizes texture analysis (TA) of intra-axial lesions both as a means to quantitatively differentiate these broad categories of disease and to help identify glial tumor grade/cell type and specific meningoencephalitis subtype in a group of 119 dogs with histologically confirmed diagnoses. Fifty-nine dogs with gliomas and 60 dogs with noninfectious inflammatory meningoencephalitis were retrospectively recruited and randomly split into training (n=80) and test (n=39) cohorts. Forty-five of 120 texture metrics differed significantly between cohorts after correcting for multiple testing (false discovery rate&nbsp

Implementation of clinically useful research discoveries in the academic environment is challenged by limited funding for early phase proof-of-concept studies and inadequate expertise in product development and commercialization. To address these limitations, the National Institutes of Health (NIH) established the National Centers for Accelerated Innovations (NCAI) program in 2013. Three centers competed successfully for awards through this mechanism. Here, we present the experience of one such center, the Boston Biomedical Innovation Center (B-BIC), and demonstrate its remarkable success at the translation of innovations to clinical application and commercialization, as well as skills development and education.

Rationale and Objectives To highlight radiology's merits and boost appeal to medical students in the digital era, it is increasingly important for radiology departments to be readily accessible to medical students. We report the results of a multivariate analysis of the virtual presence of radiology medical student education of 152 allopathic United States (US) medical schools, the first report of its kind to the authors’ knowledge. We detail eight elements to include when optimizing a radiology medical student education website. Methods In August 2020, the Department of Radiology websites at 152 allopathic US medical schools were assessed for the presence of a medical student radiology education website and accessibility of collated information about preclinical and clinical course offerings, radiology interest groups, and outreach initiatives in the form of student radiology mentorship, shadowing, and research opportunities. Results 65.1% (99/152) of allopathic US medical schools’ radiology departments have a dedicated medical student radiology education website, one of which was excluded from further review due to password protected content. 58.2% (57/98) of departmental websites include information about preclinical radiology coursework and 90.8% (89/98) of departments provide information about clinical courses. Details about interest groups were found on 26.5% (26/98) of departmental websites. Information about mentorship and shadowing was identified on less than half of departmental websites. 51% (50/98) of Department of Radiology websites provide information about research opportunities for students. Conclusions This study demonstrates that the majority of allopathic US medical schools’ radiology departments lack full information of relevance to medical students. To engage today's and tomorrow's medical learners digitally, there is opportunity and need to improve the online availability of information about preclinical and clinical radiology courses, student interest groups, shadowing opportunities, student mentorship, and student research. We detail eight elements to include when optimizing a radiology medical student education website. In most instances, this can be accomplished by revising an existing radiology department website in a manner that engages, educates, and recruits medical students. As a specialty, radiology must expand our digital footprint to reach tomorrow's colleagues and leaders.

Bexagliflozin is a potent and selective sodium glucose co-transporter 2 inhibitor. To evaluate the safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus, participants (317) were randomized to receive bexagliflozin or placebo in addition to ongoing treatment with metformin. The primary endpoint was the placebo-adjusted change in HbA1c from baseline to week 24. Changes in systolic blood pressure (SBP), fasting plasma glucose (FPG) and body mass were secondary endpoints. The study also enrolled an open label arm of participants with elevated HbA1c. Including post-rescue observations, the mean change in HbA1c was 1.09% (95% CI 1.24%, 0.94%) in the bexagliflozin arm and 0.56% ( 0.71%, 0.41%) in the placebo arm, for a difference of -0.53% ( 0.74%, 0.32%; p < 0.0001). By the last-observation-carried-forward method, the intergroup difference was -0.70% ( 0.92, 0.48; p < 0.0001). The open label cohort experienced a mean change in HbA1c of 2.82% ( 3.23%, -2.41%). The placebo-adjusted changes from baseline SBP, FPG and body mass and SBP were 7.07 mm Hg ( 9.83, -4.32; p < 0.0001), -1.35 mmol L-1 (-1.83, -0.86; p < 0.0001) and 2.51 kg (-3.45, -1.57; p < 0.0001). Adverse events were experienced by 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively, and fewer subjects in the bexagliflozin arm experienced serious adverse events. Bexagliflozin produced clinically meaningful and statistically significant improvement in measures of cardiovascular health and glycemic control in a population of diabetic adults inadequately controlled by metformin alone. ClinicalTrials.gov Identifier: NCT03259789. Disclosure Y.C. Halvorsen: Research Support; Self; Theracos, Inc. J.P. Lock: None. M.W. Freeman: Research Support; Self; Theracos, Inc.

Bexagliflozin (bexa) is a potent and selective inhibitor of SGLT2. To demonstrate its effects in patients (pts) at increased risk of cardiovascular (CV) events, pts with type 2 diabetes (T2D) ≥40 years old with HbA1c 7.5-11 % and eGFR ≥45 were enrolled in 1 of 3 groups: 1) established atherosclerotic CVD 2) heart failure (HF) or 3) ≥55 years with ≥2 CV risk factors. The primary endpoint was change in HbA1c at wk 24. Secondary endpoints included change in SBP at 24 wks in pts with SBP ≥140 mmHg, weight loss at 48 wks in pts with BMI ≥25 kg/m2, and time to hospitalization for HF or CV death. MACE+ (CV death, myocardial infarction, stroke, or unstable angina) was tested in a non-inferiority analysis to demonstrate upper 95% CI Disclosure J.J.V. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc. M.W. Freeman: Research Support; Self; Theracos, Inc. J. Massaro: Consultant; Self; Theracos, Inc. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. P. Lock: None. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. E. Lewis: Consultant; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Amgen, Novartis Pharmaceuticals Corporation, Theracos, Inc. Y.C. Halvorsen: Research Support; Self; Theracos, Inc.

Aims Chronic kidney disease (CKD) in heart failure (HF) increases the risk of hyperkalaemia (HK), limiting angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) use. Patiromer is a sodium-free, non-absorbed potassium binder approved for HK treatment. We retrospectively evaluated patiromer's long-term safety and efficacy in HF patients from AMETHYST-DN. Methods and results Patients with Type 2 diabetes, CKD, and HK [baseline serum potassium >5.0-5.5 mmol/L (mild) or >5.5- 88%) and moderate (≥73%) HK had normokalaemia at each visit from Weeks 12 to 52. Three HF patients were withdrawn because of high (n = 1) or low (n = 2) serum potassium. The most common patiromer-related adverse event was hypomagnesaemia (8.6%). Conclusions In patients with a clinical diagnosis of HF, diabetes, CKD, and HK on ACE-I/ARB, patiromer was well tolerated and effective for HK treatment over 52 weeks.

Though a general consensus exists regarding the significance of perceived performance in voters’ evaluations of incumbent governments, much of the research underlying this consensus has been carried out across political systems with little internal variance in the degree of democracy. We propose that in emerging regimes, where such uniformity in terms of the territorial diffusion of democracy is not a given, characteristics of subnational political regimes can prevent electoral linkages from forming. Specifically, we argue that in subnational contexts where some minimal level of political competition has taken hold, performance-based linkages such as those driving economic voting should surface. However, in subnational dominant-party systems, where clientelistic linkages between voters and political bosses tend to prevail, economic performance and other aspects of an incumbent’s governance record will be less consequential for the voting calculus of citizens, in both provincial and national elections. We find support for this theoretical framework in Argentina and Mexico, two democratic countries characterized by highly uneven subnational political contexts. By highlighting how subnational regime characteristics facilitate or undermine electoral accountability mechanisms, we cast light on the very real representational consequences of uneven democratization in emerging regimes.

Are CTS patients receiving equal standards of care across the country?

A Woman with Weakness, Dark Urine, and Dysphagia A 65-year-old woman was admitted to this hospital because of falls, weakness, dark urine, and difficulty swallowing. Her medical history was notable...

Diagnostic Imaging in Veterinary Dental Practice Figure 1—Intraoral photograph of the left parotid papilla of a 10-year-old 7-kg (15.4-lb) Chihuahua cross that was evaluated because of recurrent left-sided facial swelling and purulent discharge from the oral cavity. The papilla was slightly erythematous and more prominent than that on the right side. In cooperation with Figure 2—Ultrasonographic (A) and contrast-enhanced CT (B) images obtained from the same dog as in Figure 1. The ultrasonographic im- age (parasagittal view) was obtained over the region of facial swelling by use of a ven- tral approach with the animal in dorsal recumbency. The transverse CT image of the skull (slice thickness, 0.6 mm) was obtained at the level of the first maxillary molar teeth and viewed with bone (win- dow width, 2,500 Hounsfield units [HU]; window level, 480 HU) and soft tissue (window width, 750 HU; window level, 200 HU) window settings. L = Left. R = Right. History and Physical Examination Findings A 10-year-old 7-kg (15.4-lb) spayed female Chihuahua cross was referred to a veterinary teaching hospital because of recurrent left-sided facial swelling and purulent discharge from the oral cavity. The client had noticed an increase in lip smacking and licking approximately 6 months prior to the evaluation. Facial swelling and signs of pain on palpation had first been detected 10 weeks prior to the examination; the dog had been treated by the referring veterinarian for a suspected tooth root abscess or abscess secondary to a foreign body. An antimicrobial (amoxicillin trihydrate–clavulanate potassium; 18 mg/kg [8.2 mg/lb], PO, q 12 h for 14 days) and an NSAID (carprofen; 1.8 mg/kg [0.82 mg/lb], PO, q 12 h for 7 days) had been prescribed. Clinical signs had improved over the course of initial treatment but relapsed following cessation of the treatment. The referring veterinarian anesthetized the dog, obtained intraoral dental radiographs, and performed periodontal charting. Mild to moderate localized periodontitis was diagnosed with no evidence of a dentoal- veolar abscess or dental cause for the facial swelling. On examination at the referral visit, the dog was bright, alert, and responsive with no abnormalities found on general physical examination other than a fluctuating soft tissue swelling in the region over the left masseter muscle. Intraoral ex- amination revealed a prominent, erythematous left parotid papilla (Figure 1), concurrent sialorrhea upon digital manipu- lation of the ipsilateral parotid gland, hypodontia, and mild generalized plaque and calculus accumulation. Blood and urine samples were obtained for a CBC, serum biochemical analysis, and urinalysis. Laboratory test results were unremarkable. The dog was sedated with dexmedetomidine hydrochloride (3.0 mg/kg [1.36 µg/lb], IV) and butorphanol tartrate (0.1 mg/kg [0.045 mg/lb], IV), and ultrasonographic evaluation of the swollen facial region was performed; the follow- ing day, the dog was anesthetized, and contiguous transverse collimated CT images of the skull were obtained at a slice thickness of 0.6 mm before and after IV contrast medium administration (Figure 2). The images were viewed with bone (window width, 2,500 Hounsfield units [HU]; window level, 480 HU) and soft tissue (window width, 750 HU; window level, 200 HU) settings. Three-dimensional volume rendering was performed, and all digital images were reviewed on a medical-grade flat screen monitor, by use of commercially available software. a Determine whether additional studies are required, or make your diagnosis, then turn the page→ This report was submitted by Peter C. Strom, DVM; Daniel S. Bucy, DVM; and Boaz Arzi, DVM; from the Dentistry and Oral Surgery Service, William R. Pritchard Veterinary Medical Teaching Hospital (Strom, Bucy), and the Department of Surgical and Radiological Sciences (Arzi), School of Veterinary Medicine, University of California-Davis, Davis, CA 95616. Address correspondence to Dr. Arzi (barzi@ucdavis.edu). JAVMA • Vol 249 • No. 12 • December 15, 2016

Fredrik Gadler,1 Yao Ding,2 Nathalie Verin,3 Martin Bergius,4 Jeffrey D Miller,5 Gregory M Lenhart,5 Mason W Russell5 1Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden; 2Truven Health Analytics, an IBM Company, Bethesda, MD, USA; 3Boston Scientific Corporation, Hemel Hempstead, Hertfordshire, UK; 4Boston Scientific Nordic AB, Helsingborg, Sweden; 5Truven Health Analytics, an IBM Company, Cambridge, MA, USA Objective: The objective of this study was to quantify the impact that longer battery life of cardiac resynchronization therapy defibrillator (CRT-D) devices has on reducing the number of device replacements and associated costs of these replacements from a Swedish health care system perspective.Methods: An economic model based on real-world published data was developed to estimate cost savings and avoided device replacements for CRT-Ds with longer battery life compared with devices with industry-standard battery life expectancy. Base-case comparisons were performed among CRT-Ds of three manufacturers – Boston Scientific Corporation, St. Jude Medical, and Medtronic – over a 6-year time horizon, as per the available clinical data. As a sensitivity analysis, we evaluated CRT-Ds as well as single-chamber implantable cardioverter defibrillator (ICD-VR) and dual-chamber implantable cardioverter defibrillator (ICD-DR) devices over a longer 10-year period. All costs were in 2015 Swedish Krona (SEK) discounted at 3% per annum.Results: Base-case analysis results show that up to 603 replacements and up to SEK 60.4 million cumulative-associated costs could be avoided over 6years by using devices with extended ­battery life. The pattern of savings over time suggests that savings are modest initially but increase rapidly beginning in the third year of follow-up with each year’s cumulative savings two to three times theprevious year. Evaluating CRT-D, ICD-VR, and ICD-DR devices together over a longer10-year period, the sensitivity analysis showed 2,820 fewer replacement procedures and associated cost savings of SEK 249.3 million for all defibrillators with extended battery life.Conclusion: Extended battery life is likely to reduce device replacements and associated complications and costs, which may result in important cost savings and a more efficient use of health care resources as well as a better quality of life for heart failure patients in Sweden. Keywords: cost analysis, economic model, cardiac resynchronization therapy defibrillator, implantable cardioverter defibrillator, battery life, device replacement, Sweden

RATIONALE AND OBJECTIVE: Hyperglycemia exacerbates the progression of chronic kidney disease (CKD), but most glucose-lowering therapies do not address morbidities associated with CKD. Sodium-glucose cotransporter-2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with impaired kidney function. We aimed to evaluate the safety and effectiveness of bexagliflozin, a novel SGLT2 inhibitor, in patients with type 2 diabetes and CKD. STUDY DESIGN: Phase 3, double-blind, placebo-controlled, multi-center, multi-national, randomized trial SETTING AND PARTICIPANTS: 54 sites across 4 countries. Patients with CKD stage 3a or 3b, type 2 diabetes mellitus, and a hemoglobin A1c between 7.0% −10.5% and eGFR 30–59 ml/min/1.73 m(2) who were taking oral hypoglycemic agents for 8 weeks. INTERVENTIONS: Bexagliflozin, 20 mg daily versus placebo, for 24 weeks. OUTCOMES: Primary outcome was the change in percent hemoglobin A(1c) from baseline to week 24 weeks. Secondary endpoints included changes in body weight, systolic blood pressure, albuminuria and hemoglobin A(1c) stratified by CKD stage. RESULTS: 312 patients across 54 sites were analyzed. Bexagliflozin lowered hemoglobin A1c by 0.37% [95% CI 0.20, 0.54]; p

Commercializing innovations in academic environments is notoriously challenging. Here, we describe the progress of the NIH Centers for Accelerated Innovations program — initiated in 2013 to address these challenges — which we believe could help set a new standard for the early-stage commercialization of biomedical innovations in academic environments.

BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P

Prior research in photoacoustic tomography has consistently demonstrated its ability to image structures near the surface of tissue with a high degree of optical contrast. However, despite significant advancements in the field, there has been little to no development of clinical applications for photoacoustic tomography, principally due to the requirement for backwardmode operation, i.e., it must detect the photoacoustic signal on the same side of the tissue as the incident laser light. This results in the standard ultrasonic transducer occluding the path of the inciting laser beam. Therefore, developing a technique to deliver light into the tissue, while incorporating commonly available ultrasonic detection equipment without occluding the beam propagation or modifying the equipment in any way, would provide a significant benefit to the field, and potentially improve its clinical applicability. Here, we propose a new method to accomplish this aim, using planar optical waveguides that employ the optical tunneling phenomenon to transmit light directly into tissue (pig skin) through physical contact with the sample. A commercially available, 10MHz, unfocused ultrasonic transducer was positioned on the rear face of the waveguide and was used to detect photoacoustic signals generated within the tissue as the signals propagated perpendicularly through the waveguide substrate. Unlike alternative solutions to the occlusion problem, this modality does not necessitate the use of custom manufactured transducers, expensive dichroics, or additional laser systems, and thereby represents a viable approach for the easy implementation of photoacoustic tomography in a clinical setting.

Lasers have demonstrated widespread applicability in clinical dermatology as minimally invasive instruments that achieve photogenerated responses within tissue. However, before reaching its target, the incident light must first transmit through the surface layer of tissue, which is interspersed with chromophores (e.g. melanin) that preferentially absorb the light and may also generate negative tissue responses. These optical absorbers decrease the efficacy of the procedures. In order to ensure that the target receives a clinically relevant dose, most procedures simply increase the incident energy; however, this tends to exacerbate the negative complications of melanin absorption. Here, we present an alternative solution aimed at increasing epidermal energy uence while mitigating excess absorption by unintended targets. Our technique involves the combination of a waveguide-based contact transmission modality with simultaneous high-frequency ultrasonic pulsation, which alters the optical properties of the tissue through the agglomeration of dissolved gasses into micro-bubbles within the tissue. Doing so effectively creates optically transparent pathways for the light to transmit unobstructed through the tissue, resulting in an increase in forward scattering and a decrease in absorption. To demonstrate this, Q-switched nanosecond-pulsed laser light at 532nm was delivered into pig skin samples using custom glass waveguides clad in titanium and silver. Light transmission through the tissue was measured with a photodiode and integrating sphere for tissue with and without continuous ultrasonic pulsation at 510 kHz. The combination of these techniques has the potential to improve the efficiency of laser procedures while mitigating negative tissue effects caused by undesirable absorption.

SummaryA significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, –1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3, 1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2. A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A to Algorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion.Clinical Trial Registration: ClinicalTrials.gov (NCT00401414)

Our understanding of human biology has increased tremendously for the last several decades, yet the pace at which these discoveries have translated into new therapies for patients has been frustratingly stagnant. Universities and academic health centers, as the major recipients of public investment in biomedical science, have an obligation to translate new knowledge into applications that confer human benefit. However, translating fundamental discoveries into practical applications is expensive and involves highly regulated steps with which few academic scientists have experience. Challenges in engaging universities and academic health centers in translational research include building the appropriate infrastructures for human investigation, training and stabilizing the careers of young scientists and physicians interested in the requisite work, educating academic investigators about the regulatory requirements inherent in successful therapeutic discovery and development, and finding more efficient ways to match good ideas with adequate funding resources. The purpose of this article is to examine the early-stage drug development process and evaluate the role that academia could play in it. Because interest in early-stage drug development grows among academic investigators, the need for more integrated partnerships among academia, government, and industry has become increasingly apparent.

Background: Tapentadol immediate-release (IR) tablets are indicated for the treatment of moderate to severe acute pain. In clinical trials, tapentadol IR effectively reduced moderate to severe pain with improved tolerability compared with oxycodone IR at doses providing comparable analgesia. Objective: This analysis compared the cost-effectiveness of tapentadol IR with doses of oxycodone IR providing comparable analgesia in the outpatient treatment of acute postsurgical and nonsurgical pain. The perspective was that of a US managed care health plan as third-party payer. Methods: A Markov model was developed to simulate clinical-economic outcomes for tapentadol IR 100 mg compared with oxycodone IR 15 mg in the treatment of acute postsurgical pain (3 days) and for tapentadol IR 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain (10 days). The model simulated changes in pain relief; occurrence of opioid-related adverse events (AEs); opioid switching, discontinuation, and dose change; and number of quality-adjusted life-days (QALDs). Data inputs for the model were obtained from clinical trials, claims databases, surveys, Medicare fee schedules, and other published sources. Only direct costs were included. Drug costs were based on the wholesale acquisition cost. Prescription copayments were set at $5 for oxycodone IR and $25 for tapentadol IR. All costs were in 2008 US dollars. Sensitivity analyses were conducted on key model parameters. Results: The cost of pain medication per patient was higher for tapentadol IR than for oxycodone IR in both the surgical pain setting ($15.23 vs $9.57, respectively) and the nonsurgical pain setting ($57.17 vs $21.31). However, this cost difference was offset by reductions in pharmacy and medical costs associated with the treatment of AEs and opioid switching/discontinuation, resulting in a lower mean treatment cost per patient for tapentadol IR 100 mg compared with oxycodone IR 15 mg in the treatment of acute surgical pain ($52.90 vs $55.99) and for tapentadol IR 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain ($139.48 vs $144.79). Tapentadol IR also was associated with a greater mean number of treatment days with ≥30% improvement in pain intensity without opioid-related AEs compared with oxycodone IR and a greater mean number of QALDs (surgical pain: 1.73 vs 1.68; nonsurgical pain: 6.03 vs 4.92). Because both doses of tapentadol IR were dominant (ie, lower treatment costs and greater effectiveness) relative to the corresponding doses of oxycodone IR providing com- parable analgesia, incremental cost-effectiveness ratios were not calculated. Conclusion: The results of this model suggest that at doses providing comparable analgesia, tapentadol IR is a cost-effective alternative to oxycodone IR for the treatment of acute surgical and nonsurgical pain.

Follicular non-Hodgkin's lymphoma (FNHL), a slow-growing cancer of the immune system, constitutes about 15-30% of all incident non-Hodgkin's lymphoma in developed countries. Its incidence is rising worldwide. Patients can live many years, but FNHL is considered incurable. We systematically reviewed the English-language MEDLINE-indexed and non-indexed economic literature published in the past 10 years on FNHL, identifying 23 primary economic studies. The economic burden of FNHL is significant, but available data are generally limited to retrospective considerations of hospital-based direct treatment costs, with little information available regarding societal cost of illness. Most direct cost information originates from the US, with one estimate of $US36 000 for the per-patient incremental cost of FNHL care during the first year following diagnosis. The most studied treatment is rituximab, which may offer similar overall costs to fludarabine considering higher resource use with fludarabine complications. Nearly all cost-effectiveness models identified by this review evaluated rituximab for relapsed/refractory FNHL responding to chemotherapy induction. Rituximab is supported as a cost-effective addition to standard chemotherapy by two models in the UK and one in the US, as maintenance therapy instead of stem-cell transplant by one UK model, and as maintenance therapy instead of observation alone by one model each in France, Spain and Canada. The UK National Institute for Health and Clinical Excellence updated guidance on rituximab in February 2008, concluding that it is cost effective when added to induction chemotherapy, and when used as maintenance therapy. No studies of per-patient or national indirect costs of illness were identified, with the only study of indirect costs a Canadian survey documenting lost work productivity. Across all study types identified by our review, the most common focus was on the direct costs of rituximab. As new treatments for FNHL come to market, more real-life cost data are imperative to calculate their relative cost effectiveness.

Trauma is a serious injury or shock to the body from violence or crash and is an important and growing global health risk. Using 2000 to 2004 data from a comprehensive trauma registry, we estimated the prevalence of serious blunt and penetrating trauma-related hemorrhage among patients admitted to U.S. trauma centers along with excess in-hospital mortality, length of hospital stay, and inpatient costs. There were 65,750 patients with blunt trauma and 12,992 patients with penetrating trauma included in our analyses. Of patients sustaining blunt trauma, 7.6 per cent had serious hemorrhage; 18.8 per cent of patients sustaining penetrating trauma had serious hemorrhage. In-hospital mortality rates were significantly ( P < 0.05) higher for patients with serious hemorrhage than for patients without (24.9 per cent versus 8.4 per cent for blunt; 23.4 per cent versus 4.2 per cent for penetrating). Patients with serious hemorrhage had adjusted mean excess lengths of stay of 0.4 days for blunt trauma and 2.7 days for penetrating trauma ( P < 0.05); adjusted excess costs were $296 per day for patients sustaining blunt trauma and $637 per day for patients sustaining penetrating trauma ( P < 0.05). In both blunt and penetrating trauma cases, serious hemorrhage is significantly associated with excess mortality, longer hospital stays, and higher costs.

High high-density lipoprotein (HDL) levels protect against coronary artery disease (CAD) development. We hypothesized that patients with CAD and high HDL levels would have higher prevalence of other CAD risk factors compared with patients with CAD and normal HDL. We identified 41,982 patients from a single center with normal levels (40 to 60 mg/dl in men, 50 to 70 mg/dl in women) or high HDL levels (> or =70 mg/dl in men, > or =80 mg/dl in women) when last measured between January 2000 and April 2004. From this overall population, we characterized a cohort of 1,610 patients with CAD, including 98 patients with high HDL levels. We measured prevalence of traditional CAD risk factors by comparing these 98 patients with patients with CAD and normal HDL levels (n = 1,512). We performed manual chart review in patients (n = 196) matched 1:1 by age, gender, and HDL level to obtain further detail with regard to differences in family history and lifestyle factors. In patients with CAD, those with high HDL levels (98 of 1,610, 6.1%) were of similar age (71.1 vs 69.6 years, p = 0.23), had similar prevalence of hypertension (78.6% vs 88.7%, p = 0.30), lower levels of low-density lipoprotein (85.3 vs 90.9 mg/dl, p = 0.04) and triglycerides (87.1 vs 141.2 mg/dl, p

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.

The objective of this study was to generate estimates of cost-effectiveness/utility of somatropin (rDNA origin) in the treatment of growth hormone deficiency (GHD) in children.A decision-analytic model of the epidemiology and treatment of GHD in children was developed. Treatment of GHD was assessed in two hypothetical cohorts compared to no treatment--treatment with somatropin 0.030 mg/kg/day from ages 5 to 16 years, and treatment from ages 3 to 18 years. Costs (stated in 2005 US$) included those related to drug acquisition, endocrinologist consultations, and primary care office visits. Estimates of patient weight by age and sex were derived from published literature, as was the proportion of patients achieving normal height through somatropin treatment and pre/post-treatment patient utilities. Cost-effectiveness/utility was estimated over patients' expected lifetimes, and was stated alternatively as discounted (3% per annum) US dollars per normal height year (NHY) gained, and cost per quality adjusted life-year (QALY) gained. Multivariate sensitivity analyses were conducted to ensure robustness of the model.The cost-effectiveness and cost-utility of treating children from ages 5 to 16 years with somatropin was estimated at approximately $8,900 per NHY gained and $37,000 per QALY gained, respectively. Corresponding ratios pertaining to treatment of children from ages 3 to 18 years were $9,300 per NHY gained and $42,600 per QALY gained. Findings were relatively insensitive to variation in most model parameters.For both age cohorts, the cost-effectiveness/utility of somatropin in the treatment of GHD compares favorably to well-accepted threshold values. The use of somatropin represents reasonable value for money for the treatment of GHD in children.

The costs of chronic obstructive pulmonary disease (COPD) pose a major economic burden to the United States. Studies evaluating COPD costs have generated widely variable estimates; we summarized and critically compared recent estimates of the annual national and per-patient costs of COPD in the U.S. Thirteen articles reporting comprehensive estimates of the direct costs of COPD (costs related to the provision of medical goods and services) were identified from searches of relevant primary literature published since 1995. Few papers reported indirect costs of COPD (lost work and productivity). The National Heart, Lung, and Blood Institute (NHLBI) provides the single current estimate of the total (direct plus indirect) annual cost of COPD to the U.S., $38.8 billion in 2005 dollars. More than half of this cost ($21.8 billion) was direct, aligning with the $20–26 billion range reported by two other recent analyses of large national datasets. For per-patient direct costs (in $US 2005), studies using recent dat...

Patients living with human immunodeficiency virus (HIV) infection are at increased risk of cardiovascular disease [1–5]. One of the potential mechanisms for atherosclerosis developing in patients infected with HIV may relate to the effects of the virus on reverse cholesterol transport. Human immunodeficiency virus infection may affect reverse cholesterol transport by multiple mechanisms including alterations in high-density lipoprotein (HDL)-cholesterol function, impairment of cellular cholesterol efflux by the virus or one of its proteins, or other mechanisms. In this regard, in vitro studies have demonstrated HIV Nef protein can impair cellular cholesterol efflux through down-regulation of ATP-binding cassette transporter A1 (ABCA1) [6]. Genetic mutations in the ABCA1 gene (ABC1) cause Tangier disease, a rare autosomal recessive disorder in which patients have HDL-cholesterol deficiency, accumulation of cholesterol esters, and early atherosclerosis [7]. ATP-binding cassette transporter A1 plays a crucial role in stimulating cholesterol export from macrophages. Patients with HIV also have decreased HDL-cholesterol, which may be mediated in part via this mechanism [6, 8, 9]. We took advantage of a novel study, identifying patients with acute HIV infection for randomization to immediate antiretroviral therapy (ART) or no therapy, to assess the effects of reduction in viral load on cholesterol efflux capacity in a human model. Acute HIV infection is defined by the time period from viral entry to completion of seroconversion and is characterized by high-level viremia, typically reaching levels of several million viral copies/mL plasma, higher than any other period in the natural history of HIV infection [10]. Whether to initiate ART for patients diagnosed with acute HIV infection remains controversial, and an emerging hypothesis is that the “seroconversion window” represents a unique opportunity for treatment and possible early modulation of the host's immune response to the virus [11]. This acute phase of HIV infection can also provide an insightful window into processes that may drive the development of atherosclerosis in patients infected with HIV. Thus, we chose this early stage of HIV infection to study the effects of virus on cholesterol efflux because this is the phase of infection when viremia is typically at its peak. The main hypothesis of this study is that the high magnitude of viremia characteristic of acute HIV infection impairs cholesterol efflux from macrophages that could be improved with suppression of viral replication by ART.

To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia.This was a multicentre, randomized, double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score20%. A total of 625 patients was randomized in a 1:3:3:3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline,70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated.Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.

The demand for economic models that evaluate cancer treatments is increasing, as healthcare decision makers struggle for ways to manage their budgets while providing the best care possible to patients with cancer. Yet, after nearly 2 decades of cultivating and refining techniques for modeling the cost-effectiveness and budget impact of cancer therapies, serious methodologic and policy challenges have emerged that question the adequacy of economic modeling as a sound decision-making tool in oncology.We sought to explore some of the contentious issues associated with the development and use of oncology economic models as informative tools in current healthcare decision-making. Our objective was to draw attention to these complex pharmacoeconomic concerns and to promote discussion within the oncology and health economics research communities.Using our combined expertise in health economics research and economic modeling, we structured our inquiry around the following 4 questions: (1) Are economic models adequately addressing questions relevant to oncology decision makers; (2) What are the methodologic limitations of oncology economic models; (3) What guidelines are followed for developing oncology economic models; and (4) Is the evolution of oncology economic modeling keeping pace with treatment innovation? Within the context of each of these questions, we discuss issues related to the technical limitations of oncology modeling, the availability of adequate data for developing models, and the problems with how modeling analyses and results are presented and interpreted.There is general acceptance that economic models are good, essential tools for decision-making, but the practice of oncology and its rapidly evolving technologies present unique challenges that make assessing and demonstrating value especially complex. There is wide latitude for improvement in oncology modeling methodologies and how model results are presented and interpreted.Complex technical and data availability issues with oncology economic modeling pose serious concerns that need to be addressed. It is our hope that this article will provide a framework to guide future discourse on this important topic.

This paper focuses on the effects of repeated head trauma in athletes and how these repetitive blows to the head are causing a range of mental health problems. The primary focus, in terms of problems addressed, is chronic traumatic encephalopathy (often referred to as CTE) in the population of athletes, especially those participating in contact and combat sports. The disorders covered are caused by the cumulative effects of both concussive and sub-concussive blows to the head over a period of time.

To assess the clinical and economic consequences of a formulary switch from enoxaparin to dalteparin as first-line prophylaxis for deep-vein thrombosis in patients undergoing inpatient rehabilitation after total hip arthroplasty or total knee arthroplasty.Retrospective cohort study.There were 461 patients eligible for the study. The age-adjusted risk of a deep-vein thrombosis event confirmed by duplex ultrasonography among patients treated with dalteparin was substantially lower than among patients treated with enoxaparin, whereas the age-adjusted risk of a bleeding event in the dalteparin group was also lower than that in the enoxaparin group. Adjusted per capita costs of deep-vein thrombosis prophylaxis during the rehabilitation stay were $129 lower among subjects treated with dalteparin.The switch to dalteparin as a first-line therapy for deep-vein thrombosis prophylaxis in the rehabilitation period after total hip arthroplasty or total knee arthroplasty has led to substantial cost savings for Kessler Institute without compromising patient care.

Currently, 6 hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are marketed in the United States (US). Given the wide variation in the prices and efficacy of statins, formal cost-effectiveness analysis may improve drug selection decisions. To assess the cost-effectiveness of statin therapy in primary and secondary prevention of coronary heart disease, we developed a model of the costs and consequences of lipid-regulating therapy and estimated the incremental cost-effectiveness of 5 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) at usual starting doses versus no therapy. Drug effects on serum lipids were assessed using data approved by the US Food and Drug Administration for product labeling. Annual risks of coronary event occurrence were estimated using Framingham Heart Study coronary risk equations developed for use in this model. Current estimates of direct medical costs of coronary heart disease were used to assign costs to health states and acute coronary events. Main outcome measurements were net cost (statin therapy minus savings in coronary heart disease treatment), gain in life expectancy, and cost per life-year saved. The maximum gain in life expectancy was achieved with atorvastatin, which also had a lower net cost than lovastatin, pravastatin, and simvastatin. Compared with fluvastatin, atorvastatin’s greater effectiveness is attained at a lower cost per life-year saved. The cost-effectiveness of HMG-CoA reductase inhibition in primary and secondary prevention of coronary heart disease has been improved with the introduction of atorvastatin.

To generate current incidence-based estimates of the direct medical costs of coronary artery disease (CAD) in the United States, a Markov model of the economic costs of CAD-related medical care was developed. Risks of initial and subsequent CAD events (sudden CAD death, fatal/nonfatal acute myocardial infarction [AMI], unstable angina, and stable angina) were estimated using new Framingham Heart Study risk equations and population risk profiles derived from national survey data. Costs were assumed to be those related to treatment of initial and subsequent CAD events (“event-related”) and follow-up care (“nonevent-related”), respectively. Cost estimates were derived primarily from national public-use databases. First-year direct medical costs of treating CAD events are estimated to be $17,532 for fatal AMI, $15,540 for nonfatal AMI, $2,569 for stable angina, $12,058 for unstable angina, and $713 for sudden CAD death. Nonevent-related direct costs of CAD treatment are estimated to be $1,051 annually. The annual incidence of CAD in the United States is estimated at 616,900 cases, with first-year costs of treatment totaling $5.54 billion. Five- and 10-year cumulative costs in 1995 dollars for patients who are initially free of CAD are estimated at $9.2 billion and $16.5 billion, respectively; for all patients with CAD, these costs are estimated to be $71.5 billion and $126.6 billion, respectively. The direct medical costs of CAD create a large economic burden for the United States health-care system.

We used the 2002 Healthcare Cost and Utilization Project Nationwide Inpatient Sample to assess hospital length of stay (LOS) and cost among adults with a principal diagnosis of intracerebral hemorrhage (n = 13,239). Sixty-nine percent of patients were agedor =65 years, and 31% died during hospitalization. Mean LOS (cost) was 7.7 days (15,256 dollars) (survivors: 9.6 days, 17,442 dollars). Patient, hospital, and payer characteristics accounted for 69.1% of variation in cost per discharge.

Objectives: Increasing evidence supports the use of laryngeal injections of the antiangiogenic agent bevacizumab (Avastin) for the adjuvant treatment of recurrent respiratory papillomatosis (RRP). A recent prospective open-label investigation, approved by the US Food and Drug Administration, employing 12.5 mg of sublesional bevacizumab demonstrated single-site efficacy without complications; however, the safety of multiple-site injections and higher dosing has not yet been reported. The primary objective of this study was to report on the safety of increased doses of bevacizumab for the treatment of RRP. Methods: Two cohorts of adult patients were evaluated. In the first group, a prospective analysis was performed on patients with a diagnosis of laryngeal RRP after their participation in the initial clinical trial with a single-site lower dose (7.5 to 12.5 mg). They received higher doses of sublesional laryngeal bevacizumab (15 to 50 mg total) with detailed physiologic, hematologic, and serum chemistry measurements performed before and after each bevacizumab injection. A second cohort of patients received sublesional laryngeal injections of bevacizumab (15 to 88 mg total) without physiologic measurements and underwent a retrospective analysis of reported complications. Results: One hundred consecutive laryngeal injection sessions (office, 87; operating room, 13) with bevacizumab were performed in 43 patients, with a mean dose of 30 mg total per treatment (range, 15 to 88 mg). Sixty-three of the 100 sessions were accompanied by KTP laser photoangiolysis of the papilloma prior to bevacizumab injections. Eighteen patients (cohort 1) underwent detailed physiologic assessment, and no dysfunction was observed. There were no local or systemic complications of bevacizumab administration. The second group of 25 patients (cohort 2) also reported no significant local or systemic complications. Neither patient group was observed to have a local wound problem in the larynx. Conclusions: This investigation provides evidence that higher doses of bevacizumab are relatively safe in adult patients with laryngeal RRP. Further refinements in pharmacologic concentration and drug delivery will determine the optimal treatment regimens in the future.