Search

The purpose of this study was to compare assessments of breast density on synthetic 2D images as compared with digital 2D mammograms.This retrospective study included consecutive women undergoing screening with digital 2D mammography and tomosynthesis during May 2015 with a negative or benign outcome. In separate reading sessions, three radiologists with 5-25 years of clinical experience and 1 year of experience with synthetic 2D mammography read digital 2D and synthetic 2D images and assigned breast density categories according to the 5th edition of BI-RADS. Inter- and intrareader agreement was assessed for each BI-RADS density assessment and combined dense and nondense categories using percent agreement and Cohen kappa coefficient for consensus and all reads.A total of 309 patients met study inclusion criteria. Agreement between consensus BI-RADS density categories assigned for digital and synthetic 2D mammography was 80.3% (95% CI, 75.4-84.5%) with κ = 0.73 (95% CI, 0.66-0.79). For combined dense and nondense categories, agreement reached 91.9% (95% CI, 88.2-94.7%). For consensus readings, similar numbers of patients were shifted between nondense and dense categories (11 and 14, respectively) with the synthetic 2D compared with digital 2D mammography. Interreader differences were apparent; assignment to dense categories was greater with digital 2D mammography for reader 1 (odds ratio [OR], 1.26; p = 0.002), the same for reader 2 (OR, 0.91; p = 0.262), and greater with synthetic 2D mammography for reader 3 (OR, 0.86; p = 0.033).Overall, synthetic 2D mammography is comparable with digital 2D mammography in assessment of breast density, though there is some variability by reader. Practices can readily adopt synthetic 2D mammography without concern that it will affect density assessment and subsequent recommendations for supplemental screening.

Purpose Despite potential clinical benefits, implementation of pharmacogenomics (PGx) faces many technical and clinical challenges. These challenges can be overcome by a comprehensive and systematic implementation model. Methods The development and implementation of PGx was organized into eight interdependent components addressing resources, governance, clinical practice, education, testing, knowledge translation, clinical decision support (CDS) and maintenance. Several aspects of the implementation were assessed including adherence to the model, production of PGx-CDS interventions and access to educational resources. Results Between 8/2012 and 6/2015, 21 specific drug-gene interactions were reviewed and 18 of them were implemented in the electronic medical record as PGx-CDS interventions. There was complete adherence to the model with variable production time (98 to 392 days) and delay time (0 to 148 days). The implementation impacted approximately 1247 unique providers and 3788 unique patients. A total of 11 educational resources complementary to the drug-gene interactions and 5 modules specific for pharmacists were developed and implemented. Conclusion A comprehensive operational model can support PGx implementation into routine prescribing. Institutions can use this model as a roadmap to support similar efforts. However, we also identified challenges that will require major multidisciplinary and multi-institutional efforts to make PGx a universal reality.

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-doppler-ultrasound-and-resistance-vessel-function/ .

Background In infants with ductal‐dependent pulmonary blood flow, the impact of palliation strategy on interstage growth and feeding regimen is unknown. Methods and Results This was a retrospective multicenter study of infants with ductal‐dependent pulmonary blood flow palliated with patent ductus arteriosus ( PDA ) stent or Blalock‐Taussig shunt ( BTS ) from 2008 to 2015. Subjects with a defined interstage, the time between initial palliation and subsequent palliation or repair, were included. Primary outcome was change in weight‐for‐age Z ‐score. Secondary outcomes included % of patients on: all oral feeds, feeding‐related medications, higher calorie feeds, and feeding‐related readmission. Propensity score was used to account for baseline differences. Subgroup analysis was performed in 1‐ (1V) and 2‐ventricle (2V) groups. The cohort included 66 PDA stent (43.9% 1V) and 195 BTS (54.4% 1V) subjects. Prematurity was more common in the PDA stent group ( P =0.051). After adjustment, change in weight‐for‐age Z ‐score did not differ between groups over the entire interstage. However, change in weight‐for‐age Z ‐score favored PDA stent during the inpatient interstage ( P =0.005) and BTS during the outpatient interstage ( P =0.032). At initial hospital discharge, PDA stent treatment was associated with all oral feeds ( P P =0.002). Subgroup analysis revealed that 2V but not 1V patients demonstrated significant increase in weight‐for‐age Z ‐score. In the 2V cohort, feeding‐related readmissions were more common in the BTS group ( P =0.008). Conclusions In infants with ductal‐dependent pulmonary blood flow who underwent palliation with PDA stent or BTS , there was no difference in interstage growth. PDA stent was associated with a simpler feeding regimen and fewer feeding‐related readmissions.

Pharmacogenomics (PGx) clinical decision support integrated into the electronic health record (EHR) has the potential to provide relevant knowledge to clinicians to enable individualized care. However, past experience implementing PGx clinical decision support into multiple EHR platforms has identified important clinical, procedural, and technical challenges. Commercial EHRs have been widely criticized for the lack of readiness to implement precision medicine. Herein, we share our experiences and lessons learned implementing new EHR functionality charting PGx phenotypes in a unique repository, genomic indicators, instead of using the problem or allergy list. The Gen-Ind has additional features including a brief description of the clinical impact, a hyperlink to the original laboratory report, and links to additional educational resources. The automatic generation of genomic indicators from interfaced PGx test results facilitates implementation and long-term maintenance of PGx data in the EHR and can be used as criteria for synchronous and asynchronous CDS.

Background: Patients with single ventricle anatomy and ductal-dependent pulmonary blood flow may be initially palliated with either modified Blalock-Taussig shunt (BTS) or ductus arteriosus stent (DAS). Comparisons of outcomes during the interstage period and at the time of superior cavopulmonary connection (SCPC) are lacking and may differ between palliation strategies. Methods: Infants with single ventricle anatomy and ductal-dependent pulmonary blood flow palliated with either DAS or BTS from 2008 to 2015 were reviewed across 4 centers. Interstage outcomes, and for those who had SCPC, anatomy, hemodynamics, and perioperative clinical outcomes were compared. Thirty-five patients with DAS and 136 patients with BTS were included. Results: At initial palliation, demographic, clinical variables, and pulmonary artery size were similar. Interstage death, transplant, or unplanned reintervention to treat cyanosis occurred in 25.7% of DAS and 35.8% of BTS, P =0.27. Reintervention was more common with DAS (48.6% versus 2.2%; P z -score: 1.57 versus 0.65, P =0.026). SCPC intraoperative and postoperative courses were similar. Conclusions: In patients with single-ventricle anatomy and ductal-dependent pulmonary blood flow, interstage outcomes, hemodynamics before SCPC, and acute postoperative outcomes were similar. Overall reintervention was more common in the DAS group, driven by more frequent planned reintervention. Unplanned reintervention, death, and transplant were similar. Both groups demonstrated good pulmonary artery growth. DAS is a reasonable initial palliative alternative to BTS in select patients.

Background: Radiocarpal dislocations represent a high-energy wrist injury that can occur with or without concomitant fractures about the wrist. Poor outcomes are often due to radiocarpal instability and secondary ulnar translation. The purpose of this cadaveric study is to determine if there is any difference in the radiographic parameters in a wrist dislocation model given the different location of distal fixation. Methods: Ten paired fresh cadaver upper extremities were fluoroscopically evaluated with posterior-anterior (PA) and lateral views. We created a radiocarpal dislocation model and applied a dorsal bridge plate to either the second or third metacarpal. Repeat PA and lateral fluoroscopic views were obtained for evaluation of radial inclination, radial height, volar tilt, ulnar variance, radiolunate angle, radioscaphoid angle, scapholunate angle, radial rotation index, and four indices for ulnar translation (Taleisnik, Gilula, McMurtry, and Chamay). Results: Bridge plate application to the second metacarpal resulted in a significantly greater incidence of ulnar translation compared to the third metacarpal. Application to either metacarpal resulted in extension of the carpus relative to the radius. Conclusions: A more anatomic radiocarpal relationship was restored more often when distal fixation of the dorsal wrist-spanning bridge plate was applied to the third metacarpal. Further investigation is warranted to determine clinical relevance of these findings in conjunction with clinical and radiographic outcomes.

Background Transcatheter pulmonary valve replacement (TPVR) is associated with a risk of procedural serious adverse events (SAE) and exposure to ionizing radiation. Objectives The purpose of this study was to define the risk of, and associations with, SAE and high-dose radiation exposure using large-scale registry data. Methods The analysis of the multicenter C3PO-QI registry was limited to patients who underwent TPVR from January 1, 2014, to December 31, 2016. SAE were defined as the occurrence of ≥1 moderate, major, or catastrophic events. Radiation dose was reported as dose area product adjusted for weight. Associations with outcome measures were explored in univariate and multivariable analyses. Results A total of 530 patients (59% male) underwent TPVR at a median age of 18.3 years (interquartile range [IQR]: 12.9 to 27.3 years) and weight of 58 kg (IQR: 43 to 77 kg) at 14 centers. Implant substrate included homograft (41%), bioprosthesis (30%), native right ventricular outflow tract (RVOT) (27%) and other (2%). TPVR indications were pulmonary insufficiency (28%), stenosis (23%), and mixed (49%). AE and SAE occurred in 26% and 13% of cases, respectively, including 1 mortality. SAE were more frequent in homograft conduit than other RVOT substrates, although SAE type and severity differed between implant substrates. Median radiation dose was 198 μGy·m2/kg (IQR: 94 to 350 μGy·m2/kg). Higher radiation dose was associated with older age, greater RVOT obstruction, and concomitant interventions (p Conclusions The incidence of SAE during TPVR in the C3PO-QI registry is high, but mortality is uncommon. Radiation dose is greater than for other congenital interventions and is associated with patient and procedural factors. Reintervention is common during early follow-up.

Many practitioners who have not had pharmacogenomic education are required to apply pharmacogenomics to their practices. Although many aspects of pharmacogenomics are similar to traditional concepts of drug-drug interactions, there are some differences. We searched PubMed with the search terms pharmacogenomics and pharmacogenetics (January 1, 2005, through December 31, 2019) and selected articles that supported the application of pharmacogenomics to practice. For inclusion, we gave preference to national and international consortium guidelines for implementation of pharmacogenomics. We discuss special considerations important in the application of pharmacogenomics to assist clinicians with ordering, interpreting, and applying pharmacogenomics in their practices.

Fractures of the proximal radius represent 5% to 10% of all elbow fractures in children. These fractures have many treatment options and have a high risk of complication, particularly loss of forearm rotation. Nonsurgical management of minimally displaced radial neck fractures produces excellent results in most patients. For displaced fractures, numerous methods of closed and percutaneous reduction have been proposed, whereas open reduction has been associated with particularly poor outcome. Many additional factors, including fracture angulation, patient age, associated injury, articular involvement, and internal fixation, may lead to worse outcomes. Because the literature is limited to retrospective case series, few studies provide high-level evidence to guide the treatment of pediatric proximal radius fractures; however, certain management principles have been established that are reviewed here.

Purpose The blood pressure ‘error signal’ represents the difference between an individual’s mean diastolic blood pressure and the diastolic blood pressure at which 50% of cardiac cycles are associated with a muscle sympathetic nerve activity burst (the ‘‘T50’’). In this study we evaluated whether T50 and the error signal related to the extent of change in blood pressure during autonomic blockade in young and older women, to study potential differences in sympathetic neural mechanisms regulating blood pressure before and after menopause. Methods We measured muscle sympathetic nerve activity and blood pressure in 12 premenopausal (25 ± 1 years) and 12 postmenopausal women (61 ± 2 years) before and during complete autonomic blockade with trimethaphan camsylate. Results At baseline, young women had a negative error signal (-8 ± 1 versus 2 ± 1 mmHg, p\0.001; respectively) and lower muscle sympathetic nerve activity (15 ± 1 versus 33 ± 3 bursts/min, p\0.001; respectively) than older women. The change in diastolic blood pressure after autonomic blockade was associated with baseline T50 in older women (r = -0.725, p = 0.008) but not in young women (r = -0.337, p = 0.29). Women with the most negative error signal had the lowest muscle sympathetic nerve activity in both groups (young: r = 0.886, p\0.001; older: r = 0.870, p\0.001). Conclusions Our results suggest that there are differences in baroreflex control of muscle sympathetic nerve activity between young and older women, using the T50 and error signal analysis. This approach provides further information on autonomic control of blood pressure in women.

Central (aortic) blood pressure, arterial stiffness, and sympathetic nerve activity increase with age in women. However, it is unknown if the age-related increase in sympathetic activity influences aortic hemodynamics and carotid-femoral pulse wave velocity (cfPWV), an index of central aortic stiffness. The goal of this study was to determine if aortic hemodynamics and cfPWV are directly influenced by sympathetic nerve activity by measuring aortic hemodynamics, cfPWV, and muscle sympathetic nerve activity (MSNA) in women before and during autonomic ganglionic blockade with trimethaphan camsylate. We studied 12 young premenopausal (23 ± 4 yr) and 12 older postmenopausal (57 ± 3 yr) women. These women did not differ in body mass index or mean arterial pressure ( P > 0.05 for both). At baseline, postmenopausal women had higher aortic pulse pressure, augmented pressure, augmentation index adjusted for a heart rate of 75 beats/min, wasted left ventricular pressure energy, and cfPWV than young women ( P < 0.05). During ganglionic blockade, postmenopausal women had a greater decrease in these variables in comparison to young women ( P < 0.05). Additionally, baseline MSNA was negatively correlated with the reductions in aortic pulse pressure, augmented pressure, and wasted left ventricular pressure energy during ganglionic blockade in postmenopausal women ( P < 0.05) but not young women. Baseline MSNA was not correlated with the changes in augmentation index adjusted for a heart rate of 75 beats/min or cfPWV in either group ( P > 0.05 for all). Our results suggest that some aortic hemodynamic parameters are influenced by sympathetic activity to a greater extent in older postmenopausal women than in young premenopausal women.NEW & NOTEWORTHY Autonomic ganglionic blockade results in significant decreases in multiple aortic pulse wave characteristics (e.g., augmented pressure) and central pulse wave velocity in older postmenopausal women but not in young premenopausal women. Certain aortic pulse wave parameters are negatively influenced by sympathetic activity to a greater extent in older postmenopausal women.

Background New pharmacotherapies to treat alcohol use disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice. To test the hypothesis that suppression of high EtOH consumption is a general property of tetracyclines, we screened several derivatives for antidrinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose–response relationship. Methods Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% EtOH over a 4-day period. Mice were administered a tetracycline or its vehicle 20 hours prior to drinking. Water and EtOH consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for EtOH content measurement immediately following the final bout of drinking. Results Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced EtOH drinking, and doxycycline showed a strong effect size trend toward reduced drinking. Subsequent studies with these 3 drugs revealed a dose-dependent decrease in EtOH consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on EtOH drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in EtOH consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition coefficients or distribution constants. Conclusions Due to its effectiveness in reducing high EtOH consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.

Background and objective Acute exacerbations of cystic fibrosis (CF) occur frequently throughout the course of the disease. Dyspnoea is the most common and distressing symptom experienced by patients during these episodes. We tested the hypothesis that pulmonary hyperinflation is an important determinant of dyspnoea severity during acute exacerbations. Methods We studied patients during an acute exacerbation of CF. Lung volumes, spirometry and dyspnoea scores were measured at Day 0, Day 7, at the end of treatment (EOT) and 14 days following the EOT. Results At the start of treatment, mean residual volume (RV)/total lung capacity (TLC) was 54.9%, which decreased significantly with treatment, as did vital capacity (VC), inspiratory capacity (IC) and dyspnoea scores. IC was the only independent predictor of dyspnoea severity. Conclusion Our study demonstrates significant improvements in hyperinflation, spirometry and dyspnoea scores with treatment of acute exacerbations of CF. Hyperinflation, rather than airflow limitation, may contribute towards the increased dyspnoea during exacerbations.

BACKGROUND Daratumumab (DARA) consistently interferes with routine blood bank serologic testing by directly binding to CD38 expressed on reagent red blood cells (RBCs). Treating RBCs with dithiothreitol (DTT) eliminates the DARA interference. We conducted an international, multicenter, blinded study aimed at validating the DTT method for use by blood bank laboratories worldwide. STUDY DESIGN AND METHODS Paired plasma sample unknowns were sent to 25 participating blood bank laboratories. Sample 1 was spiked with DARA only (10 µg/mL), and Sample 2 with DARA plus a clinically significant RBC antibody (anti-D [n = 6], anti-Fya [n = 9], or anti-s [n = 10]). Sites were instructed to perform an antibody screen with and without DTT-treated RBCs and to use a DTT-treated RBC panel for antibody identification. Qualitative data about the DTT method were collected by online survey. The primary outcome was the proportion of study sites able to identify the antibody unknown in the presence of DARA. RESULTS All sites observed the DARA interference with the antibody screen. The DARA interference was seen with all testing methods (gel, tube, or solid phase). Using the DTT method, 25 of 25 sites (100%) successfully identified the antibody unknown in the presence of DARA. Feedback on the DTT method was positive, with 17 of 19 (90%) sites responding to the survey indicating that they planned to use the DTT method to test clinical samples from DARA-treated patients. CONCLUSION The DTT method is robust and reproducible and can be implemented by transfusion services worldwide to help provide safe blood products to patients treated with DARA.

Extranodal lymphoma represents fewer than 0.5% of all breast malignancies. Secondary involvement of the breast with lymphoma is more common than primary breast lymphoma. The most common primary breast lymphoma is B-cell lymphoma. The initial imaging study of choice for a woman with a new breast mass is a diagnostic mammogram. In younger women ultrasound is more commonly the first imaging modality performed. Diagnosis is made from image-guided or physical examination-directed needle biopsy. Treatment is different from that for breast cancer, in that surgery is not the mainstay. Patients with breast lymphoma are treated primarily with chemotherapy and radiation.

Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic CD8(+) DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43–containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction–mediated Ag transfer pathway between monocytes and CD8(+) DCs and suggest that administration of tumor Ag–loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers.

Following Fontan palliation for univentricular congenital heart disease (uCHD), life-threatening complications related to this unique physiology often develop. Surgical takedown (TD) is associated with a 40% mortality, and few options exist for refractory Fontan failure. A 5-year-old with

Neonates with tetralogy of Fallot and symptomatic cyanosis (sTOF) may undergo palliation to delay complete repair (CR) with a systemic to pulmonary artery connection (SPC) or right ventricular outflow tract intervention (RVOTI). Comparison of these palliative strategies is lacking. Consecutive

Introduction With the introduction of the National Optimal Lung Cancer Pathway, rapid access to image-guided biopsies has become essential. In many centres, this service is provided through interventional radiology and can introduce delays. In response to this need, our interventional pulmonology service commenced targeted biopsies of peripheral lung masses and pleural-based lesions that were visible on thoracic ultrasound (TUS). Methods Suitable patients were identified by the interventional pulmonology team after review of CT imaging and TUS. All biopsies were performed under direct TUS guidance with an 18G core cutting needle (Argon super-core), by a respiratory consultant and/or training registrar, with a minimum of level 1 TUS Royal College of Radiologists competence. Post-procedure, TUS was recorded, followed by interval chest X-ray(s) at 1 (all procedures) and 4 hours (lung biopsies). Results Between September 2017 and July 2018, 40 patients with a median age of 75 years [IQR 70–79] were biopsied. The median time from referral to intervention was 2 days [1–6]. 31/40 (77%) procedures were performed as a day-case. A median number of 6 [5–8] biopsies were taken during each procedure. All biopsies were histologically representative and were sufficient for molecular testing. A true diagnosis was made in 37/40 (93%) patients. Of the 3 non-diagnostic cases, one lung biopsy was necrotic and a diagnosis of malignancy was made on bronchoscopy; whilst two pleural biopsies had a diagnosis of malignancy made on pleural fluid cytology and EBUS respectively. Complications occurred in 1/40 (2%) patients; a pneumothorax post-pleural biopsy, recognised on post-procedural TUS, and managed with a chest drain. Conclusion Physician-led TUS-guided transthoracic biopsy in patients undergoing investigation for suspected thoracic malignancy is associated with a high diagnostic yield and low complication rate. This service can streamline diagnostic pathways, whilst reducing dependence on and waiting times for radiology.

Clinical research in the treatment of patients with congenital heart disease (CHD) is limited by the wide variety of CHD manifestations and therapeutic options as well as the generally low incidence of CHD. The availability of comprehensive, contemporary outcomes studies is therefore limited. This inadequacy may result in a lack of data-driven medical decision making. In 2013, clinician scientists at two centers began a research collaboration, the Congenital Catheterization Research Collaborative (CCRC). Over time, the CCRC has grown to include nine cardiac centers from across the United States, with a common data coordinating center. The CCRC seeks to generate high-quality, contemporary, statistically robust, and generalizable outcomes research which can help address important clinical questions in the treatment of CHD. To date, the CCRC has reported on multicenter outcomes in: neonates with congenital aortic stenosis, infants undergoing right ventricular decompression for pulmonary atresia and intact ventricular septum, and infants with ductal-dependent pulmonary blood flow. The CCRC has been successful at leveraging large multicenter cohorts of patients in a contemporary period to perform comparative studies. In the future, the CCRC plans to continue to perform hypothesis-driven retrospective and prospective observational studies of CHD populations where controversy exists or where novel interventions or therapies have emerged. Quality improvement efforts including lesion-specific registry development may be an additional potential future target.

The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein–mediated or β-arrestin–mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein– and β-arrestin–mediated signaling, we identified and characterized small-molecule, biased agonists of the receptor. In a mouse model of T cell–mediated allergic contact hypersensitivity (CHS), topical application of a β-arrestin–biased, but not a G protein–biased, agonist potentiated inflammation. T cell recruitment was increased by the β-arrestin–biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and β-arrestin in T cells. In mouse and human T cells, the β-arrestin–biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that β-arrestin–biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors.

© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society Key Points: The mechanisms affecting recruitment patterns of postganglionic sympathetic nerves remain unclear. The divergent and convergent preganglionic innervation patterns of postganglionic neurons and the presence of differently sized postganglionic nerves suggest that the ganglia may participate in modifying the discharge patterns of single sympathetic postganglionic neurons innervating the skeletal muscle circulation. Whether the ganglia affect the ordered behaviour of varying sized postganglionic sympathetic neurons in humans has not been studied. Trimethaphan infusion produced an ordered pattern of action potential (AP) de-recruitment whereby the firing of larger, low probability APs present at baseline was abolished first, followed by progressive decreased probability of smaller APs. Although integrated sympathetic bursts were no longer detected after several minutes of trimethaphan, firing of the smallest APs was detected. These data suggest the ganglia affect the distribution of firing probabilities exhibited by differently sized sympathetic neurons. The ganglia may contribute to sympathetic neural emission patterns involved in homeostatic regulation. Abstract: Do the ganglia contribute to the ordered behaviour of postganglionic neuronal discharge within the sympathetic nervous system? To further understand the functional organization of the sympathetic nervous system we employed the microneurographic approach to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to study postganglionic action potential (AP) behaviour during nicotinic blockade at the ganglia (trimethaphan camsylate, 1–7 mg min−1) in seven females (37 ± 5 years). Trimethaphan elicited a progressive reduction in sympathetic outflow characterized by fewer integrated bursts with decaying amplitude. Underlying trimethaphan-mediated attenuations in integrated MSNA were reductions in AP incidence (186 ± 101 to 29 ± 31 AP (100 beats)−1) and AP content per integrated burst (7 ± 2 to 3 ± 1 APs burst−1) (both P < 0.01) in the final minute of detectable bursting activity in the trimethaphan condition, compared to baseline. We observed an ordered de-recruitment of larger to smaller AP clusters active at baseline (14 ± 3 to 8 ± 2 active AP clusters, P < 0.01). Following cessation of integrated bursts in the trimethaphan condition, the smallest 6 ± 2 sympathetic AP clusters persisted to fire in an asynchronous pattern (49 ± 41 AP (100 beats)−1) in all participants. Valsalva's manoeuvre did not increase the incidence of these persistent APs (60 ± 42 AP (100 beats)−1, P = 0.52), or recruit any larger APs in six of seven participants (6 ± 1 total AP clusters, P = 0.30). These data suggest that the ganglia participate in the ordered recruitment of differently sized postganglionic sympathetic nerves.

Objectives To evaluate differences in radiation dose and image quality across institutions, fluoroscope vendors and generations of fluoroscopes for pediatric cardiac catheterization. Background Increased recognition of the potentially harmful effects of ionizing radiation has spurred technological advances in fluoroscopes, as well as increased focus on optimizing fluoroscope performance. There is currently little understanding of variability in the dose-image quality relationship across institutions, fluoroscope vendor and/or generation of equipment. Methods We evaluated latest generation fluoroscopes from Phillips, Siemens, GE, and Toshiba, and an older generation Phillips fluoroscope (release date 2003) at three different institutions. Radiation dose was measured using an anthropomorphic dose-assessment phantom with effective dose in mSv estimated from Monte Carlo simulations. Image quality phantom images were scored on a 12-point scale by three blinded reviewers. Results Fluoroscope effective doses ranged from 0.04 to 0.14 mSv/1,000 pulses for fluoroscopy with associated composite image quality scores ranging from 8.0 ± 0.6 to 10.4 ± 1.3. For cineangiography, effective doses ranged from 0.17 to 0.57 mSv/1,000 frames with image quality scores ranging from 10.1 ± 0.3 to 11.1 ± 0.3. There was modest correlation between effective dose and image quality (r = 0.67, P = 0.006). The older generation fluoroscope delivered consistently higher doses than the newer generation systems (2.3- to 3.5-fold higher for fluoroscopy; 1.1- to 3.4-fold higher for cineangiography) without appreciable differences in image quality. Conclusion Technological advances have markedly improved fluoroscope performance. Comparing latest generation systems across vendors and institutions, we found variability in the dose-IQ relationship and speculate that this reflects both equipment and institutional optimization practices.

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5–1.2 µg·kg−1·min−1, n = 13) or PE (0.2–1.0 µg·kg−1·min−1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Purpose To compare the outcome of architectural distortion (AD) without associated mass only on digital breast tomosynthesis (DBT) with AD seen at two-dimensional (2D) mammography and to evaluate if the incidence of malignancy is influenced by the presence of a correlate at ultrasonography (US). Materials and Methods This retrospective study had institutional review board approval and was HIPAA compliant. All consecutive cases in which patients with AD were ultimately assigned Breast Imaging Reporting and Data System (BI-RADS) 4 or 5 categories from 2009 to 2016 were reviewed by three readers for visibility (2D vs DBT). The level of suspicion was assigned using a Likert scale. Pathologic results were compared between 2D-detected and DBT-detected AD. Frequencies were compared by using the McNemar and Pearson χ

Long-term daily azithromycin therapy reduces the frequency of exacerbations in chronic obstructive pulmonary disease (COPD) in a randomized controlled clinical trial setting. Concerns exist regarding arrhythmic and auditory toxicities from chronic use in the real-world setting. We hypothesized that risk factors for adverse drug reactions to azithromycin would be more frequent than previously reported, that certain specific subgroups would have different frequencies of these risk factors and that the whispered voice test would be a useful test with which to test for hearing deficits.Following ethical approval, 47 consecutive hospital-based patients with a mean age 69 years ± 8.2, and with physician-diagnosed COPD (mean FEVIn total, 38 patients (80.9 %) had at least one risk factor or contraindication to azithromycin treatment. 19 patients (40.4 % of total) had subjective hearing impairment. 17 (36.1 %) had prolonged QTc intervals. 4 patients (8.51 %) had contraindicating co-morbidities. Those on long-term oxygen therapy were significantly more likely to have at least one risk factors or contraindications to azithromycin (p = 0.0025).In a COPD population who would otherwise potentially be candidates for long-term daily azithromycin therapy, over 80 % had risk factors for complications from long-term daily azithromycin. Preventative treatment with long-term daily azithromycin may be appropriate for fewer COPD patients than previously thought, especially in those on long-term oxygen therapy.

Propranolol, a non-selective β-blocker, has been found to have a tremendous array of indications. Recent evidence has suggested that propranolol may be effective in patients suffering from post-traumatic stress disorder by suppressing activity in the amygdala and thereby inhibiting emotional memory formation. Dosage requirements have been well established in the pediatric and adult population, however, there has been no definitive geriatric dose recommended in the package inserts made available to the public. The aim of this paper is to use pharmacokinetic simulations in order to establish a pharmacokinetic profile dosage equivalent for the elderly as has been found in young patients. After completing the Monte-Carlo simulations for the elderly and young patients, a single 10mg dose in the elderly has shown comparable pharmacokinetic profiles as found in young patients administered a 40mg single dose.

Aim: To assess impact and value of using clinical decision support (CDS) to drive providers toward online pharmacogenomics education. Materials & methods: CDS was used to target prescribers of codeine/tramadol, send an educational email, display alert/inbox and provide links to an online resource. Providers were surveyed to assess impact. Results: Of the methods used to target providers, educational email was more effective (7.2%). Survey response rate was 29.2% (n = 528/1817). Of respondents, 57.4% reported opening the email and 27.1% accessed the online resource. Of those accessing the resource, 89% found it useful and learned something new about pharmacogenomics. Conclusion: The impact of using CDS to target pharmacogenomics education was limited. However, providers accessing the online resource found it useful and educational.

© 2015 Taylor & Francis. Partnership is currently the focus of much work within higher education and advocated as an important process to address a range of higher education goals. In this paper, we propose the term inclusive partnership to conceptualise a non-selective staff–student relationship. While recognising the challenges of inclusive partnership working for institutions, staff and students, this paper outlines the opportunities it offers and provides detailed case studies of inclusive partnerships within the geography curriculum. We conclude with some guiding principles to inform the development of inclusive partnerships in a range of settings.

Objective The objective is to quantify radiation dose in children undergoing cardiac catheterization and determine the impact of increased reporting transparency on total radiation exposure. Background: Cardiac catheterization (cath) can result in significant radiation exposure in children. There has been growing interest in quantifying and reducing radiation exposure in pediatric cath procedures. Our center underwent a slight change in practice recently that resulted in direct physician reporting of radiation dose following every case. Methods We reviewed cath procedures across three different eras in four cath categories: post-heart transplant annual cath, unilateral pulmonary artery (PA) stent placement, pre-Fontan cath, and pre-Glenn cath. The eras were defined as: Era 1, 1/2009 – 1/2011; Era 2, 1/2011 – 9/2013; and Era 3, 9/2013 – 5/2014. In Era 3, the physician performing the cath was responsible for reporting the radiation data. Results Across the three eras, there were significant decreases in cumulative air KERMA (mGy) among all four cath categories. From Era 2 to Era 3, the greatest decreases in radiation were noted, particularly in dose area product (cGy·cm2) in the transplant annual evaluation and pre-Glenn cases. In Era 1, 2 cases (1.2%) had a frame rate reduction, while in Era 2, 22 cases (12.0%), and in Era 3, 83 cases (21.6%) had frame rate changes (P

Objectives The purpose of this study was to examine the outcomes of catheter dilation interventions in general upon surgical anastomotic sites in the immediate postoperative period. Background Early postoperative cardiac catheter intervention is regarded as high-risk, particularly when a dilation intervention across a fresh suture line is performed. Methods All catheter dilation interventions performed upon a fresh suture line within 30 days of congenital heart surgery between August 2005 and December 2013 were reviewed. Values are reported as median and interquartile range (IQR). Primary endpoint was procedural success, which was defined as an increase in vessel diameter of >75% of the adjacent normal vessel or 50% increase over pre-dilation diameter. Secondary endpoints included procedural complications and survival to hospital discharge. Results Forty-five patients, median age 0.15 years (0.03–0.51 years), weight 4.1 kg (3.1–6.4 kg), underwent 62 interventional procedures on median postoperative day 7 (3–13 days). Among the 62 dilation interventions at surgical anastomotic areas, were 30 stent and 32 balloon angioplasty procedures. There were two major complications including: arterial dissection during stent placement and a procedural mortality due to pulmonary artery avulsion during angioplasty. There were 12 deaths (27%) prior to hospital discharge. The median ratio of maximum stent diameter to stenosis diameter was 2.62 (2.27–3.73). The median ratio of maximum balloon diameter to stenosis diameter was 2.27 (1.84–2.94). Stent placement was more likely to result in procedural success (OR 2.1; 95% confidence interval 1.6–2.8). Conclusion Though caution is paramount, early postoperative catheter dilation intervention across fresh suture lines can be performed safely in small, critically ill children. © 2015 Wiley Periodicals, Inc.

Serotonin released in the nerve synapses is cleared through reuptake into presynaptic neurons and metabolism with monoamine oxidase (MAO). Therapy with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors increases serotonin concentration in the synaptic cleft and may result in serotonin syndrome (SS). Our patient undergoing sentinel lymph node biopsy was on fluoxetine (SSRI) and intraoperatively developed SS after receiving fentanyl (200 μg) and methylene blue (MAO inhibitor), 7 mg subcutaneously into the scalp. Initial presentation was several episodes of generalized muscle activity, which was later diagnosed as lower extremity myoclonus consistent with SS. Upon awakening, the patient showed no evidence of encephalopathy, and the clonus was less intense. The patient was discharge home the next day. Our case suggests the possibility that even a small dose of methylene blue, when administered simultaneously with other serotoninergic medications, may be associated with serotonin toxicity.

Prior to initiation of a formal screening program, 30 % of patients referred for device closure of an atrial septal defect (ASD) at our institution had atrial septal anatomy which precluded ASD device closure. This resulted in inefficiencies in workflow, staff utilization, and inconvenience for families. Our objective was to report our experience with an ASD prescreening evaluation/protocol and family consultation process. This is a retrospective study of pediatric patients who underwent a comprehensive ASD prescreening evaluation at Children's Healthcare of Atlanta between January 2011 and June 2013. The comprehensive prescreening process included a detailed transthoracic echocardiogram and family consultation. Upon establishing a formal prescreening process for patients with secundum ASDs, 138 patients were screened for appropriateness of ASD device closure. At time of prescreening, 40 patients (29 %) were deemed not to be suitable candidates for device ASD closure. In 9 patients (6.5 %), after discussion with the interventionalist, parents elected to pursue surgical ASD closure. A total of 78 patients (56.5 %) underwent successful transcutaneous ASD device closure. In addition, there was a significant discrepancy in the reported size of the ASD between the outside evaluation and the ASD size discovered during the prescreening process. The addition of a prescreening program for transcatheter ASD closure has decreased the incidence of unsuccessful ASD closure from 30 to 10.3 %. The use of a comprehensive evaluation process for ASD device closure improves the likelihood of successful device implantation and permits adequate preprocedural counseling for the patient and family.

BACKGROUND Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS DARA binding to CD38+ or CD38– HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38– controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K– units are provided to these patients.

Purpose Low-and middle-income countries disproportionately comprise 65% of cancer deaths. Cancer care delivery in resource-limited settings, especially low-income countries in sub-Saharan Africa, is exceedingly complex, requiring multiple modalities of diagnosis and treatment. Given the vast human, technical, and financial resources required, access to radiotherapy remains limited in sub-Saharan Africa. Through 2017, Rwanda has not had in-country radiotherapy services. The aim of this study was to describe the implementation and early outcomes of the radiotherapy referral program at the Butaro Cancer Centre of Excellence and to identify both successful pathways and barriers to care. Methods Butaro District Hospital is located in a rural area of the Northern Province and is home to the Butaro Cancer Centre of Excellence. We performed a retrospective study from routinely collected data of all patients with a diagnosis of cervical, head and neck, or rectal cancer between July 2012 and June 2015. Results Between 2012 and 2015, 580 patients were identified with these diagnoses and were potential candidates for radiation. Two hundred eight (36%) were referred for radiotherapy treatment in Uganda. Of those referred, 160 (77%) had cervical cancer, 31 (15%) had head and neck cancer, and 17 (8%) had rectal cancer. At the time of data collection, 101 radiotherapy patients (49%) were alive and had completed treatment with no evidence of recurrence, 11 (5%) were alive and continuing treatment, and 12 (6%) were alive and had completed treatment with evidence of recurrence. Conclusion This study demonstrates the feasibility of a rural cancer facility to successfully conduct out-of-country radiotherapy referrals with promising early outcomes. The results of this study also highlight the many challenges and lessons learned in providing comprehensive cancer care in resource-limited settings., SCOPUS: ar.j, info:eu-repo/semantics/published

Background. Cervical interlaminar epidural steroid injections (ESIs) are commonly performed procedures to treat painful cervical radiculopathy, but little is known about the systemic absorption and serum levels of steroids following injection. The primary objective of this study was to investigate the pharmacokinetics of fluoroscopy-guided cervical epidural-administered triamcinolone acetonide in a cohort of patients with cervical radicular pain seeking treatment in a pain medicine clinic.Methods. The study cohort included eight patients undergoing a fluoroscopically guided C7-T1 interlaminar ESI at a pain medicine specialty clinic. Blood was collected prior to the ESI and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injection. The sample extract was analyzed by tandem mass spectrometry.Results. The terminal elimination half-life of cervical epidural-administered triamcinolone in a noncompartmental analysis was 219 hours. In the noncompartmental analysis, peak triamcinolone concentrations of 5.4 ng/mL were detected within 22.1 hours after administration.Conclusions. The pharmacokinetics of cervical epidural-administered triamcinolone is consistent with our previous study of lumbar ESI, demonstrating that the elimination half-life is longer than that which has been reported following intravenous triamcinolone. The elimination half-life was shorter following cervical ESI than that which has been reported following lumbar ESI.

Objectives Opioid treatment of chronic noncancer pain (CNCP) adds complexity and uncertainty to patient interactions. We sought to assess clinician attitudes, beliefs, practice styles, and concerns around opioid prescribing following the release of the US Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids for chronic pain. Methods E-mailed electronic survey to clinicians at a large academic medical institution. Results A total of 961 clinicians responded to the survey (response rate = 40%), 720 of whom prescribed opioids and were not in training. Sixty-five percent were physicians, and 35% were nurse practitioners or physician assistants, with a mean age of 47 years (SD ± 11.4 years). Eighty-two percent were reluctant to prescribe opioids for CNCP, and only 47% expressed confidence in their care for CNCP patients. Sixty-seven percent were aware of the CDC guideline, 55% were enrolled in the state Prescription Drug Monitoring Program (PDMP), and 2% always or frequently prescribed naloxone to patients on opioids. Guideline awareness was associated with increased confidence in caring for CNCP patients. Clinicians having knowledge of a patient overdose were 31% more likely to be enrolled in the PDMP (relative rate= 1.31, 95% confidence interval = 1.14-1.52, chi-square = 11.00, P

A number of barriers exist for adoption of pharmacogenomics into practice. Physicians, pharmacists, and nurses report limited knowledge about pharmacogenomics and its use in patient care. Lack of pharmacogenomics education curricula as part of professional schools or postgraduate training programs has been reported as a potential cause. Understanding pharmacogenomics is further complicated by a complex and nonstandard lexicon, limited medication guidelines, rapidly changing evidence, and insufficient awareness of test availability and utility.