Citations

Two-dimensional echocardiography (echo) is the method of choice for noninvasive evaluation of the left ventricle (LV) function owing to its low cost, fast acquisition time, and high temporal resolution. However, it only provides the LV boundaries in discrete 2D planes, and the 3D LV geometry needs to be reconstructed from those planes to quantify LV wall motion, acceleration, and strain, or to carry out flow simulations. An automated method is developed for the reconstruction of the 3D LV endocardial surface using echo from a few standard cross sections, in contrast with the previous work that has used a series of 2D scans in a linear or rotational manner for 3D reconstruction. The concept is based on a generalized approach so that the number or type (long-axis (LA) or short-axis (SA)) of sectional data is not constrained. The location of the cross sections is optimized to minimize the difference between the reconstructed and measured cross sections, and the reconstructed LV surface is meshed in a standard format. Temporal smoothing is implemented to smooth the motion of the LV and the flow rate. This software tool can be used with existing clinical 2D echo systems to reconstruct the 3D LV geometry and motion to quantify the regional akinesis/dyskinesis, 3D strain, acceleration, and velocities, or to be used in ventricular flow simulations.

ObjectiveTo develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).MethodsWe conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.ResultsThe guideline covers the use of traditional disease‐modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat‐to‐target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.ConclusionThis RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision‐making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Objective To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA). Methods We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. Results The guideline covers the use of traditional disease‐modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat‐to‐target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. Conclusion This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision‐making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

ABSTRACT This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease‐modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available. © 2015 International Parkinson and Movement Disorder Society

AbstractThis document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances. © 2015 International Parkinson and Movement Disorder Society

OBJECT The authors sought to determine whether flow diversion with the Pipeline Embolization Device (PED) can approximate microsurgical decompression in restoring function after cranial neuropathy following carotid artery aneurysms. METHODS This multiinstitutional retrospective study involved 45 patients treated with PED across the United States. All patients included presented between November 2009 and October 2013 with cranial neuropathy (cranial nerves [CNs] II, III, IV, and VI) due to intracranial aneurysm. Outcome analysis included clinical and procedural variables at the time of treatment as well as at the latest clinical and radiographic follow-up. RESULTS Twenty-six aneurysms (57.8%) were located in the cavernous segment, while 6 (13.3%) were in the clinoid segment, and 13 (28.9%) were in the ophthalmic segment of the internal carotid artery. The average aneurysm size was 18.6 mm (range 4–35 mm), and the average number of flow diverters placed per patient was 1.2. Thirty-eight patients had available information regarding duration of cranial neuropathy prior to treatment. Eleven patients (28.9%) were treated within 1 month of symptom onset, while 27 (71.1%) were treated after 1 month of symptoms. The overall rate of cranial neuropathy improvement for all patients was 66.7%. The CN deficits resolved in 19 patients (42.2%), improved in 11 (24.4%), were unchanged in 14 (31.1%), and worsened in 1 (2.2%). Overtime, the rate of cranial neuropathy improvement was 33.3% (15/45), 68.8% (22/32), and 81.0% (17/21) at less than 6, 6, and 12 months, respectively. At last follow-up, 60% of patients in the isolated CN II group had improvement, while in the CN III, IV, or VI group, 85.7% had improved. Moreover, 100% (11/11) of patients experienced improvement if they were treated within 1 month of symptom onset, whereas 44.4% (12/27) experienced improvement if they treated after 1 month of symptom onset; 70.4% (19/27) of those with partial deficits improved compared with 30% (3/10) of those with complete deficits. CONCLUSIONS Cranial neuropathy caused by cerebral aneurysm responds similarly when the aneurysm is treated with the PED compared with open surgery and coil embolization. Lower morbidity and higher occlusion rates obtained with the PED may suggest it as treatment of choice for some of these lesions. Time to treatment is an important consideration regardless of treatment modality.

Abstract Prior to PanIN formation, acinar cells harboring oncogenic Kras gradually lose their acinar character and take on a ductal phenotype in a process known as acinar-to-ductal metaplasia. Rather than mimicking a normal pancreatic duct, metaplastic ducts take on a proliferative biliary progenitor phenotype, marked by the expression of SOX17 and PDX1 and the presence of numerous tuft cells, recently identified as a PanIN initiating cells. Manipulation of SOX17 and PDX1 in vivo reveal them to be a transdifferentiation promoter and suppressor, respectively, both greatly affecting tuft cell genesis and tumor formation. These opposing roles of developmental transcription factors during tumorigenesis implicate the usurpation of a differentiation program that significantly contributes to cellular heterogeneity within early pre-cancerous lesions of the pancreas. Citation Format: Kenneth K. Takeuchi, Kathleen E. Delgiorno, Christopher J. Halbrook, Howard C. Crawford. Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA13.

Abstract Nearly all pancreatic ductal adenocarcinomas are caused by oncogenic mutations in the KRAS gene. Pharmacological inhibition of mutant KRAS has thus far been unsuccessful in the clinical setting, precipitating a need to understand the pathways downstream of KRAS which may prove more easily targeted with small molecule inhibitors. Here we show that PI3K p110α is absolutely required for pancreatic tumorigenesis while p110β is dispensable for this process. Surprisingly, ablation of p110α does not impair the ability of KRAS to activate AKT, demonstrating that AKT activation is not sufficient for transformation. Instead we find that p110α is required for robust activation of RAC1, a small GTPase required for pancreatic metaplasia. Consistent with this, our data show that p110α is necessary for regulating epithelial expression and activation of RAC-GEFs including Vav1, Tiam1 and Ect2. Ultimately, these results define the mechanistic role of p110α in pancreatic tumorigenesis and suggest selective inhibition of this PI3K isoform as a promising therapeutic approach to treating patients with pancreas cancer. Citation Format: Kenneth K. Takeuchi, Eileen Carpenter, Claire Wu, Christopher J. Halbrook, Richard Z. Lin, Howard C. Crawford. PI3K regulation of RAC1 is required for Kras-induced pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A04.