Intuitive concepts in internal medicine and their occurrence in undergraduate medical students in different semesters.

Background: Dealing with errors in medical practice is of great importance for patient safety. In the natural sciences, intuitive concepts, so-called misconceptions, are increasingly coming into focus of teaching because they lead to a faulty understanding of contexts and thus to faulty scientific reasoning. In medicine, intuitive concepts still play a subordinate role. However, once intuitive concepts have been memorized, they can become firmly established and, under certain circumstances, lead to diagnostic and treatment errors in medical practice. The aim of this study was to identify potential intuitive concepts in internal medicine and to analyze their occurrence in medical students from different semesters. Methods: Eight internists from different subspecialties were asked about intuitive concepts by means of a structured interview. A total of 17 intuitive concepts were identified. Using these concepts, a multiple-choice test was created with 17 patient cases. For each case, there were four possible answers: the correct answer, an incorrect answer that included the intuitive concept, the answer "both are incorrect", and the answer "I am not sure", which is to be understood in the sense of "I do not know whether one of the three answers is correct". As an online multiple-choice test, these 17 cases were made available to all 2nd, 6th, and 12th semester students (N=1170, n=418 from the 2nd semester, n=425 from the 6th semester, and n=327 from the 12th semester, i.e., the final year) for four weeks in June 2015. The test had to be answered within nine minutes. A mixed logistic regression model was used for evaluation. Results: Of the N=317 participating students (n=97 from the 2nd semester, n=124 from the 6th semester, and n=96 from the internship year, overall response rate 27.1%), on average, students from all three groups chose the intuitive concept most often, approximately 40%, although the correct answer increased toward the final year with simultaneously decreasing uncertainty and decreasing feeling of not knowing, respectively. In the final year, compared to the 2nd semester, the intuitive concept was selected significantly more often for two questions (p<0.01). For four questions, the intuitive concept was selected significantly less frequently in the final year (p<0.01). Conclusion: Intuitive concepts can be identified in internal medicine and do not appear to be significantly reduced in students during the course of their studies. This suggests that this could also be the case for other medical subjects. Therefore, similar studies should be conducted for other medical subjects in order to identify potential sources of error in clinical work. In addition, suitable didactic methods should be developed and tested with which students learn not to succumb to intuitive concepts as far as possible in order to prevent diagnostic or therapeutic errors in later medical practice.

Magnetic resonance imaging and ultrasound for prediction of residual tumor size in early breast cancer within the ADAPT subtrials.

BACKGROUND: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes. METHODS: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values. RESULTS: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors. CONCLUSIONS: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).

Gene therapy for infantile malignant osteopetrosis: review of pre-clinical research and proof-of-concept for phenotypic reversal.

Infantile malignant osteopetrosis is a devastating disorder of early childhood that is frequently fatal and for which there are only limited therapeutic options. Gene therapy utilizing autologous hematopoietic stem and progenitor cells represents a potentially advantageous therapeutic alternative for this multisystemic disease. Gene therapy can be performed relatively rapidly following diagnosis, will not result in graft versus host disease, and may also have potential for reduced incidences of other transplant-related complications. In this review, we have summarized the past sixteen years of research aimed at developing a gene therapy for infantile malignant osteopetrosis; these efforts have culminated in the first clinical trial employing lentiviral-mediated delivery of TCIRG1 in autologous hematopoietic stem and progenitor cells.

How a-Type Anomalies Can Depend on Marginal Couplings.

Even dimensional defects and boundaries in conformal field theory support type a anomalies on their world volume. We show that the one-point functions of marginal operators, in the presence of defects and boundaries, are anomalous, and that the Wess-Zumino consistency condition relates them to the derivative of the a anomaly with respect to the marginal coupling. We also argue that the constant term F for odd dimensional surfaces can depend on marginal parameters.

[Facet infiltration and periradicular therapy]. / Facetteninfiltration und periradikuläre Therapie.

BACKGROUND: Spinal complaints affect a large proportion of the population and lead to numerous doctor visits. PURPOSE: The different techniques of CT-guided infiltration of spinal disorders, taking into account facet infiltration, periradicular infiltration and epidural flooding are demonstrated. MATERIALS AND METHODS: Discussion of basic work and expert recommendations as well as presentation of different treatment steps for everyday clinical practice. RESULTS: The CT-guided application of the different types of infiltration allows precise execution of the therapy. Both facet infiltration and periradicular infiltration and epidural flooding have their place depending on the clinical symptoms. The optimal combination of drugs to administer is still the subject of numerous studies and sometimes controversial discussions. CONCLUSION: An exact clinical and imaging evaluation of the pain symptoms in the back is the basic requirement for a targeted therapy.

Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention. / Aktualisierte S3-Leitlinie zur Diagnostik und Therapie des kolorektalen Karzinoms: Bedeutung für die radiologische Diagnostik und Intervention.

The updated German S3 guidelines "Colorectal Carcinoma" were created as part of the oncology program of the Association of the Scientific Medical Societies (AWMF), German Cancer Society and the German Cancer Aid under the auspices of the German Society for Digestive and Metabolic Disorders (DGVS) and they replace the previous guidelines from 2013. The main changes in the updated guidelines include the latest recommendations regarding endoscopy and adjuvant/neoadjuvant therapies as well as a complete restructuring of the section regarding therapeutic approach in metastases and in the palliative situation. The present manuscript discusses the importance of the current recommendations for radiological diagnosis and treatment and is intended to enhance the quality of patient information and patient care by widespread distribution. KEY POINTS:: · Radiological recommendations for treating patients with colorectal carcinoma are presented.. · The different possibilities of radiological imaging for diagnosis are documented in detail.. · Radiologists should be acquainted with the different possibilities of oncological intervention in patients with colorectal carcinoma.. CITATION FORMAT: · Vogl TJ, Pereira PL, Schreyer AG et al. Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention. Fortschr Röntgenstr 2019; 191: 298 - 310.

Displacement Operators and Constraints on Boundary Central Charges.

Boundary conformal field theories have several additional terms in the trace anomaly of the stress tensor associated purely with the boundary. We constrain the corresponding boundary central charges in three- and four-dimensional conformal field theories in terms of two- and three-point correlation functions of the displacement operator. We provide a general derivation by comparing the trace anomaly with scale dependent contact terms in the correlation functions. We conjecture a relation between the a-type boundary charge in three dimensions and the stress tensor two-point function near the boundary. We check our results for several free theories.

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial.

OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. METHODS: We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.

Universal thermal corrections to single interval entanglement entropy for two dimensional conformal field theories.

We consider single interval Rényi and entanglement entropies for a two dimensional conformal field theory on a circle at nonzero temperature. Assuming that the finite size of the system introduces a unique ground state with a nonzero mass gap, we calculate the leading corrections to the Rényi and entanglement entropy in a low temperature expansion. These corrections have a universal form for any two dimensional conformal field theory that depends only on the size of the mass gap and its degeneracy. We analyze the limits where the size of the interval becomes small and where it becomes close to the size of the spatial circle.

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease.

BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120).

This paper reassesses the currently accepted viewpoint that targeting the terminal fields (i.e. striatum) of degenerating nigrostriatal dopamine neurons with neurotrophic factors in Parkinson's disease (PD) is sufficient for achieving an optimal neurotrophic response. Recent insight indicating that PD is an axonopathy characterized by axonal transport deficits prompted this effort. We tested whether a significantly greater neurotrophic response might be induced in SN neurons when the neurotrophic factor neurturin (NRTN) is also targeted to the substantia nigra (SN), compared to the more conventional, striatum-only target. While recognizing the importance of maintaining the integrity of nigrostriatal fibers and terminals (especially for achieving optimal function), we refocused attention to the fate of SN neurons. Under conditions of axonal degeneration and neuronal transport deficits, this component of the nigrostriatal system is most vulnerable to the lack of neurotrophic exposure following striatal-only delivery. Given the location of repair genes induced by neurotrophic factors, achieving adequate neurotrophic exposure to the SN neurons is essential for an optimal neurotrophic response, while the survival of these neurons is essential to the very survival of the fibers. Two separate studies were performed using the 6-OHDA model of nigrostriatal degeneration, in conjunction with delivery of the viral vector AAV2-NRTN (CERE-120) to continuously express NRTN to either striatum or nigra alone or combined striatal/nigral exposure, including conditions of ongoing axonopathy. These studies provide additional insight for reinterpreting past animal neurotrophic/6-OHDA studies conducted under conditions where axon transport deficiencies were generally not accounted for, which suggested that targeting the striatum was both necessary and sufficient. The current data demonstrate that delivering NRTN directly to the SN produces 1) expanded NRTN distribution within the terminal field and cell bodies of targeted nigrostriatal neurons, 2) enhanced intracellular neurotrophic factor signaling in the nigrostriatal neurons, and 3) produced greater numbers of surviving dopamine neurons against 6-OHDA-induced toxicity, particularly under the conditions of active axonopathy. Thus, these data provide empirical support that targeting the SN with neurotrophic factors (in addition to striatum) may help enhance the neurotrophic response in midbrain neurons, particularly under conditions of active neurodegeneration which occurs in PD patients.

Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients.

OBJECTIVE: In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures). METHODS: After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen. RESULTS: Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery. CONCLUSIONS: Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.

Influence of observer experience and training on proficiency in coronary CT angiography interpretation.

PURPOSE: To assess the influence of experience and training on the proficiency in coronary CT angiography (CCTA) interpretation of practitioners with different levels of experience. METHODS AND MATERIALS: Nine radiologist and cardiologist observers with varying prior CCTA experience ranging from novice to expert independently analyzed two case series of 50 catheter-correlated CCTA studies for coronary artery stenosis (0%, ≤49%, 50-74%, 75-99%, or 100%). Results of the first case series were unblinded and presented along with catheter angiography results to each reader before proceeding to the second series. Diagnostic accuracy on a per-segment basis was compared for all readers and both case series, respectively. RESULTS: Correlation coefficients between CCTA and catheter angiography initially ranged between good (r=0.87) and poor (r=0.26), depending on reader experience, and significantly (p<0.05) improved in the second case series (range: r=0.42 to r=0.91). Diagnostic accuracy was significantly (p<0.05) higher for more experienced readers (range: 96.5-97.8%) as compared to less experienced observers (range: 90.7-93.6%). After completion of the second case series for less experienced readers sensitivity and PPV significantly (p<0.05) improved (range: 62.7-67.8%/51.4-84.1%), but still remained significantly (p<0.05) lower as compared to more experienced observers (range: 89.8-93.3%/80.6-93.3%). CONCLUSION: The level of experience appears to be a strong determinant of proficiency in CCTA interpretation. Limited one-time training improves proficiency in novice readers, but not to clinically satisfactory levels.

Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating "clinical proof-of-concept" for AAV-neurturin (CERE-120) in Parkinson's disease.

Neurotrophic factors have long shown promise as potential therapies for age-related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE-120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long-term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof-of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol-prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational research and development for age-related and other neurodegenerative diseases.

64-slice multidetector-row computed tomography in the diagnosis of coronary artery disease: interobserver agreement among radiologists with varied levels of experience on a per-patient and per-segment basis.

PURPOSE: To assess the interobserver variability of 4 radiologists with different levels of experience in the evaluation of 64-slice coronary computed tomographic angiography (cCTA). MATERIALS AND METHODS: Two board-certified radiologists with 10 and 8 years of experience in reading cCTA and 2 radiology residents, 1 with 3 years of experience in reading cCTA and 1 with experience in reading general computed tomographic scans but without dedicated cCTA training, participated in the study. All the observers independently analyzed 50 cCTA studies for signs of coronary artery disease (stenosis of 0%, ≤49%, 50% to 74%, 75% to 99%, or 100%). Diagnostic accuracy of the 4 readers for stenosis detection on cCTA was compared with that of conventional angiography on a per-segment and per-patient basis. No patients, vessels, or segments were excluded from analysis. RESULTS: On a per-segment basis, correlation between cCTA and invasive coronary angiography was good for readers with more than 10 (r=0.75), more than 8 (r=0.75), and more than 3 (r=0.73) years of cCTA experience. The correlation coefficient was poor (r=0.39) for the untrained reader. Sensitivity was not significantly (P=0.56) different between observers with more than 8 and more than 10 years of experience but was significantly (P>0.05) lower for the reader with less than 3 years experience and for the untrained reader. However, we found no significant difference in overall diagnostic accuracy on a per-patient (P=0.86) and on a per-segment level (P=0.72) among the 4 readers. CONCLUSION: The level of experience significantly influences the sensitivity of coronary artery stenosis detection at cCTA, and thus highlights the need for dedicated training in cCTA interpretation.

Dual energy CT for the assessment of reperfused chronic infarction - a feasibility study in a porcine model.

BACKGROUND: Detection of myocardial infarction has been the focus of considerable research over the past few decades. Recently developed dual source computed tomography (DSCT) scanners with dual energy mode have been used to detect myocardial infarction, but the studies on this topic are few. PURPOSE: To evaluate the feasibility and performance of dual energy CT (DECT) during arterial phase in coronary CT angiography for the detection of chronic infarction compared with late enhancement MRI (LE-MRI) and histopathology in a porcine model of reperfused myocardial infarction. MATERIAL AND METHODS: Myocardial infarctions were induced by 30 min occlusion of the proximal left anterior descending coronary artery in eight minipigs. DECT, post-contrast LE-MRI and histopathology were performed 60 days after infarct induction. The CT scan was performed in dual energy mode using a dedicated protocol. Myocardial iodine distribution was superimposed as color maps on grey scale multiplanar reformats of the heart. Two radiologists in consensus interpreted all imaging studies for presence of gadolinium uptake at LE-MRI reduced iodine content at DECT and hypoenhanced areas in the initial 100 kV coronary CT angiography images that were acquired during the DECT-acquisition. Results were compared with histopathology. RESULTS: Based on evaluable segments, DECT showed a sensitivity and specificity of 0.72 and 0.88; LE-MRI showed a sensitivity and specificity of 0.78 and 0.92; and the 100 kV data-set of the DECT scan showed a sensitivity and specificity of 0.60 and 0.93, respectively, for the detection of histological proved ischemia. CONCLUSION: DECT during arterial phase coronary CT angiography, which is ordinarily used for coronary artery evaluation, is feasible for the detection of a chronic reperfused myocardial infarction.

Properly scaled and targeted AAV2-NRTN (neurturin) to the substantia nigra is safe, effective and causes no weight loss: support for nigral targeting in Parkinson's disease.

Recent analyses of autopsied brains from subjects previously administered AAV2-neurturin (NRTN) gene transfer argues that optimizing the effects of neurotrophic factors in Parkinson's disease (PD) likely requires delivery to both the degenerating cell bodies (in substantia nigra) and their terminals (in striatum). Prior to implementing this novel dosing paradigm in humans, we conducted eight nonclinical experiments with three general objectives: (1) evaluate the feasibility, safety and effectiveness of targeting the substantia nigra (SN) with AAV2-NRTN, (2) better understand and appraise recent warnings of serious weight loss that might occur with targeting the SN with neurotrophic factors, and (3) define an appropriate dose of AAV2-NRTN that should safely and effectively cover the SN in PD patients. Toward these ends, we first determined SN volume for rats, monkeys and humans, and employed these values to calculate comparable dose equivalents for each species by scaling each dose, based on relative SN volume. Using this information, we next injected AAV2-GFP to monkey SN to quantify AAV2-vector distribution and confirm reasonable SN coverage. We then selected and administered a ~200-fold range of AAV2-NRTN doses (and a single AAV2-GDNF dose) to rat SN, producing a wide range of protein expression. In contrast to recent warnings regarding nigra targeting, no dose produced any serious side effects or toxicity, though we replicated the modest reduction in weight gain reported by others with the highest AAV2-NRTN and the AAV2-GDNF dose. A dose-related increase in NRTN expression was seen, with the lower doses limiting NRTN to the peri-SN and the highest dose producing mistargeted NRTN well outside the SN. We then demonstrated that the reduction in weight gain following excessive-doses can be dissociated from NRTN in the targeted SN, and is linked to mistargeted NRTN in the diencephalon. We also showed that prior destruction of the dopaminergic SN neurons via 6-OHDA had no impact on the weight loss phenomenon, further dissociating neurotrophic exposure to the SN as the culprit for weight changes. Finally, low AAV2-NRTN doses provided significant neuroprotection against 6-OHDA toxicity, establishing a wide therapeutic index for nigral targeting. These data support targeting the SN with AAV2-NRTN in PD patients, demonstrating that properly targeted and scaled AAV2-NRTN provides safe and effective NRTN expression. They also provided the means to define an appropriate human-equivalent dose for proceeding into an ongoing clinical trial, using empirically-based scaling to account for marked differences in SN volume between species.

Accuracy of coronary artery stenosis detection with CT versus conventional coronary angiography compared with composite findings from both tests as an enhanced reference standard.

OBJECTIVE: To prospectively compare the accuracy of coronary CT angiography (CCTA) and conventional coronary angiography (CCA) for stenosis detection using composite findings from both tests as an enhanced reference standard. METHODS: One hundred thirteen patients underwent CCTA and CCA. Per-segment and per-patient accuracy of CCTA compared with initial CCA interpretation were determined. Angiographers were then unblinded to the CCTA results and re-evaluation of the CCA studies was performed with knowledge of CCTA findings, which was used as an enhanced reference standard to compare the diagnostic accuracy of CCTA versus CCA. RESULTS: When using the enhanced reference standard instead of initial CCA interpretation, CCTA accuracy for identifying segments (patients) with ≥50% stenosis increased from 97.7% (96.5%) to 98.1% (98.2%), sensitivity from 90.5% (100%) to 90.8% (100%), and specificity from 98.4% (94.3%) to 98.9% (97.1%). CCTA identified six segments and two patients with stenoses ≥50% missed on initial CCA interpretation. Compared with the enhanced reference standard the accuracies of CCTA and of initial CCA interpretation were not different (p = 0.87). CONCLUSION: CCTA compares favourably with CCA for stenosis detection. Use of a composite reference standard combining findings from both tests can control for the effect of false-negative CCA results when evaluating the accuracy of CCTA.

Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains.

BACKGROUND: AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic-factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). METHODS: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated. RESULTS: NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons. DISCUSSION: These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved.