Estimating conformational landscapes from Cryo-EM particles by 3D Zernike polynomials.

The new developments in Cryo-EM Single Particle Analysis are helping us to understand how the macromolecular structure and function meet to drive biological processes. By capturing many states at the particle level, it is possible to address how macromolecules explore different conformations, information that is classically extracted through 3D classification. However, the limitations of classical approaches prevent us from fully understanding the complete conformational landscape due to the reduced number of discrete states accurately reconstructed. To characterize the whole structural spectrum of a macromolecule, we propose an extension of our Zernike3D approach, able to extract per-image continuous flexibility information directly from a particle dataset. Also, our method can be seamlessly applied to images, maps or atomic models, opening integrative possibilities. Furthermore, we introduce the ZART reconstruction algorithm, which considers the Zernike3D deformation fields to revert particle conformational changes during the reconstruction process, thus minimizing the blurring induced by molecular motions.

Enhancing social functioning in young people at Ultra High Risk (UHR) for psychosis: A pilot study of a novel strengths and mindfulness-based online social therapy.

BACKGROUND: Psychological and pharmacological treatments have been shown to reduce rates of transition to psychosis in Ultra High Risk (UHR) young people. However, social functioning deficits have been unresponsive to current treatments. AIMS: The study aims were to: i) describe the theoretical basis and therapeutic targets of a novel intervention targeting social functioning in UHR young people; and ii) examine its acceptability, safety and preliminary effect on social functioning. METHODS: An international, multidisciplinary team developed a new intervention (MOMENTUM) to improve social functioning in UHR young people. MOMENTUM blends two novel approaches to social recovery: strengths and mindfulness-based intervention embedded within a social media environment, and application of the self-determination theory of motivation. The acceptability and safety of MOMENTUM were tested through a 2-month pilot study with 14 UHR participants. RESULTS: System usage was high, with over 70% of users being actively engaged over the trial. All participants reported a positive experience using MOMENTUM, considered it safe and would recommend it to others. 93% reported it to be helpful. There were large, reliable improvements in social functioning (d = 1.83, p < 0.001) and subjective wellbeing (d = 0.75, p = 0.03) at follow-up. There were significant increases in the mechanisms targeted by the intervention including strengths usage (d = 0.70, p = 0.03), mindfulness skills (d = 0.66, p = 0.04) and components of social support. Social functioning improvement was significantly correlated with indicators of system usage. CONCLUSION: MOMENTUM is engaging and safe. MOMENTUM appeared to engage the hypothesized mechanisms and showed promise as a new avenue to improve social functioning in UHR young people.

Parallel transmit excitation at 1.5 T based on the minimization of a driving function for device heating.

PURPOSE: To provide a rapid method to reduce the radiofrequency (RF) E-field coupling and consequent heating in long conductors in an interventional MRI (iMRI) setup. METHODS: A driving function for device heating (W) was defined as the integration of the E-field along the direction of the wire and calculated through a quasistatic approximation. Based on this function, the phases of four independently controlled transmit channels were dynamically changed in a 1.5 T MRI scanner. During the different excitation configurations, the RF induced heating in a nitinol wire immersed in a saline phantom was measured by fiber-optic temperature sensing. Additionally, a minimization of W as a function of phase and amplitude values of the different channels and constrained by the homogeneity of the RF excitation field (B1) over a region of interest was proposed and its results tested on the benchtop. To analyze the validity of the proposed method, using a model of the array and phantom setup tested in the scanner, RF fields and SAR maps were calculated through finite-difference time-domain (FDTD) simulations. In addition to phantom experiments, RF induced heating of an active guidewire inserted in a swine was also evaluated. RESULTS: In the phantom experiment, heating at the tip of the device was reduced by 92% when replacing the body coil by an optimized parallel transmit excitation with same nominal flip angle. In the benchtop, up to 90% heating reduction was measured when implementing the constrained minimization algorithm with the additional degree of freedom given by independent amplitude control. The computation of the optimum phase and amplitude values was executed in just 12 s using a standard CPU. The results of the FDTD simulations showed similar trend of the local SAR at the tip of the wire and measured temperature as well as to a quadratic function of W, confirming the validity of the quasistatic approach for the presented problem at 64 MHz. Imaging and heating reduction of the guidewire were successfully performed in vivo with the proposed hardware and phase control. CONCLUSIONS: Phantom and in vivo data demonstrated that additional degrees of freedom in a parallel transmission system can be used to control RF induced heating in long conductors. A novel constrained optimization approach to reduce device heating was also presented that can be run in just few seconds and therefore could be added to an iMRI protocol to improve RF safety.

MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30±10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility.

Variability in diagnosing Creutzfeldt-Jakob disease using standard and proposed diagnostic criteria.

INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia with a median survival of 2-14 months. The diagnosis can only be made accurately by biopsy/autopsy. However, this is not always feasible or desirable. Thus, diagnostic criteria have been proposed by UCSF, European MRI-CJD Consortium, and WHO. We will compare these criteria. PATIENTS AND METHODS: Retrospective study of 31 patients (average age of 69.2 years) between 2003 to 2010 by ICD9 codes 046.1, 046.11, and 046.19. RESULTS: All patients presented with rapidly progressive dementia (mean duration of 4.25 months). Pyramidal and extrapyramidal findings, myoclonus, cerebellar changes, akinetic mutism, and visual disturbances were observed in 6.5-48.4%. Five had periodic pattern on EEG. CSF biomarker 14-3-3 was positive in 11. Tau was positive in 6. Neuron specific enolase was positive in 9. By consensus (kappa = 0.62), MRI was "typical" of CJD in 23 with cortical ribboning (n = 16), basal ganglia hyperintensity (n = 15), or combination (n = 8). By WHO criteria, which does not include neuroimaging, CJD was diagnosed in 10, but 14 if any CSF biomarker was used (p = NS). The UCSF criteria, which does not include CSF biomarkers, diagnosed 18 cases, and the European MRI-CJD Consortium, which includes neuroimaging and CSF biomarkers but with less neurological signs, diagnosed 23 cases (p < 0.05 and p < 0.001, respectively). CJD-mimics included urosepsis, neurosarcoidosis, idiopathic left temporal lobe epilepsy, alcohol intoxication, central nervous system vasculitis, viral encephalitis, and non-Hodgkin's lymphoma. CONCLUSION: This study illustrates the variability in diagnosing CJD and emphasizes the diagnostic utility of neuroimaging. It also highlights false-positives that occur with neuroimaging.

On the HORYZON: moderated online social therapy for long-term recovery in first episode psychosis.

BACKGROUND: Early intervention services have demonstrated improved outcomes in first episode psychosis (FEP); however, recent evidence shows that treatment benefits may not be sustainable over time. These findings have resulted in repeated recommendations for the implementation of longer term treatment programs. An Internet-based intervention specifically designed for young people with psychosis may provide a cost-effective alternative to prevent loss of treatment benefits from early intervention. METHODS: Our multi-disciplinary team has developed a highly novel online intervention (HORYZONS) in regular consultation with stakeholders within a specialist early psychosis program. HORYZONS integrates: i) peer-to-peer social networking, ii) individually tailored interactive psychosocial interventions, and iii) expert interdisciplinary and peer-moderation in a coherent platform designed to improve long-term outcomes in FEP. The acceptability, safety and initial clinical benefits of HORYZONS were examined through a 1-month pilot study with 20 participants with FEP. RESULTS: There were no dropouts during the pilot study. Seventy per cent of participants utilised the system for at least 3weeks, 95% used the social networking features, and 60% completed at least 3 therapy modules. System usage was high during the study. There were no incidents and the majority of participants reported feeling safe, empowered and more socially connected using HORYZONS. Analysis revealed a significant reduction in depressive symptoms at follow-up. CONCLUSIONS: Our results indicate that HORYZONS is feasible, engaging and safe and may augment social connectedness and empowerment in FEP. These findings have significant implications for the enhancement of specialist FEP services. The potential of HORYZONS to improve long-term recovery is worthy of further investigation.

Internet-based interventions for psychosis: a sneak-peek into the future.

The Internet and mobile technologies are becoming ubiquitous. However, the potential of these technologies to support people with psychosis has been unexplored and the development of innovative e-based interventions is overdue. Research suggests the acceptability and effectiveness of such interventions in psychosis. Internet-based technologies have the potential to transform psychosis treatment by enhancing the accessibility of evidence-based interventions, fostering engagement with mental health services, and maintaining treatment benefits over the long term. This article reviews the current evidence on Internet-based interventions for psychosis, including potential benefits, risks, and future challenges. Recommendations are proposed for developing future online interventions for psychosis.

Increasing response rates from physicians in oncology research: a structured literature review and data from a recent physician survey.

Although the physician survey has become an important tool for oncology-focused health services research, such surveys often achieve low response rates. This mini-review reports the results of a structured review of the literature relating to increasing response rates for physician surveys, as well as our own experience from a survey of physicians as to their referral practices for suspected haematologic malignancy in the United States. PubMed and PsychINFO databases were used to identify methodological articles assessing factors that influence response rates for physician surveys; the results were tabulated and reviewed for trends. We also analysed the impact of a follow-up telephone call by a physician investigator to initial non-responders in our own mailed physician survey, comparing the characteristics of those who responded before vs after the call. The systematic review suggested that monetary incentives and paper (vs web or email) surveys increase response rates. In our own survey, follow-up telephone calls increased the response rate from 43.7% to 70.5%, with little discernible difference in the characteristics of early vs later responders. We conclude that in addition to monetary incentives and paper surveys, physician-to-physician follow-up telephone calls are an effective method to increase response rates in oncology-focused physician surveys.

Real-time magnetic resonance imaging to guide pediatric endovascular procedures.

Although x-ray fluoroscopy (XRF) has guided diagnostic and therapeutic transcatheter procedures for decades, certain limitations still exist. XRF still visualizes tissue poorly and relies on projection of shadows that do not convey depth information. Adjunctive echocardiography overcomes some of these limitations but still suffers suboptimal or unreliable imaging windows. Furthermore, ionizing radiation exposure in children imparts a cancer risk. An interventional platform using real-time magnetic resonance imaging (MRI) may offer superior image guidance without radiation. Although there are many remaining challenges, but real-time MRI has the potential to revolutionize transcatheter therapeutics.

Systems failure in hospitals--using Reason's model to predict problems in a prescribing information system.

Both hospitals and hospital patients are bearing a massive cost as a result of the occurrence of medication prescribing errors in the public health system (Bates, D., et al. J. Am. Med. Inform. Assoc. 8(4):299-308, 2001; Lombardi, T. Medscape Pharm. Online J. 02(1), 2001; Roberts, M., and Stokes, J. eMed. J. Aust. 168:317-318, 1998). Consequently, it is important to examine and address the possible causes of this problem. In this paper we suggest that poor information systems may be a contributing factor in the occurrence of these errors. We research this issue in an HIV ward of a large public hospital through interviews and a survey instrument. We find that in a significant number of instances prescribing errors are linked to situations where information is unavailable or inaccessible. This link, between problems in information delivery and prescribing errors, is a link whose extent has not been measured previously. It is, however, a link which exposes all stakeholders in the hospital system, the patient, the clinicians, the hospital, and governments funding prescription medications, to possible loss and damage and indicates a need for the implementation of more effective systems in this area. We use Reason's model for predicting systems error (Vincent, C. BMJ 316:1154-1157, 1998) as a tool to suggest that prescribing errors have an increased likelihood of occurring if one or more of the types of failure identified in the model are present in the existing prescribing information delivery process in the hospital. While Reason's model has been applied in a medical context, it has not been previously applied to errors which result from information systems failure. We feel that applying it in this way may shed some light on the causes of prescribing error.

Computerized evaluation of mammographic lesions: what diagnostic role does the shape of the individual microcalcifications play compared with the geometry of the cluster?

OBJECTIVE: The objective of this study was to compare the diagnostic role of features reflecting the geometry of clusters with features reflecting the shape of the individual microcalcification in a mammographic computer-aided diagnosis system. MATERIALS AND METHODS: Three hundred twenty-four cases of clustered microcalcifications with biopsy-proven results were digitized at 42-microm resolution and analyzed on a computerized system. The shape factor and number of neighbors were computed for each microcalcification, and the eccentricity of the cluster was computed as well. The shape factor is related to the individual microcalcification; the average number of neighbors and the cluster eccentricity reflect the cluster geometry. Stepwise discriminant analysis was used to evaluate the contribution of the extracted features in predicting malignancy. The performance of a classifier based on the features selected by stepwise discriminant analysis was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: To obtain the best discrimination model, we used stepwise discriminant analysis to select the average number of neighbors and the shape of the individual microcalcification, but excluded cluster eccentricity. A classification scheme assigned the average number of neighbors a weighting factor, which was 1.49 times greater than that assigned to the shape factor of the individual microcalcification. A scheme based only on these two features yielded an ROC curve with an area under the curve (A(z)) of 0.87, indicating a positive predictive value of 61% for 98% sensitivity. CONCLUSION: Computerized analysis permitted calculations reflecting the shape of individual microcalcification and the geometry of clusters of microcalcifications. For the computerized classification scheme studied, the cluster geometry was more effective in differentiating benign from malignant clusters than was the shape of individual microcalcification.

Delivery and tracking of therapeutic cell preparations for clinical cardiovascular applications.

Experimental observations suggesting adult stem cell plasticity and cross-lineage transdifferentiation have underpinned the investigation of cell therapy for cardiovascular disease. Many challenges still face the full realization of cardiovascular regenerative medicine. This brief review will highlight some of these, with emphasis on the choice of cell preparation, route of cell delivery and tracking of delivered cells.

Feasibility of implementing intervention methods in an adolescent worksite tobacco control study.

OBJECTIVE: To present feasibility data on SMART, the first teen worksite behavioural tobacco control intervention. DESIGN: This phase II study was designed to estimate the efficacy and feasibility of a small scale, randomised, controlled intervention. SETTING AND SUBJECTS: This study, addressing youths aged 15-18 years, was implemented in four intervention and five control grocery stores that had an average of 44 eligible teens. INTERVENTIONS: The tobacco use cessation and prevention interventions were based on social influences and peer leader models. Employee break rooms served as centres both for interactive activities including open houses, teen advisory boards, peer leader interviews, games and contests; and non-interactive interventions including bulletin boards and table tents with health messages and home mailings. MAIN PROCESS MEASURES: Project staff collected process data on the extent of implementation of intervention activities, participation rates in activities, and contacts with peer leaders. On the final survey, teens reported on awareness of, participation in, and motivation for participating in project activities. RESULTS: Indicators of feasibility were identified and discussed, including the number of activities implemented, teen participation, management support, cost, and barriers to and facilitators of implementation. During the 12 month intervention, a mean of 24.1 interactive activities and 55.3 non-interactive activities were implemented, and a mean 14.2% participation rate per activity per site was achieved. Eighty four per cent of teens reported being aware of SMART, and 39% reported participating in interactive and 67% in non-interactive activities. CONCLUSIONS: Teen smoking cessation rates in worksite programmes might be improved if they are conducted in companies where there is job stability and if teen programmes are part of worksite-wide tobacco control programmes that include both teens and adults.

West Nile virus infection: a new acute paralytic illness.

OBJECTIVE: To determine the clinical, laboratory, electrodiagnostic, radiologic, and pathologic characteristics that define the spectrum of CNS disease caused by West Nile virus (WNV) infection. METHODS: The records of all patients hospitalized at the Cleveland Clinic from August 2002 to September 2002 with WNV infection were reviewed. RESULTS: Of 23 cases, the median age was 74 years old, and 74% were men. Symptoms included fever (100%), altered mental status (74%), gastrointestinal complaints (43%), back pain (35%), and rash (26%). In half, meningitis or encephalitis overlapped with flaccid weakness that progressed over 3 to 8 days, with a tendency to be proximal and asymmetric. Laboratory abnormalities included hyponatremia (30%) and initial CSF neutrophilic pleocytosis. Electrodiagnostic studies in two patients showed reduced motor amplitudes with normal conduction velocities and active denervation. In two other patients, reduced sensory amplitudes were also seen. MRI changes included cauda equina enhancement and parenchymal spinal cord signal abnormalities and parenchymal or leptomeningeal signal changes in the brain. Autopsy in three cases showed chronic perivascular inflammation in the brain and inflammatory changes with anterior horn cell loss in the spinal cord. CONCLUSION: An overlapping spectrum of meningitis, encephalitis, and myeloradiculitis occurs in CNS WNV infection. Fever, rash, abdominal and back pain, preceding a proximal, asymmetric flaccid weakness, with CSF pleocytosis help distinguish the motor syndrome from Guillain-Barré syndrome. Pathologic changes in the CNS resembled poliomyelitis.

Ultrasound-guided thrombin injection for the treatment of iatrogenic pseudoaneurysm of the femoral artery.

BACKGROUND: Pseudoaneurysm occurring after catheterization of the femoral artery is associated with significant morbidity. Percutaneous ultrasound-guided thrombin injection has recently emerged as a potential first-line therapy. OBJECTIVES: To evaluate the efficacy of this treatment in eight patients with iatrogenic femoral artery pseudoaneurysm. METHODS: After attempted treatment with external compression had failed, eight patients with iatrogenic femoral artery pseudoaneurysm were treated with thrombin injection. Treatment performed between 2 and 9 days following arterial puncture. The study group comprised seven males and one female ranging in age from 23 to 89 years (median 70). Seven had undergone cardiac catheterization with or without intervention, and five were receiving antiplatelet and/or anticoagulant drugs. Arterial pseudoaneurysm resulted from femoral vein catheterization in one patient. Using a sterile technique and real-time Doppler ultrasound guidance, a dilute solution of bovine thrombin (average dose 250 units, range 100-600), was slowly injected directly into the pseudoaneurysm until cessation of flow was seen. Patients were allowed to walk within 2 hours of the procedure and were followed up clinically and by color Doppler ultrasound during the admission. RESULTS: Cardiac catheterization had been inadvertently performed via the superficial or profunda femoris arteries in four of the eight patients. Thrombin injection was initially successful in all eight patients without complication. Thrombosis occurred immediately in every case. Early recanalization of pseudoaneurysm occurred in one patient despite repeat thrombin injection and attempted ultrasound-guided compression. He eventually required surgical repair. The final success rate was 87.5% (7/8). CONCLUSION: Faulty puncture technique is an important risk factor for the development of post-catheterization femoral artery pseudoaneurysm. Ultrasound-guided thrombin injection is a safe, rapid, well-tolerated, inexpensive and successful therapy. If initial external compression with a sandbag fails to result in thrombosis of the pseudoaneurysm then thrombin injection should be considered as first-line therapy. If unsuccessful, it does not preclude the use of alternative treatment modalities. Further study is necessary to assess the long-term effects of thrombin injection.

Primary renal artery stenting: characteristics and outcomes after 363 procedures.

BACKGROUND: Stenting improves the acute results of percutaneous balloon angioplasty for atherosclerotic renal artery stenosis. Predictors of benefit and angiographic restenosis are not well understood. We describe the technical and clinical success of renal artery stenting in a large consecutive series of patients with hypertension or renal insufficiency. We identify clinical, procedural, and anatomic factors that might influence outcome, restenosis, and survival. METHODS: Primary renal artery stenting was performed in 300 consecutive patients who underwent 363 stent procedures in 358 arteries. Angiograms were analyzed quantitatively. Clinical and angiographic follow-up data are available after a median of 16.0 months. RESULTS: At baseline, 87% of patients had hypertension, and 37% had chronic renal insufficiency. The mean age was 70 years (interquartile range 63.1-74.6) years. The stenosis was unilateral in 49% and bilateral in 48% and involved a solitary functioning kidney in 3.6%. The stenting procedure was successful in all attempts. There were no procedural deaths or emergency renal surgical procedures. Postprocedure azotemia was seen in 45 of 363 (12%) procedures but persisted in only 6 patients (2%), all of whom had baseline renal insufficiency. Systolic and diastolic blood pressures were significantly reduced (systolic blood pressure from 164.0 +/- 28.7 to 142.4 +/- 19.1 mm Hg, P <.001). At follow-up, 70% of patients had improved blood pressure control regardless of renal function. In patients with baseline renal insufficiency, 19% had improvement in serum creatinine levels at follow-up, 54% had stabilization, and 27% had deterioration. Follow-up mortality was 10% and was predicted by baseline creatinine levels (odds ratio 1.72 for each 1 mg/dL creatinine increment, 95% confidence interval 1.13-2.49) and extent of coronary artery disease (odds ratio 1.66 for each diseased coronary artery, 95% confidence interval 1.03-2.67). Angiographic restenosis was found in 21% of 102 patients overall and was less common (12%) in arteries with a reference caliber >4.5 mm (P <.01 vs caliber <4.5 mm). Neither poststenotic dilation nor severity of angiographic stenosis predicted clinical outcome. CONCLUSIONS: Primary renal artery stenting can be performed safely with nearly uniform technical success. The majority of patients with hypertension or renal insufficiency derive benefit. Follow-up mortality is 5-fold higher in patients with baseline renal insufficiency. Clinical and angiographic features did not predict blood pressure or renal functional outcome. Restenosis is more common in renal arteries with a reference caliber less than 4.5 mm.

Detection of atherosclerosis using a novel positron-sensitive probe and 18-fluorodeoxyglucose (FDG).

Inflammation contributes to atherosclerotic plaque remodeling, enlargement and rupture. Non-invasive imaging of coronary artery inflammation could help target therapy to 'vulnerable' atheromata, but is limited because of small tissue mass and arterial motion. Local radiopharmaceutical imaging may overcome some of these limitations. We used a positron-sensitive fiberoptic probe, which can distinguish positron emissions from annihilation photons, to identify diseased from healthy endothelium in an atherosclerotic model. New Zealand White rabbits underwent Fogarty-catheter injury of an iliac artery and then were fed a high-fat diet for 3 weeks. Fasted animals received 90-180 MBq of 18-fluorodeoxyglucose (FDG) 2-4 h before sacrifice and harvest of injured and uninjured iliacs. Arteries were incised longitudinally and the probe was placed in contact with the arterial intima. Multiple measurements were obtained along 1 cm artery segments in 60 s intervals, and corrected for 18F decay and background. Measurements were recorded over 93 injured and normal artery segments in 11 animals. Mean probe Z-scores were 4.8-fold higher (CI 3.4-6.3) over injury atherosclerosis compared with uninjured normal iliac artery segments (P<0.001). Gamma counting confirmed that injured artery segments accumulated more FDG per gram than did normal segments (0.203% x kg injected dose per gram of tissue versus 0.042, P<0.001). Non-arterial tissue also accumulated FDG avidly, particularly reticuloendothelial tissues and blood. Delayed sacrifice, 4 h compared with 2 h after animal FDG injection, further reduced blood background counts and improved the signal-to-noise ratio. Histopathology confirmed that injured iliac artery had significantly higher intimal and medial cross-sectional area compared with uninjured artery. Injured artery also had significantly higher macrophage and smooth muscle cell density. Positron-sensitive probe counts correlated with the intima to media ratio (r =0.63, P = 0.03). Our positron-sensitive probe distinguishes atherosclerotic from healthy artery in a blood-free field. Intravascular study of plaque biology may be feasible using FDG and a positron-sensitive probe.