Program management model study

Two models, a system performance model and a program assessment model, have been developed to assist NASA management in the evaluation of development alternatives for the Earth Observations Program. Two computer models were developed and demonstrated on the Goddard Space Flight Center Computer Facility. Procedures have been outlined to guide the user of the models through specific evaluation processes, and the preparation of inputs describing earth observation needs and earth observation technology. These models are intended to assist NASA in increasing the effectiveness of the overall Earth Observation Program by providing a broader view of system and program development alternatives

Sustainability of Individual EndoAnchor Implants in Therapeutic Use to Treat Type Ia Endoleak After Endovascular Aneurysm Repair

Purpose: To investigate changes in penetration depths and angles of EndoAnchor implants with initially good penetration after therapeutic use in endovascular aneurysm repair. Materials and Methods: Patients were selected from the Aneurysm Treatment Using the Heli-FX Aortic Securement System Global Registry (ANCHOR; ClinicalTrials.gov identifier NCT01534819). Inclusion criteria were (1) EndoAnchor implantation to treat intraoperative or late type Ia endoleak and (2) at least 2 postoperative computed tomography angiography (CTA) scans. Exclusion criteria were the use of adjunct procedures. Based on these criteria, 54 patients (44 men) with 360 EndoAnchor implants were eligible for this analysis. Penetration depth of each EndoAnchor implant into the aortic wall was judged as (1) good (2-mm penetration), (2) borderline (</p

Promoting Fc-Fc interactions between anti-capsular antibodies provides strong immune protection against Streptococcus pneumoniae.

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and an important cause of childhood mortality. Despite the introduction of successful vaccines, the global spread of both non-vaccine serotypes and antibiotic-resistant strains reinforces the development of alternative therapies against this pathogen. One possible route is the development of monoclonal antibodies (mAbs) that induce killing of bacteria via the immune system. Here, we investigate whether mAbs can be used to induce killing of pneumococcal serotypes for which the current vaccines show unsuccessful protection. Our study demonstrates that when human mAbs against pneumococcal capsule polysaccharides (CPS) have a poor capacity to induce complement activation, a critical process for immune protection against pneumococci, their activity can be strongly improved by hexamerization-enhancing mutations. Our data indicate that anti-capsular antibodies may have a low capacity to form higher-order oligomers (IgG hexamers) that are needed to recruit complement component C1. Indeed, specific point mutations in the IgG-Fc domain that strengthen hexamerization strongly enhance C1 recruitment and downstream complement activation on encapsulated pneumococci. Specifically, hexamerization-enhancing mutations E430G or E345K in CPS6-IgG strongly potentiate complement activation on S. pneumoniae strains that express capsular serotype 6 (CPS6), and the highly invasive serotype 19A strain. Furthermore, these mutations improve complement activation via mAbs recognizing CPS3 and CPS8 strains. Importantly, hexamer-enhancing mutations enable mAbs to induce strong opsonophagocytic killing by human neutrophils. Finally, passive immunization with CPS6-IgG1-E345K protected mice from developing severe pneumonia. Altogether, this work provides an important proof of concept for future optimization of antibody therapies against encapsulated bacteria

An intervention to support stroke survivors and their carers in the longer term (LoTS2Care): study protocol for a cluster randomised controlled feasibility trial

Background Despite the evidence that many stroke survivors report longer term unmet needs, the provision of longer term care is limited. To address this, we are conducting a programme of research to develop an evidence-based and replicable longer term care strategy. The developed complex intervention (named New Start), which includes needs identification, exploration of social networks and components of problem solving and self-management, was designed to improve quality of life by addressing unmet needs and increasing participation. Methods/Design A multicentre, cluster randomised controlled feasibility trial designed to inform the design of a possible future definitive cluster randomised controlled trial (cRCT) and explore the potential clinical and cost-effectiveness of New Start. Ten stroke services across the UK will be randomised on a 1:1 basis either to implement New Start or continue with usual care only. New Start will be delivered by trained facilitators and will be offered to all stroke survivors within the services allocated to the intervention arm. Stroke survivors will be eligible for the trial if they are 4–6 months post-stroke and residing in the community. Carers (if available) will also be invited to take part. Invitation to participate will be initiated by post and outcome measures will be collected via postal questionnaires at 3, 6 and 9 months after recruitment. Outcome data relating to perceived health and disability, wellbeing and quality of life as well as unmet needs will be collected. A ‘study within a trial’ (SWAT) is planned to determine the most acceptable format in which to provide the postal questionnaires. Details of health and social care service usage will also be collected to inform the economic evaluation. The feasibility of recruiting services and stroke survivors to the trial and of collecting postal outcomes will be assessed and the potential for effectiveness will be investigated. An embedded process evaluation (reported separately) will assess implementation fidelity and explore and clarify causal assumptions regarding implementation. Discussion This feasibility trial with embedded process evaluation will allow us to gather important and detailed data regarding methodological and implementation issues to inform the design of a possible future definitive cRCT of this complex intervention. Trial Registration ISRCTN38920246. Registered 22 June 2016

MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR-135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness

Assessment of changes in stent graft geometry after chimney endovascular aneurysm sealing

Background: Chimney endovascular aneurysm sealing (ch-EVAS) could potentially minimize gutter-associated endoleaks in patients with juxtarenal abdominal aortic aneurysms resulting from the use of the conformable endobags surrounding the chimney stent grafts (ch-SGs). The aim of the present study was to quantify the (non)apposition of the endobags in the proximal aortic neck, migration of the endograft stent frames, and changes in geometry of the ch-SGs during the follow-up period. Methods: The prospective data from 20 patients undergoing elective ch-EVAS were retrospectively reviewed. The aortic anatomy was analyzed on preoperative and postoperative computed tomography scans. The (non)apposition of the endobags in the aortic neck, Nellix (Endologix, Irvine, Calif) stent frame migration, and chimney graft geometry and migration were assessed. Results: The median preoperative infrarenal neck lengthwas 4.0 mm (interquartile range [IQR], 0-6.0 mm). The median seal length in the juxtarenal aortic neck at the first follow-up was 23.0 mm (IQR 18.0-30.8 mm). Five type IA endoleaks were identified on postoperative imaging; one at 1 month and four newly diagnosed at 1 year. Of these five type IA endoleaks, two were type Is1 (not extending into the aneurysm sac) and did not need reintervention and other three were type Is2 (extending into the aneurysmsac). One of these patients died of malignancy before reintervention could be performed. Bilateral ch-SG occlusions in one patient were documented at the 1-month follow-up (patient needed hemodialysis) and two patients with a new single ch-SG occlusion were found at the 1-year follow-up. No reinterventions were performed for the ch-SG occlusions. An occluded Nellix stent frame in one patient was treated with femorofemoral crossover bypass. Kaplan-Meier estimate of reintervention-free survival was 85.0% after 1 year. Migration >= 5 mm of the proximal end of the Nellix stent frames was observed in 20.0% of the patients, but no reintervention was performed at the 1-year follow-up. Imaging showed 20.1% of the available sealing surface was not used, and the nonapposition surface increased to 30.6% of the preoperative aortic neck surface at 1 year. Median migration was 3.5 mm (IQR, 2.4-5.0 mm) and 3.1 mm (IQR, 2.0-4.8 mm) for the left and right proximal end of the Nellix stent frames, respectively, and was 3.0 mm (IQR, 2.2-4.8 mm) for the proximal end of the ch-SGs at 1 year of follow-up. Conclusions: Substantial distal migration of the Nellix endograft and positional changes of the ch-SGs in the juxtarenal aortic neck were observed at 1 year of follow-up, resulting in a 25.0% type IA endoleak rate, with three of these type IA endoleaks extending into the aneurysm sac. The reintervention-free survival rate was 85.0% at 1 year in this cohort of 20 patients. Careful follow-up after ch-EVAS is advised because changes are often subtle. The authors have stopped the ch-EVAS procedure so far. Long-term follow-up data on the stability of the Nellix endograft and the consequences of migration on ch-SGs is required before this technique should be used in clinical practice

The use of 3D image fusion for percutaneous transluminal angioplasty and stenting of iliac artery obstructions: validation of the technique and systematic review of literature

INTRODUCTION: The effect of the insertion of guidewires and catheters on fusion accuracy of the three-dimensional (3D) image fusion technique during iliac percutaneous transluminal angioplasty (PTA) procedures has not yet been investigated. EVIDENCE ACQUISITION: Technical validation of the 3D fusion technique was evaluated in 11 patients with common and/or external iliac artery lesions. A preprocedural contrast-enhanced magnetic resonance angiogram (CE-MRA) was segmented and manually registered to a conebeam computed tomography image created at the beginning of the procedure for each patient. The treating physician visually scored the fusion accuracy (i.e., accurate [5 mm]) of the entire vasculature of the overlay with respect to the digital subtraction angiography (DSA) directly after the first obtained DSA. Contours of the vasculature of the fusion images and DSAs were drawn after the procedure. The cranial-caudal, lateral-medial, and absolute displacement were calculated between the vessel centerlines. To determine the influence of the catheters, displacement of the catheterized iliac trajectories were compared with the noncatheterized trajectories. Electronic databases were systematically searched for available literature published between January 2010 till August 2017. EVIDENCE SYNTHESIS: The mean registration error for all iliac trajectories (N.=20) was small (4.0±2.5 mm). No significant difference in fusion displacement was observed between catheterized (N.=11) and noncatheterized (N.=9) iliac arteries. The systematic literature search yielded 2 manuscripts with a total of 22 patients. The methodological quality of these studies was poor (≤11 MINORS Score), mainly due to a lack of a control group. CONCLUSIONS: Accurate image fusion based on preprocedural CE-MRA is possible and could potentially be of help in iliac PTA procedures. The flexible guidewires and angiographic catheters, routinely used during endovascular procedures of iliac arteries, did not cause significant displacement that influenced the image fusion. Current literature on 3D image fusion in iliac PTA procedures is of limited methodological quality

Analysis of the position of EndoAnchor implants in therapeutic use during endovascular aneurysm repair

Objective: The aim of this study was to analyze the penetration depth, angles, distribution, and location of deployment of individual EndoAnchor (Medtronic Vascular, Santa Rosa, Calif) implants. Methods: Eighty-six primary and revision arm patients (procedural success, 53; persistent type IA endoleak, 33) treated for type IA endoleaks with a total of 580 EndoAnchor implants from a subset of the Aneurysm Treatment Using the Heli-FX Aortic Securement System Global Registry (ANCHOR) were included in this study. Procedural success was defined as the absence of a type IA endoleak on the first postprocedural computed tomography scan after the EndoAnchor implantation procedure. Endograft malapposition along the circumference was assessed at the first postoperative computed tomography scans and expressed as clock-face range and width in degrees and normalized such that the center was translated to 0 degrees. The position and penetration of each EndoAnchor implant were measured as the clock-face orientation. EndoAnchor implant penetration into the aortic wall was categorized as follows: good penetration, >= 2 mm; borderline penetration, = 2-mm gap between the endograft and aortic wall; or no penetration. The orthogonal and longitudinal angles between the EndoAnchor implant and the interface plane of the aortic wall were determined. Location of deployment was investigated for each EndoAnchor implant and classified as maldeployed when it was above the fabric or in a gap >2mm between the endograft and aortic wall due to >2-mm thrombus or positioning of the EndoAnchor implant below the aortic neck. Results: A total of 170 (29%) EndoAnchor implants had maldeployment and were therefore beyond recommended use and not useful. After EndoAnchor implantation, the procedural success and persistent type IA endoleak groups had 3 (1%) and 4 (2%) EndoAnchor implants positioned above the fabric as well as 60 (18%) and 103 (42%) placed in a gap >2 mm, respectively. The amount of EndoAnchor implants with good, borderline, and no penetration was significantly different between both groups (success vs type IA endoleak) after exclusion of maldeployed EndoAnchor implants (235 [87.4%], 14 [5.2%], and 20 [7.4%] vs 97 [68.8%], 18 [12.8%], and 26 [18.4%], respectively; P 2-mm gaps, EndoAnchor implants alone may not provide the intended sealing, and additional devices should be considered