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Concept: The Final

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Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ((177)Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either (177)Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ((177)Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the (177)Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the (177)Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the (177)Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the (177)Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with (177)Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the (177)Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Concepts: Scientific method, Clinical trial, Cancer, Oncology, Randomized controlled trial, Chemotherapy, Neuroendocrine tumor, The Final

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Microscale soft-robots hold great promise as safe handlers of delicate micro-objects but their wider adoption requires micro-actuators with greater efficiency and ease-of-fabrication. Here we present an elastomeric microtube-based pneumatic actuator that can be extended into a microrobotic tentacle. We establish a new, direct peeling-based technique for building long and thin, highly deformable microtubes and a semi-analytical model for their shape-engineering. Using them in combination, we amplify the microtube’s pneumatically-driven bending into multi-turn inward spiraling. The resulting micro-tentacle exhibit spiraling with the final radius as small as ~185 μm and grabbing force of ~0.78 mN, rendering itself ideal for non-damaging manipulation of soft, fragile micro-objects. This spiraling tentacle-based grabbing modality, the direct peeling-enabled elastomeric microtube fabrication technique, and the concept of microtube shape-engineering are all unprecedented and will enrich the field of soft-robotics.

Concepts: The Final, Carnivorous plant, Actuator, Spiral, Pneumatics, Pneumatic actuator, Tentacle, Tentacle erotica

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Because oral polio vaccine has been associated with cases of paralysis, it is essential to discontinue its use after polio eradication has been certified. The first step is a shift from a trivalent OPV to a bivalent one, which requires a multipronged global strategy.

Concepts: Vaccine, Vaccination, Poliomyelitis, Polio vaccine, The Final, World, Poliomyelitis eradication, OPV AIDS hypothesis

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BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer’s disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer’s disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer’s disease. FUNDING: Octapharma AG.

Concepts: Alzheimer's disease, Clinical trial, Clinical research, Placebo, The Trial, The Final, Medical treatments, Beta amyloid

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Restless Legs Syndrome (RLS) is estimated to affect 5-15 percent of the U.S. population. There are few studies investigating non-pharmacological treatments for RLS, such as physical therapy and/or peripheral neural mobilization. The traction straight leg raise (tSLR) technique is one such mobilization that may affect central and peripheral neural pathways and reduce RLS symptoms. The purpose of this study is to determine the effects of a tSLR on the symptoms associated with RLS. A cohort of fifteen people was enrolled. Thirteen subjects (11 female) between the ages of 32-64 completed the study. Subjects completed two questionnaires to quantify their severity of RLS before treatment was initiated and at the final session. These measures included: the Restless Legs Syndrome Rating Scale (RLSRS) 0-40, an RLS Ordinal Scale, and a Global Rating of Change (GROC) assessments (-7, 0, +7). Patients were treated with tSLR bilaterally for four total visits on days 1, 3, 8, and 15. Results indicated an RLSRS pre-treatment average of 24.8 (severe) and post-treatment average of 9.2 (mild), representing a 63% improvement from baseline (p < 0.05). Ten of 13 subjects reported a GROC of +4 or higher at the final session, indicating at least a moderate improvement in patient status from baseline. Our results indicate that following a series of tSLR treatments symptoms were reduced in individuals with idiopathic RLS. A prospective, randomized controlled trial is necessary to evaluate the potential for a tSLR to effectively manage idiopathic RLS symptoms.

Concepts: Patient, Randomized controlled trial, Evaluation methods, Syndromes, The Final, Dopamine, Restless legs syndrome, Straight leg raise

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The original aim was to examine the effect of perceived distance, induced by the Ponzo illusion, on left/right asymmetries for line bisection. In Experiment 1, university students (n = 29) made left/right bisection judgements for lines presented in the lower or upper half of the screen against backgrounds of the Ponzo stimuli, or a baseline. While the Ponzo illusion had relatively little effect on line bisection, elevation in the baseline condition had a strong effect, whereby the leftward bias was increased for upper lines. Experiment 2 (n = 17) eliminated the effect of elevation by presenting the line in the middle and moving the Ponzo stimuli relative to the line. Despite this change, the leftward bias was still stronger in the upper condition in the baseline condition. The final experiment (n = 17) investigated whether upper/lower visual stimulation, which was irrelevant to the task, affected asymmetries for line bisection. The results revealed that a rectangle presented in the upper half of the screen increased the leftward line bisection bias relative to a baseline and lower stimulation condition. These results corroborate neuroimaging research, showing increased right parietal activation associated with shifts of attention into the upper hemispace. This increased right parietal activation may increase the leftward attentional bias-resulting in a stronger leftward bias for line bisection.

Concepts: Attention, Perception, Sense, Relative, The Final, Relative clause, Optical illusion, Ponzo illusion

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Due to the bicontinuous phase structure of Nafion® with small hydrophilic channels, formation of composites with silica colloids to improve thermal stability, hydration and proton conductivity should be influenced by size and surface functionality of the colloids. To test this hypothesis we prepared batches of silica particles between 20 - 400 nm in diameter with narrow polydispersities using a modified Stöber procedure. Some particles were subsequently surface modified using mercaptopropyltriethoxysilane. Enough particles were mixed with Nafion® in alcohols to achieve 5wt% silica in the final membranes, which were made by casting and drying. Membrane top and bottom surface and cross-section morphologies were examined with AFM and SEM to determine how the particles were dispersed. We discovered that casting the membranes from dispersions with viscosities less than 65 Centapoise led to larger particles floating to the top surface of the membrane where they were easily dislodged from the dry membrane. Membranes cast from more viscous solutions exhibited homogeneous distributions of particles. Water up-take was over 60% higher in nanocomposites with un-modified silica particles than for Nafion® and about 15% higher than for Nafion® with in situ generated silica particles, but showed no trend in water uptake correlating with changing particle size. Surface silated particles of all sizes appeared to have reduced water uptake relative to Nafion® alone.

Concepts: Function, Particle physics, Ethanol, The Final, Solution, Particle, Nanocomposite, Membrane

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The objective of this study was to describe the solid-state forms in which roxithromycin may exist and the significant influence of solution-mediated phase transformation on the dissolution and solubility behavior of these forms. Roxithromycin may exist as: Form I (monohydrate), Form II (amorphous), Form III (anhydrate) and a mixture of Forms I and III. Form III and Mixture I/III have not been reported previously, probably due to incomplete solid-state characterization or the use of a standard production method which consistently yielded the same solid-state form. Solution-mediated phase transformations of Forms II and III to the stable Form I were proved through dissolution studies and quantification of the phase proportions, as a function of time, utilizing XRPD. This study showed that pharmacopoeial identification methods for roxithromycin do not allow accurate identification of the different solid-state forms. The various forms differed significantly in terms of dissolution profiles, which could have a marked influence on bioavailability and performance of the final dosage form. It was demonstrated that solvent replacement, during dissolution testing, masks the characteristic profile usually obtained with a metastable form undergoing solution-mediated transformation. Finally, we propose that peak dissolution concentrations should be used to give a more exact indication of the aqueous solubility enhancement ratio obtained with metastable forms of APIs.

Concepts: Solubility, Phase, Phase transition, The Final, Glass transition, Theory of Forms, Phase diagram, Spinodal decomposition

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The goal of this study was to develop a more accurate formula to forecast tooth-size discrepancies in patients based on not only the size of the whole teeth but also functional arch components derived from normal cusp-fossa interdigitation that should be obtained as the final treatment goal.

Concepts: Prediction, Future, The Final, Forecasting, 3D scanner

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The research of the Energy Research Group (ERG) at the University of Illinois at Urbana-Champaign through the 1970s and early 1980s has recurring bouts of popularity. That research traced the flow of various energy types from nature to the final product or service, using modified economic input-output analysis. That information allowed for a comparison of alternative uses of products and services that delivered the same demand. The goal of the study was to identify the energy-conserving potential of the alternatives. Interest in that research has risen and fallen with the price of energy through three cycles now, with the current interest also encompassing materials conservation. Although the specific numerical results of this work are dated, the process by which the analysis was conducted creates, at least, a suggestion for future analysis in the arena of materials research. A review of the ERG history, including techniques pioneered for investigating the potential for energy conservation and some of the ancillary lessons learned along the way, may be of some use to those working on issues of materials conservation today. In the coming years, the most relevant research will include assessment of the socio-economic-ecological impact of technological materials conservation policies.

Concepts: Energy, Force, The Final, Potential energy, The Current, Work, Conservation of energy, Energy conservation