Conventional additive manufacturing processes, where parts are built through layer-wise deposition of material on a horizontal plane, can be limiting when a part must be printed or fit onto uneven ...surfaces. Such situations will arise with increasing frequency as additive manufacturing application areas such as construction and medical devices continue to grow. In this work, we develop a simple and practical approach to generate toolpaths to print 3D structures onto uneven surfaces conformally. The algorithm uses only conventional planar toolpaths of both the structure to be printed and the substrate to be printed on and converts these to non-planar toolpaths, allowing easy integration with existing additive manufacturing workflows. The technique is demonstrated by printing flexible seals onto bespoke rigid face mask frames conformally via a conventional single-material 3D printer using the generated conformal toolpath. A notable improvement in air seal performance was observed for customized face masks with conformal soft seals compared to conventionally 3D-printed fully rigid face masks. This also shows the potential of the developed toolpath generation method to aid in the prototyping and fabrication of conformal medical and other devices.
Ghana is the focus of extensive economic development interest, and is undergoing a substantial increase in population from 5 million in 1950 to an estimated 50 million in 2050. Population growth is ...impacting the natural environment, mostly through land cover and land use change (LCLUC), and particularly associated with agriculture expansion and urbanization. Monitoring LCLUC is necessary in order to understand the overall dynamics of population, LCLU and quality of life. However, extensive cloud cover in the region complicates satellite-based monitoring of LCLUC. Our objectives are to evaluate an innovative “dense stack” approach to image classification with extremely cloudy, multi-temporal Landsat 7 ETM+ imagery, map and quantify LCLU within southern Ghana for circa 2000 and circa 2010, examine LCLU changes, and assess the utility of the approach for monitoring human-induced change. Maximum value composite images (derived from the dense stacks) provide unique information for classifying the LCLU classes of interest, and accuracy assessment results indicate effective overall classification of the six LCLU classes mapped using semi-automated methods. A product we developed and refer to as the spectral variability vegetation index (SVVI) plays a major role in discriminating three natural vegetation classes and agriculture. Derived circa 2000 and circa 2010 LCLU maps indicate that approximately 26% of the study area exhibited LCLU change during the study period. Sixty-two percent (62%) of the changes are associated with conversion to Agriculture, with 33% from Secondary Forest, 26% from Savanna, and 3% from Forest. During the same period, 18% of circa 2000 land classified as Agriculture was fallow or abandoned by circa 2010. Change to Built represented 6% of the LCLU change, which includes 5% from Agriculture and 1% from Secondary Forest circa 2000. Freely available Landsat 7 ETM+ imagery and the time-series classification methods developed here may be used to further monitor LCLU change in the region and throughout the world, particularly in cloud-prone equatorial areas.
•Southern Ghana, equatorial study area with extensive cloud cover year round•Dense stack classification approach with Landsat 7 ETM+ time-series data•Novel spectral vegetation index for natural vegetation/agriculture classification•Land cover and land use change from c. 2000 to c. 2010 are mapped and quantified.•Predominant changes are natural veg. to ag. (69%) and ag. to built (6%).
Summary Background In a phase 2 study, dexpramipexole (25–150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of ...function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. Methods In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18–80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice–interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12–18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale–revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov , number NCT01281189. Findings Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43–468·08) and those in the placebo group (438·84, 412·81–464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (–13·34 in the dexpramipexole group vs −13·42 in the placebo group; p=0·90) or time to death (74 16% vs 79 17%; hazard ratio 1·03 0·75–1·43; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. Interpretation Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. Funding Biogen Idec.
This article provides an overview of the current knowledge relating to the potential use of transplanted stem cells in the treatment of patients with multiple sclerosis (MS). Two types of stem cells, ...CNS-derived neural stem/precursor cells (NPCs) and bone marrow-derived mesenchymal stem cells (MSCs) are considered to provide reproducible and robust therapeutic effects when intravenously or intrathecally injected into both rodents and primates with experimental autoimmune encephalomyelitis. Furthermore, preliminary safety data concerning the use of intrathecally injected autologous MSCs in patients with progressive MS are available. We discuss how the data gathered to date challenge the narrow view that the therapeutic effects of NPCs and MSCs observed in the treatment of MS are accomplished solely by cell replacement. Both types of stem cell, when transplanted systemically, might instead influence disease outcome by releasing a plethora of factors that are immunomodulatory or neuroprotective, thereby directly or indirectly influencing the regenerative properties of intrinsic CNS stem/precursor cells.
Objective To investigate whether placebo effects can experimentally be separated into the response to three components—assessment and observation, a therapeutic ritual (placebo treatment), and a ...supportive patient-practitioner relationship—and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components.Design A six week single blind three arm randomised controlled trial.Setting Academic medical centre.Participants 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale.Interventions For three weeks either waiting list (observation), placebo acupuncture alone (“limited”), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence (“augmented”). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks.Main outcome measures Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life.Results At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus “limited” versus “augmented,” respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01).Results were similar at six week follow-up.Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component.Trial registration Clinical Trials NCT00065403.
•Effects of exercise modalities and hypoxia on appetite are explored.•Short exposure to hypoxia causes appetite suppressions.•Appetite responses to exercise are not dependant on exercise ...modality.•Suppressed appetite may be explained by decreased circulating acylated ghrelin.
This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (V˙O2max) and during HIIE performed 6 × 3 min running at 90% V˙O2max interspersed with 6 × 3 min active recovery at 50% V˙O2max with a 7 min warm-up and cool-down at 70% V˙O2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p < 0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p < 0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality.
Sinonasal myxoma (SNM) is a rare benign mesenchymal tumor that arises in the sinonasal cavity or maxilla and almost exclusively affects young children. Currently, it is considered a specific entity, ...but its molecular characteristics have not been reported. Lesions diagnosed as SNM and odontogenic myxoma/fibromyxoma were identified from the participating institutions, and the clinicopathologic features were recorded. Immunohistochemistry for β-catenin was performed in all cases with available tissue. Next-generation sequencing was performed in all cases with SNM. Five patients with SNM were identified, including 3 boys and 2 girls with an age range of 20-36 months (mean: 26 months). The tumors were well defined, centered in the maxillary sinus, surrounded by a rim of woven bone, and composed of a moderately cellular proliferation of spindle cells oriented in intersecting fascicles in a variably myxocollagenous stroma that contained extravasated erythrocytes. Histologically, the tumors resembled myxoid desmoid fibromatosis. Three tested cases showed nuclear expression of β-catenin. In 3 tumors, next-generation sequencing revealed intragenic deletions of APC exons 5-6, 9 and 15, or 16, respectively, with concurrent loss of the other wild-type copy of APC predicted to result in biallelic inactivation. The deletions were identical to those that occur in desmoid fibromatosis, and copy number analysis raised the possibility that they were germline. In addition, 1 case showed the possible deletion of APC exons 12-14, and another case exhibited a CTNNB1 p. S33C mutation. Ten patients with odontogenic myxoma/fibromyxoma were identified, including 4 women and 6 men (mean age: 42 years). Seven tumors involved the mandible and 3 the maxilla. Histologically, the tumors differed from SNM, and all cases lacked nuclear expression of β-catenin. These findings suggest that SNM represents a myxoid variant of desmoid fibromatosis that often arises in the maxilla. The APC alterations might be germline, and therefore, genetic testing of the affected patients should be considered.
Objective
We explored the potential of embryonic stem cell–derived motor neurons to functionally replace those cells destroyed in paralyzed adult rats.
Methods
We administered a phosphodiesterase ...type 4 inhibitor and dibutyryl cyclic adenosine monophosphate to overcome myelin‐mediated repulsion and provided glial cell–derived neurotrophic factor within the sciatic nerve to attract transplanted embryonic stem cell–derived axons toward skeletal muscle targets.
Results
We found that these strategies significantly increased the success of transplanted axons extending out of the spinal cord into ventral roots. Furthermore, transplant‐derived axons reached muscle, formed neuromuscular junctions, were physiologically active, and mediated partial recovery from paralysis.
Interpretation
We conclude that restoration of functional motor units by embryonic stem cells is possible and represents a potential therapeutic strategy for patients with paralysis. To our knowledge, this is the first report of the anatomical and functional replacement of a motor neuron circuit within the adult mammalian host. Ann Neurol 2006;60:32–44
Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a ...nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, “distinctive nested glomoid neoplasm.” Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.
Abstract
Our objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients' clinical outcomes based on ...survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. Historically, ALS clinical trials have assessed survival and function as independent endpoints. Combined endpoints have been used in other diseases to decrease the confounding effect of mortality on analysis of functional outcomes. We explored the application of a similar approach in ALS, the CAFS endpoint, which was used as a pre-specified secondary analysis in a phase II study of dexpramipexole. Those results and some hypothetical examples based on modeling exercises are presented here. CAFS is the primary endpoint of a dexpramipexole phase III study in ALS. In conclusion, the CAFS is a robust statistical tool for ALS clinical trials and appropriately accounts for and weights mortality in the analysis of function.
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