Helminth parasites are a highly successful group of pathogens that challenge the immune system in a manner distinct from rapidly replicating infectious agents. Of this group, roundworms (nematodes) ...that dwell in the intestines of humans and other animals are prevalent worldwide. Currently, more than one billion people are infected by at least one species, often for extended periods of time. Thus, host-protective immunity is rarely complete. The reasons for this are complex, but laboratory investigation of tractable model systems in which protective immunity is effective has provided a mechanistic understanding of resistance that is characterized almost universally by a type 2 T helper 2 response. Greater understanding of the mechanisms of susceptibility has also provided the basis for defining host immunoregulation and parasite-evasion strategies, helping place in context the changing patterns of immunological disease observed worldwide.
This paper reviews progress in environmental impact assessment (EIA) over the last 40 years, with particular emphasis on the last 15-20 years, and poses the question: is EIA ready to meet future ...challenges? The first part of the paper briefly examines the spread of EIA around the world, recent trends in the uptake of EIA, and the continuing emergence of variants of impact assessment. The second part of the paper concentrates on current issues in EIA, under three broad headings: theory and EIA, practice issues and EIA effectiveness. An important thread running through the second part of the paper is how discussions about EIA theory, a feature of the last 15 years, are affecting the different areas of EIA practice and evaluation.
Deep brain stimulation (DBS) surgery is increasingly prominent in the treatment of various disorders refractory to medication. Despite the procedure's efficacy, the community at large continues to be ...hesitant about presumed associated risks. The main object of this study was to assess the incidence of various surgical complications occurring both during and after DBS device implantation in a large population of patients with movement disorders in an effort to better quantify patient risk, define management plans, and develop methods for risk avoidance. A second aim was to corroborate the low procedural complication risk of DBS reported by others, which in light of the procedure's efficacy is needed to promote its widespread acceptance.
All patients who had undergone new DBS device implantation surgery between 2002 and 2010 by a single surgeon were entered into a database after being verified by cross-referencing manufacturer implantation records. All surgical records and charts were reviewed to identify intraoperative, perioperative, and long-term surgical complications, including any characteristics predictive of an adverse event.
Seven hundred twenty-eight patients received 1333 new DBS electrodes and 1218 new internal pulse generators (IPGs) in a total of 1356 stereotactic procedures for the treatment of movement disorders. Seventy-eight percent of the patients had staged lead and IPG implantations. Of the 728 patients, 452 suffered from medically refractory Parkinson disease; in the other patients, essential tremor (144), dystonia (64), mixed disease (30), and other hyperkinetic movement disorders (38) were diagnosed. Severe intraoperative adverse events included vasovagal response in 6 patients (0.8%), hypotension in 2 (0.3%), and seizure in 2 (0.3%). Postoperative imaging confirmed asymptomatic intracerebral hemorrhage (ICH) in 4 patients (0.5%), asymptomatic intraventricular hemorrhage in 25 (3.4%), symptomatic ICH in 8 (1.1%), and ischemic infarction in 3 (0.4%), associated with hemiparesis and/or decreased consciousness in 13 (1.7%). Long-term complications of DBS device implantation not requiring additional surgery included hardware discomfort in 8 patients (1.1%) and loss of desired effect in 10 (1.4%). Hardware-related complications requiring surgical revision included wound infections in 13 patients (1.7%), lead malposition and/or migration in 13 (1.7%), component fracture in 10 (1.4%), component malfunction in 4 (0.5%), and loss of effect in 19 (2.6%).
The authors confirmed that the overall risk of both procedure- and hardware-related adverse events is acceptably low. They offer advice on how to avoid the most common complications.
This study evaluates the performance of diffusion‐weighted magnetic resonance imaging (DWI) for the detection of hepatocellular carcinoma (HCC) in pre–liver transplantation patients, compared and ...combined with contrast‐enhanced T1‐weighted imaging (CET1WI), using liver explant as the standard of reference. We included 52 patients with cirrhosis (40 men, 12 women; mean age, 56 years) who underwent DWI and CET1WI within 90 days of liver transplantation. Magnetic resonance images were analyzed for HCC detection in three separate sessions by two independent observers: DWI images (DW‐set), CET1WI (CE‐set), and all images together (All‐set). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), per‐patient accuracy, and per‐lesion PPV were calculated for each image set. A total of 72 HCCs were present in 33 patients at explant (mean size, 1.5 cm range, 0.3‐6.2 cm). Per‐patient sensitivity and NPV of CE‐set were significantly higher than those of DW‐set when using pooled data between observers (P = 0.02 and 0.03, respectively), whereas specificity, PPV, and accuracy were equivalent. Per‐lesion sensitivity was significantly higher for CE‐set versus DW‐set (59.0% versus 43.8%; P = 0.008, pooled data from two observers). When stratified by lesion size, the difference was significant only for lesions with a size between 1 and 2 cm (42.0% for DW‐set versus 74.0% for CE‐set; P = 0.001). The addition of DWI to CET1WI improved sensitivity for the more experienced observer. Conclusion: DWI is outperformed by CET1WI for detection of HCC, but represents a reasonable alternative to CET1WI for detection of HCC with a size above 2 cm. The addition of DWI to CET1WI slightly increases the detection rate. (HEPATOLOGY 2012;56:140–148)
Lack of assurance of quality with additively manufactured (AM) parts is a key technological barrier that prevents manufacturers from adopting AM technologies, especially for high-value applications ...where component failure cannot be tolerated. Developments in process control have allowed significant enhancement of AM techniques and marked improvements in surface roughness and material properties, along with a reduction in inter-build variation and the occurrence of embedded material discontinuities. As a result, the exploitation of AM processes continues to accelerate. Unlike established subtractive processes, where in-process monitoring is now commonplace, factory-ready AM processes have not yet incorporated monitoring technologies that allow discontinuities to be detected in process. Researchers have investigated new forms of instrumentation and adaptive approaches which, when integrated, will allow further enhancement to the assurance that can be offered when producing AM components. The state-of-the-art with respect to inspection methodologies compatible with AM processes is explored here. Their suitability for the inspection and identification of typical material discontinuities and failure modes is discussed with the intention of identifying new avenues for research and proposing approaches to integration into future generations of AM systems.
Example concepts for integration of a sensor unit (green) for in-situ monitoring of laser powder bed fusion. Display omitted
•An overview of state-of-the-art methods for assessing the quality of additive manufacturing processes is presented.•The need for new sensors and monitoring methods for emergent additive manufacturing processes is introduced.•Material discontinuities resulting from well understood processes are explored and the case for in-situ monitoring is made.•The industrial opportunities and potential benefits of using these advanced methods are explored.
The stable structural conformations that occur along the complete reaction coordinate for ion channel opening have never been observed. In this study, we describe the equilibrium ensemble of ...structures of Slo2.2, a neuronal Na+-activated K+ channel, as a function of the Na+ concentration. We find that Slo2.2 exists in multiple closed conformations whose relative occupancies are independent of Na+ concentration. An open conformation emerges from an ensemble of closed conformations in a highly Na+-dependent manner, without evidence of Na+-dependent intermediates. In other words, channel opening is a highly concerted, switch-like process. The midpoint of the structural titration matches that of the functional titration. A maximum open conformation probability approaching 1.0 and maximum functional open probability approaching 0.7 imply that, within the class of open channels, there is a subclass that is not permeable to ions.
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•Cryo-EM and functional titrations of Slo2.2•Structures of Slo2.2 in open and closed conformations•Switch-like activation mechanism between open and closed conformations•Evidence of non-conductive channels in an open conformation
Cryo-EM analyses of a protein ensemble under a range of conditions show that a neuronal Na+-activated K+ channel uses an all-or-nothing approach to opening.
We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point ...mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.
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► Smokers with lung cancer show 10× the number of point mutations than never-smokers ► Novel lung cancer genes, including DACH1, CFTR, RELN, ABCB5, and HGF were identified ► Novel pathway alterations in lung cancer include cell-cycle and JAK-STAT pathways ► Alterations were identified in 54 genes for which targeted drugs are available
Whole-genome sequencing of 17 lung cancer patients reveals that smokers with lung cancer show 10× the number of point mutations than patients who were never smokers. Alterations were identified in 54 genes for which targeted drugs are available.
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