Primary central nervous system vasculitis (PCNSV) is an uncommon condition in which lesions are limited to vessels of the brain and spinal cord. Because the clinical manifestations are not specific, ...the diagnosis is often difficult, and permanent disability and death are frequent outcomes. This study is based on a cohort of 163 consecutive patients with PCNSV who were examined at the Mayo Clinic over a 29-year period from 1983 to 2011. The aim of the study was to define the characteristics of these patients, which represents the largest series in adults reported to date. A total of 105 patients were diagnosed by angiographic findings and 58 by biopsy results. The patients diagnosed by biopsy more frequently had at presentation cognitive dysfunction, greater cerebrospinal fluid total protein concentrations, less frequent cerebral infarcts, and more frequent leptomeningeal gadolinium-enhanced lesions on magnetic resonance imaging (MRI), along with less mortality and disability at last follow-up. The patients diagnosed by angiograms more frequently had at presentation hemiparesis or a persistent neurologic deficit or stroke, more frequent infarcts on MRI and an increased mortality. These differences were mainly related to the different size of the vessels involved in the 2 groups. Although most patients responded to therapy with glucocorticoids alone or in conjunction with cyclophosphamide and tended to improve during the follow-up period, an overall increased mortality rate was observed. Relapses occurred in one-quarter of the patients and were less frequent in patients treated with prednisone and cyclophosphamide compared with those treated with prednisone alone. The mortality rate and degree of disability at last follow-up were greater in those with increasing age, cerebral infarctions on MRI, angiographic large vessel involvement, and diagnosis made by angiography alone, but were lower in those with gadolinium-enhanced lesions on MRI and in those with cerebral amyloid angiopathy. The annual incidence rate of PCNSV was estimated at 2.4 cases per 1,000,000 person-years. PCNSV appears to consist of several subsets defined by the size of the vessels involved, the clinical characteristics at presentation, MRI findings, and histopathological patterns on biopsy. Early recognition and treatment may reduce poor outcomes.
While delirium is associated with cognitive decline and dementia, there is limited evidence to support causality for this relationship. Clarification of how delirium may cause cognitive decline, ...perhaps through evidence of contemporaneous neuronal injury, would enhance plausibility for a causal relationship. Dose-dependence of neuronal injury with delirium severity would further enhance the biological plausibility for this relationship. We tested whether delirium is associated with neuronal injury in 114 surgical patients recruited to a prospective biomarker cohort study. Patients underwent perioperative testing for changes in neurofilament light, a neuronal injury biomarker, as well as a panel of 10 cytokines, with contemporaneous assessment of delirium severity and incidence. A subset of patients underwent preoperative MRI. Initially we confirmed prior reports that neurofilament light levels correlated with markers of neurodegeneration hippocampal volume (ΔR2 = 0.129, P = 0.015) and white matter changes including fractional anisotropy of white matter (ΔR2 = 0.417, P < 0.001) with similar effects on mean, axial and radial diffusivity) in our cohort and that surgery was associated with increasing neurofilament light from preoperative levels mean difference (95% confidence interval, CI) = 0.240 (0.178, 0.301) log10 (pg/ml), P < 0.001, suggesting putative neuronal injury. Next, we tested the relationship with delirium. Neurofilament light rose more sharply in participants with delirium compared to non-sufferers mean difference (95% CI) = 0.251 (0.136, 0.367) log10 (pg/ml), P < 0.001. This relationship showed dose-dependence, such that neurofilament light rose proportionately to delirium severity (ΔR2 = 0.199, P < 0.001). Given that inflammation is considered an important driver of postoperative delirium, next we tested whether neurofilament light, as a potential marker of neurotoxicity, may contribute to the pathogenesis of delirium independent of inflammation. From a panel of 10 cytokines, the pro-inflammatory cytokine IL-8 exhibited a strong correlation with delirium severity (ΔR2 = 0.208, P < 0.001). Therefore, we tested whether the change in neurofilament light contributed to delirium severity independent of IL-8. Neurofilament light was independently associated with delirium severity after adjusting for the change in inflammation (ΔR2 = 0.040, P = 0.038). These data suggest delirium is associated with exaggerated increases in neurofilament light and that this putative neurotoxicity may contribute to the pathogenesis of delirium itself, independent of changes in inflammation.
Macroscale additive manufacturing has seen significant advances recently, but these advances are not yet realized for the bottom-up formation of nanoscale polymeric features. We describe a platform ...technology for creating crosslinked polymer features using rapid surface-initiated crosslinking and versatile macrocrosslinkers, delivered by a microfluidic-coupled atomic force microscope known as FluidFM. A crosslinkable polymer containing norbornene moieties is delivered to a catalyzed substrate where polymerization occurs, resulting in extremely rapid chemical curing of the delivered material. Due to the living crosslinking reaction, construction of lines and patterns with multiple layers is possible, showing quantitative material addition from each deposition in a method analogous to fused filament fabrication, but at the nanoscale. Print parameters influenced printed line dimensions, with the smallest lines being 450 nm across with a vertical layer resolution of 2 nm. This nanoscale 3D printing platform of reactive polymer materials has applications for device fabrication, optical systems and biotechnology.
As acute type A aortic dissection (ATAAD) remains a challenge, the extent of resection of the transverse arch remains debated during operative repair. The purpose of this study was to compare the ...outcomes of total arch repair versus ascending/proximal arch repair for ATAAD.
We retrospectively reviewed our aortic database of ATAAD between October 1999 and December 2014. Patients were divided into two groups: total arch repair versus proximal arch repair (hemiarch). Indications for arch replacement during ATAAD include aneurysm greater than 5 cm, complex arch tear, and arch rupture. Inhospital and long-term outcomes were compared between the two groups using univariate analysis and multiple logistic regression analysis. Survival was analyzed using Kaplan-Meier and log rank statistics, and assessment of risk factors for survival was conducted by Cox proportional hazards regression analysis.
During the study period, we performed 489 repairs of ATAAD, 49 patients (10%) with total arch replacement and 440 patients (90%) with proximal arch replacement. Patients with total arch repair were older (62.4 ± 13.4 years versus 57.9 ± 14.8 years, p = 0.046) and had significantly increased retrograde aortic dissection, circulatory arrest, and retrograde cerebral perfusion times. The incidences of early mortality, stroke, and need for renal dialysis between the total arch and proximal arch group were not significantly different: 20.4% (10 of 49) versus 12.9% (57 of 440), 8.2% (4 of 49) versus 10.5% (46 of 440), and 27% (13 of 49) versus 17.6% (76 of 432), respectively. Late survival did not demonstrate a difference between groups.
Acute type A aortic dissection remains a challenge associated with significant mortality and morbidity. When compared with a less aggressive resection, total arch replacement performed in an individualized fashion can be associated with acceptable early and late outcomes for ATAAD and was not associated with worse outcomes.
Mutations occur at four specific sites in the hTERT promoter in >75% of glioblastomas and melanomas, but the mechanism by which the mutations affect gene expression remains unexplained. We report ...biophysical computational studies that show that the hTERT promoter sequence forms a novel G-quadruplex structure consisting of three contiguous, stacked parallel quadruplexes. The reported hTERT mutations map to the central quadruplex within this structure, and lead to an alteration of its hydrodynamic properties and stability.
Summary
Bacterial pathogens must overcome host sequestration of zinc (Zn2+), an essential micronutrient, during the infectious disease process. While the mechanisms to acquire chelated Zn2+ by ...bacteria are largely undefined, many pathogens rely upon the ZnuABC family of ABC transporters. Here we show that in Yersinia pestis, irp2, a gene encoding the synthetase (HMWP2) for the siderophore yersiniabactin (Ybt) is required for growth under Zn2+‐deficient conditions in a strain lacking ZnuABC. Moreover, growth stimulation with exogenous, purified apo‐Ybt provides evidence that Ybt may serve as a zincophore for Zn2+ acquisition. Studies with the Zn2+‐dependent transcriptional reporter znuA::lacZ indicate that the ability to synthesize Ybt affects the levels of intracellular Zn2+. However, the outer membrane receptor Psn and TonB as well as the inner membrane (IM) ABC transporter YbtPQ, which are required for Fe3+ acquisition by Ybt, are not needed for Ybt‐dependent Zn2+ uptake. In contrast, the predicted IM protein YbtX, a member of the Major Facilitator Superfamily, was essential for Ybt‐dependent Zn2+ uptake. Finally, we show that the ZnuABC system and the Ybt synthetase HMWP2, presumably by Ybt synthesis, both contribute to the development of a lethal infection in a septicaemic plague mouse model.
Objective
To provide evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).
Methods
A core group led the ...development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework.
Results
In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS.
Conclusion
These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.
In view of advances in early detection and treatment, the 5-year relative survival rate for all cancer patients combined is now approximately 66%. As a result, there are more than 13.7 million cancer ...survivors in the United States, with this number increasing by 2% annually. For many patients, improvements in survival have been countered by therapy-associated adverse effects that may seriously impair long-term functional status, workplace productivity, and quality of life. Approximately 20% to 40% of cancer patients given neurotoxic chemotherapy develop chemotherapy-induced peripheral neurotoxicity (CIPN), which represents one of the most common and potentially permanent nonhematologic side effects of chemotherapy. Permanent bilateral hearing loss and/or tinnitus can result from several ototoxic therapies, including cisplatin- or carboplatin-based chemotherapy. CIPN and ototoxicity represent important challenges because of the lack of means for effective prevention, mitigation, or a priori identification of high-risk patients, and few studies have applied modern genomic approaches to understand underlying mechanisms/pathways. Translational genomics, including cell-based models, now offer opportunities to make inroads for the first time to develop preventive and interventional strategies for CIPN, ototoxicity, and other treatment-related complications. This commentary provides current perspective on a successful research strategy, with a focus on cisplatin, developed by an experienced, transdisciplinary group of researchers and clinicians, representing pharmacogenomics, statistical genetics, neurology, hearing science, medical oncology, epidemiology, and cancer survivorship. Principles outlined herein are applicable to the construction of research programs in translational genomics with strong clinical relevance and highlight unprecedented opportunities to understand, prevent, and treat long-term treatment-related morbidities.
Mislabelling of seafood products has been documented in numerous countries for over three-quarters of a century. With a trend towards increased consumption of seafood, the informed consumer demands ...accurately labelled products that provide full disclosure of composition. DNA barcoding can be used to accurately identify a seafood product to species based on its genetic signature, and so provides a means to test the authenticity and accuracy of seafood labelling. This can be especially useful for products such as fillets which have few or no unambiguous identifying characters, and can easily be mislabelled. We investigated labelling accuracy in seafood retailers in Tasmania, Australia. Thirty-eight seafood products were obtained from seafood retailers, sequenced for the barcoding gene region cytochrome oxidase subunit 1(CO1), and subsequently identified to species level by querying GenBank and Barcode of Life Data Systems (BOLD) DNA sequence records. Results were compared with standard fish names (SFN) prescribed under the Australian Fish Names Standard (AFNS) and FishBase. Of the 38 samples, none were deemed to have been mislabelled under Australian regulation, although in some cases naming discrepancies and ambiguity may cause confusion for some consumers. Our work, while reflecting high standards in Tasmanian seafood, highlights the need for mandatory standard labelling across all seafood products so as to eliminate any possible misrepresentation.
•We investigated labelling accuracy in seafood retailers in Tasmania, Australia.•We examined thirty-eight seafood samples obtained anonymously from retailers.•Sequenced these for barcoding region CO1 and identified to species level by querying BOLD records.•Results compared with Standard Fish Names prescribed under the AFNS and FishBase.•No mislabelling observed under Australian regulation, suggesting high labelling standards.
The HEART Pathway is a validated risk stratification protocol for Emergency Department patients with chest pain that has yet to be tested in the prehospital setting. This study seeks to test the ...performance of a prehospital modified HEART Pathway (PMHP). A prospective cohort study of adults with chest pain without ST-segment elevation myocardial infarction was conducted at three EMS agencies between 12/2016-1/2018. To complete a PMHP assessment, paramedics drew blood, measured point-of-care (POC) troponin (i-STAT; Abbott Point of Care) and calculated a HEAR score. Patients were stratified into three groups: high-risk based on an elevated troponin, low-risk based on a HEAR score 4 with a negative troponin, or moderate risk for a HEAR score greater than or equal to4 with a negative troponin. Sensitivity, specificity, negative and positive predictive values of the PMHP for detection of major adverse cardiac events (MACE: cardiac death, MI, or coronary revascularization) at 30-days were calculated. A total of 506 patients were accrued, with PMHP completed in 78.1% (395/506). MACE at 30-days occurred in 18.7% (74/395). Among these patients, 7.1% (28/395) were high risk yielding a specificity and PPV for 30-day MACE of 96.6% (95%CI: 94.0-98.3%) and 60.7% (95%CI: 40.6-78.6%) respectively. Low-risk assessments occurred in 31.4% (124/395), which were 90.5% (95%CI: 81.5-96.1%) sensitive for 30-day MACE with a NPV of 94.4% (95%CI: 88.7-97.7%). Moderate-risk assessments occurred in 61.5% (243/395), of which 20.6% had 30-day MACE. The PMHP is able to identify high-risk and low-risk groups with high specificity and negative predictive value for 30-day MACE. Clinical trial registration clinicaltrials.gov (NCT02709135).
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