Safety and efficacy of teriparatide treatment for severe osteoporosis in patients with Duchenne muscular dystrophy.

Osteoporosis is a major concern in patients with Duchenne muscular dystrophy. In this novel study of teriparatide treatment in 6 patients with severe osteoporosis, bone health (fractures, vertebral morphometry, and DXA) remained stable, with no adverse events. These findings will help inform future osteoporosis research in this challenging population. INTRODUCTION: Despite standard therapy with vitamin D and bisphosphonates (BP), many patients with Duchenne muscular dystrophy (DMD) continue to sustain fragility fractures due to long-term glucocorticoid treatment and limited mobility. We aimed to evaluate the safety and efficacy of teriparatide for the treatment of severe osteoporosis in adolescent and young adult patients with DMD. METHODS: We prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20 mcg subcutaneously daily for 1-2 years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. We examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, bone mineral density and content, bone formation markers, safety indices, and adverse events. RESULTS: The mean age at teriparatide start was 17.9 years (range 13.9-22.1 years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5 years) and 5 were non-ambulatory. Five patients had been treated with BP for 7.9 ± 4.2 years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); one patient sustained a long bone fracture at 6 months of treatment. Trajectories for change in bone mineral density and content were not different post- vs. pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning. No adverse events were observed. CONCLUSION: In six patients with DMD treated with teriparatide for severe osteoporosis, we observed stable bone health and modest increases in P1NP, without safety concerns. Further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.

TimeSets: Temporal Sensemaking in Intelligence Analysis.

TimeSets is a temporal data visualization technique designed to reveal insights into event sets, such as all the events linked to one person or organization. In this article, we describe two TimeSets-based visual analytics tools for intelligence analysis. In the first case, TimeSets is integrated with other visual analytics tools to support open-source intelligence analysis with Twitter data, particularly the challenge of finding the right questions to ask. The second case uses TimeSets in a participatory design process with analysts that aims to meet their requirements of uncertainty analysis involving fake news. Lessons learned are potentially beneficial to other application domains.

Drain-free parotidectomy: a pilot study using ARTISS fibrin sealant.

PURPOSE: Parotidectomy is the definitive procedure for diagnosis and treatment of most parotid masses but, due to the risk of haematoma and seroma formation, has traditionally included a drain. The drain itself comes with its own risks and, in most hospitals, the need for overnight admission, which has significant cost implications (Mallon et al. Ann R Coll Surg Engl 95(4):258-262; 2013). Fibrin glue, with its haemostatic and adhesive properties, reduces the risk of collection or haematoma and therefore may negate the need for a drain. This is the first study to look at the use of ARTISS as an alternative to drains in parotidectomy. METHODS: We performed a retrospective study of all the patients who underwent a partial parotidectomy over a 4-year period from 2014 until 2018 under the same senior surgeon. Patients were divided into those that had a drain and those that had ARTISS. Their operative record, inpatient notes and clinic letters were reviewed to record information regarding length of stay, histology, complications and recurrence. RESULTS: A total of 34 patients were identified; 17 ARTISS and 17 drain patients. We showed that the mean length of stay improved significantly from 1.6 days with the drain to 0.5 days with ARTISS (Fig. 1) but without a difference in complication rate (Fig. 2), which was 5/17 (29%) in each group. CONCLUSIONS: In conclusion, parotidectomy can be undertaken safely as a day-case procedure with the application of ARTISS. This new approach to parotid surgery not only offers less morbidity for patients but also positive financial revenue for public health institutions.

SensePath: Understanding the Sensemaking Process Through Analytic Provenance.

Sensemaking is described as the process of comprehension, finding meaning and gaining insight from information, producing new knowledge and informing further action. Understanding the sensemaking process allows building effective visual analytics tools to make sense of large and complex datasets. Currently, it is often a manual and time-consuming undertaking to comprehend this: researchers collect observation data, transcribe screen capture videos and think-aloud recordings, identify recurring patterns, and eventually abstract the sensemaking process into a general model. In this paper, we propose a general approach to facilitate such a qualitative analysis process, and introduce a prototype, SensePath, to demonstrate the application of this approach with a focus on browser-based online sensemaking. The approach is based on a study of a number of qualitative research sessions including observations of users performing sensemaking tasks and post hoc analyses to uncover their sensemaking processes. Based on the study results and a follow-up participatory design session with HCI researchers, we decided to focus on the transcription and coding stages of thematic analysis. SensePath automatically captures user's sensemaking actions, i.e., analytic provenance, and provides multi-linked views to support their further analysis. A number of other requirements elicited from the design session are also implemented in SensePath, such as easy integration with existing qualitative analysis workflow and non-intrusive for participants. The tool was used by an experienced HCI researcher to analyze two sensemaking sessions. The researcher found the tool intuitive and considerably reduced analysis time, allowing better understanding of the sensemaking process.

Relative position vectors: an alternative approach to conflict detection in air traffic control.

OBJECTIVE: We explore whether the visual presentation of relative position vectors (RPVs) improves conflict detection in conditions representing some aspects of future airspace concepts. BACKGROUND: To help air traffic controllers manage increasing traffic, new tools and systems can automate more cognitively demanding processes, such as conflict detection. However, some studies reveal adverse effects of such tools, such as reduced situation awareness and increased workload. New displays are needed that help air traffic controllers handle increasing traffic loads. METHOD: A new display tool based on the display of RPVs, the Multi-Conflict Display (MCD), is evaluated in a series of simulated conflict detection tasks. The conflict detection performance of air traffic controllers with the MCD plus a conventional plan-view radar display is compared with their performance with a conventional plan-view radar display alone. RESULTS: Performance with the MCD plus radar was better than with radar alone in complex scenarios requiring controllers to find all actual or potential conflicts, especially when the number of aircraft on the screen was large. However performance with radar alone was better for static scenarios in which conflicts for a target aircraft, or target pair of aircraft, were the focus. CONCLUSION: Complementing the conventional plan-view display with an RPV display may help controllers detect conflicts more accurately with extremely high aircraft counts. APPLICATIONS: We provide an initial proof of concept that RPVs may be useful for supporting conflict detection in situations that are partially representative of conditions in which controllers will be working in the future.

An extensible framework for provenance in human terrain visual analytics.

We describe and demonstrate an extensible framework that supports data exploration and provenance in the context of Human Terrain Analysis (HTA). Working closely with defence analysts we extract requirements and a list of features that characterise data analysed at the end of the HTA chain. From these, we select an appropriate non-classified data source with analogous features, and model it as a set of facets. We develop ProveML, an XML-based extension of the Open Provenance Model, using these facets and augment it with the structures necessary to record the provenance of data, analytical process and interpretations. Through an iterative process, we develop and refine a prototype system for Human Terrain Visual Analytics (HTVA), and demonstrate means of storing, browsing and recalling analytical provenance and process through analytic bookmarks in ProveML. We show how these bookmarks can be combined to form narratives that link back to the live data. Throughout the process, we demonstrate that through structured workshops, rapid prototyping and structured communication with intelligence analysts we are able to establish requirements, and design schema, techniques and tools that meet the requirements of the intelligence community. We use the needs and reactions of defence analysts in defining and steering the methods to validate the framework.

Using interactive visual reasoning to support sense-making: implications for design.

This research aims to develop design guidelines for systems that support investigators and analysts in the exploration and assembly of evidence and inferences. We focus here on the problem of identifying candidate 'influencers' within a community of practice. To better understand this problem and its related cognitive and interaction needs, we conducted a user study using a system called INVISQUE (INteractive Visual Search and QUery Environment) loaded with content from the ACM Digital Library. INVISQUE supports search and manipulation of results over a freeform infinite 'canvas'. The study focuses on the representations user create and their reasoning process. It also draws on some pre-established theories and frameworks related to sense-making and cognitive work in general, which we apply as a 'theoretical lenses' to consider findings and articulate solutions. Analysing the user-study data in the light of these provides some understanding of how the high-level problem of identifying key players within a domain can translate into lower-level questions and interactions. This, in turn, has informed our understanding of representation and functionality needs at a level of description which abstracts away from the specifics of the problem at hand to the class of problems of interest. We consider the study outcomes from the perspective of implications for design.

Cartilage shear dynamics during tibio-femoral articulation: effect of acute joint injury and tribosupplementation on synovial fluid lubrication.

OBJECTIVE: To determine the effects of acute injury and tribosupplementation by hyaluronan (HA) on synovial fluid (SF) modulation of cartilage shear during tibio-femoral articulation. METHODS: Human osteochondral blocks from the lateral femoral condyle (LFC) and tibial plateau (LTP) were apposed, compressed 13%, and subjected to sliding under video microscopy. Tests were conducted with equine SF from normal joints (NL-SF), SF from acutely injured joints (AI-SF), and AI-SF to which HA was added (AI-SF+HA). Local and overall shear strain (E(xz)) and the lateral displacement (Deltax) at which E(xz) reached 50% of peak values (Deltax(1/2)) were determined. RESULTS: During articulation, LFC and LTP cartilage E(xz) increased with Deltax and peaked when surfaces slid, with peak E(xz) being maintained during sliding. With AI-SF as lubricant, surface and overall Deltax(1/2) were approximately 40% and approximately 20% higher, respectively, than values with NL-SF and AI-SF+HA as lubricant. Also, peak E(xz) was markedly higher with AI-SF as lubricant than with NL-SF as lubricant, both near the surface (approximately 80%) and overall (50-200%). Following HA supplementation to AI-SF, E(xz) was reduced from values with AI-SF alone by 30-50% near the surface and 20-30% overall. Magnitudes of surface and overall E(xz) were markedly (approximately 50 to 80%) higher in LTP cartilage than LFC cartilage for all lubricants. CONCLUSION: Acute injury impairs SF function, elevating cartilage E(xz) markedly during tibio-femoral articulation; such elevated E(xz) may contribute to post-injury associated cartilage degeneration. Since HA partially restores the function of AI-SF, as indicated by E(xz), tribosupplements may be beneficial in modulating normal cartilage homeostasis.

Steroid therapy and cardiac function in Duchenne muscular dystrophy.

Duchenne muscular dystrophy leads to progressive deterioration in skeletal and cardiac muscle function. Steroids prolong ambulation and improve respiratory muscle strength. The authors hypothesized that steroid treatment would stabilize cardiac muscle function. Echocardiograms performed from 1997 to 2004 for 111 subjects 21 years of age or younger with Duchenne muscular dystrophy were restrospectively reviewed. The medical record was reviewed for steroid treatment. Untreated and steroids-treated subjects did not differ in age, height, weight, body mass index, systolic and diastolic blood pressure, or left ventricular mass. The shortening fraction was lower in the untreated group. Of those treated, 29 received prednisone and 19 received deflazacort. There was no difference in the shortening fraction between the two treated subgroups. Treated subjects not receiving steroids still had a normal shortening fraction, which was no different from the shortening fraction of those still receiving treatment. As compared with the treated subjects, the untreated subjects 10 years of age or younger were 4.4 times more likely to have a shortening fraction less than< 28% (p = 0.03), and the untreated subjects older than 10 years were 15.2 times more likely to have a shortening fraction less than< 28% (p < 0.01). This retrospective study suggests that the progressive decline in cardiac function of patients with Duchenne muscular dystrophy can be altered by steroid treatment. The effect appears to be sustained beyond the duration of treatment and independent of steroid type.

High-sensitivity determination of the degradation products of chemical warfare agents by capillary electrophoresis-indirect UV absorbance detection.

Capillary electrophoresis coupled with indirect UV absorbance detection was employed for the determination of the chemical warfare agent degradation products: methylphosphonic acid, ethyl methylphosphonate, isopropyl methylphosphonate, and pinacolyl methylphosphonate. Glutamic acid was used as a buffering agent at its isoelectric point (pH 3.22). In its zwitterionic form, glutamic acid does not act as a competing co-anion in the system, thus providing buffering capacity while maintaining high sensitivity. The indirect probe (phenylphosphonic acid) concentration was lowered to 1 mM from the 10 mM in previous literature studies, further enhancing sensitivity. Detection limits of 2 microM were achieved with hydrodynamic injection and up to 100-fold lower using electrokinetic injection. The increased buffering capacity of this system over previous methods led to migration time reproducibility RSD values of 0.18 to 0.22%. This represents a 10-fold improvement in reproducibility over previous studies with comparable or improved sensitivity.

3D-QSAR model of flavonoids binding at benzodiazepine site in GABAA receptors.

With flavone as a structural template, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies and ab initio calculations were performed on a series of flavonoids. A reasonable pharmacophore model was built through CoMFA, CoMSIA, and HQSAR analyses and electrostatic potential calculations. A plausible binding mode for flavonoids with GABA(A) receptors was rationalized. On the basis of the commonly recognized binding site, the specific S1 and S2 subsites relating to substituent positions were proposed. The different binding affinities could be explained according to the frontier orbitals and electrostatic potential (ESP) maps. The ESP could be used as a novel starting point for designing more selective BZ-binding-site ligands.

Two-step immobilized enzyme conversion of cephalosporin C to 7-aminocephalosporanic acid.

The first large-scale production of 7-aminocephalosporanic acid (7ACA) from cephalosporin C (CPC) using a wholly enzymatic synthesis method is reported here. We produced 7ACA from CPC in as high a molar yield as 85% using the immobilized enzymes D-amino acid oxidase (D-AOD) and glutaryl-7-ACA acylase (GL-acylase). In the first reactor, CPC is converted to keto-adipyl-7-aminocephalosporanic acid (keto-7ACA) using an immobilized D-AOD isolated from a yeast, Trigonopsis variabilis. The keto-7ACA is then spontaneously converted to glutaryl-7-aminocephalosporanic acid (GL-7ACA) via a chemical reaction with hydrogen peroxide. The hydrogen peroxide is also a product of the D-AOD reaction. Near quantitative conversion of the keto-7ACA to GL-7ACA was observed. The second reactor converts GL-7ACA to 7ACA using an immobilized GL-acylase, which was isolated from a recombinant Escherichia coli. The final 7ACA crystalline product is a high quality product. The reactions are conducted under very mild aqueous conditions: pH 8.0 and 20 degrees to 25 degrees C. The production of desacetyl side products is minimal. This process is currently being implemented on an industrial scale to produce 7ACA.

Purification of a lymphoid cell line product with leukocyte inhibitory factor activity.

Leukocyte inhibitory factor (LIF), a lymphokine that inhibits the random and directed migration of polymorphonuclear (PMN) leukocytes, was purified from a human non-T, non-B leukemia cell line (Reh). From 10 liters of serum-free supernatant, 1.3 microgram of protein with LIF activity was obtained by the sequential use of affinity chromatography with concanavalin A-Sepharose, hydrophobic chromatography with hexylagarose, and gel filtration chromatography. The specific activity of LIF recovered represented an 80,000-fold purification over that of the initial crude serum-free supernatants, and the preparation at that point was estimated to be 80--90% pure. To both assess the purity of the preparation and provide a further purification step, Reh LIF activity recovered by the above procedures was subjected to isoelectric focusing. One major stainable protein band was identified; its isoelectric point was pH 5.4--5.5. Gels run in parallel for recovery of biologic activity revealed only one region (pH 5.4--5.5) with ability to inhibit PMN leukocyte migration. Iodination of Reh LIF resulted in a loss of biologic activity, but isoelectric focusing of this material revealed one major 125I-labeled band (pH 5.1) and several minor bands. The coincidence of biologic LIF activity with one stainable protein band as identified by isoelectric focusing implies that the final product may be homogeneous.