Safety and outcomes with efgartigimod use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Multiple novel therapies have been approved for patients with myasthenia gravis. Our aim is to describe the early experience of efgartigimod use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG). METHODS: This multicenter retrospective study included AChR+ve gMG patients from five major neuromuscular centers who were treated with efgartigimod and had both pre- and post-efgartigimod myasthenia gravis activities of daily living (MG-ADL) scores. Information regarding MG history, concomitant treatment(s), MG-ADL and other MG-specific measures, laboratory data, and adverse events were recorded. RESULTS: A total of 37 patients (M:23, F:14) with a mean age of 65.56 (±14.74) y were included in this cohort. A total of 36/37 patients completed at least one cycle and 28 patients completed at least two cycles of efgartigimod. A total of 72% (26/36) of patients had a clinically meaningful reduction (≥2 point change) in MG-ADL after the completion of the first cycle of efgartigimod (mean pre-efgartigimod 8.02) (±3.09) versus post-efgartigimod 4.33 (±3.62). Twenty-five percent (9/36) achieved minimal symptom expression status after one cycle and 25% (7/28) after the second cycle. Treatment benefit was sustained after cycle 2. Three out of four patients with thymoma in this cohort had clinically significant reductions in MG-ADL scores. Immunoglobulin G (IgG) levels decreased by about 60% (n = 10). One patient had a relapse of Clostridium difficile infection resulting in the discontinuation of therapy. Four patients had mild side effects. DISCUSSION: Efgartigimod led to clinically meaningful improvement in MG-ADL in diverse AChR+ve gMG patients but treatment frequency to achieve optimal symptom control needs to be explored.

GNE myopathy: History, etiology, and treatment trials.

GNE myopathy is an ultrarare muscle disease characterized by slowly progressive muscle weakness. Symptoms typically start in early adulthood, with weakness and atrophy in the tibialis anterior muscles and with slow progression over time, which largely spares the quadriceps muscles. Muscle biopsy shows atrophic fibers and rimmed vacuoles without inflammation. Inherited in an autosomal recessive manner, patients with GNE myopathy carry mutations in the GNE gene which affect the sialic acid synthesis pathway. Here, we look at the history and clinical aspects of GNE myopathy, as well as focus on prior treatment trials and challenges and unmet needs related to this disorder.

A framework for localizing global climate solutions and their carbon reduction potential.

Localized carbon reduction strategies are especially critical in states and regions that lack top-down climate leadership. This paper illustrates the use of coupled systems in assessments of subnational climate solutions with a case study of Georgia, a state located in the southeastern United States that does not have statewide climate goals or plans. The paper illustrates how robust place-specific plans for climate action could be derived from foundational global and national work and by embedding that research into the context of socio-ecological-technological systems. Our replicable methodology advances the traditional additive sectoral wedge analysis of carbon abatement potential by incorporating solution interdependencies and by spanning both carbon sources and sinks. We estimate that a system of 20 solutions could cut Georgia's carbon footprint by 35% in 2030 relative to a business-as-usual forecast and by 50% relative to Georgia's emissions in 2005. We also produce a carbon abatement cost curve that aligns private and social costs as well as benefits with units of avoided CO2-e. The solutions are affiliated with various social co-costs and co-benefits that highlight societal concerns extending beyond climate impacts, including public health, environmental quality, employment, and equity.

Translating a Global Emission-Reduction Framework for Subnational Climate Action: A Case Study from the State of Georgia.

Subnational entities are recognizing the need to systematically examine options for reducing their carbon footprints. However, few robust and comprehensive analyses are available that lay out how US states and regions can most effectively contribute. This paper describes an approach developed for Georgia-a state in the southeastern United States called "Drawdown Georgia", our research involves (1) understanding Georgia's baseline carbon footprint and trends, (2) identifying the universe of Georgia-specific carbon-reduction solutions that could be impactful by 2030, (3) estimating the greenhouse gas reduction potential of these high-impact 2030 solutions for Georgia, and (4) estimating associated costs and benefits while also considering how the solutions might impact societal priorities, such as economic development opportunities, public health, environmental benefits, and equity. We began by examining the global solutions identified by Project Drawdown. The resulting 20 high-impact 2030 solutions provide a strategy for reducing Georgia's carbon footprint in the next decade using market-ready technologies and practices and including negative emission solutions. This paper describes our systematic and replicable process and ends with a discussion of its strengths, weaknesses, and planned future research.

The groundwater risk index: Development and application in the Middle East and North Africa region.

Overreliance on predominantly non-renewable groundwater resources and their subsequent depletion has given rise to adverse environmental, political, economic, and social effects. The high costs of groundwater depletion are exacerbated by the notable absence of tools designed to identify and diagnose areas at risk of groundwater degradation. In this study, a Groundwater Risk Index (GRI) was developed as a distributed composite index to assess and evaluate groundwater depletion risk by combining different environmental and socioeconomic datasets and models. GRI is designed to be used by end-users (e.g. governments, NGOs) as a multicriteria diagnostic tool to identify and determine the probability and severity of an entity experiencing the adverse effects of groundwater mining. Annual GRI results indicate that groundwater risk is highly dependent on governance and food security. Surprisingly, groundwater storage reserves were indeterminate of groundwater risk. Given the centrality of agricultural production in groundwater consumptive use, MENA countries are recommended to mitigate groundwater depletion by establishing reliable and secure virtual water transfers (agricultural trade) to achieve food security, as opposed to unsustainably exploiting finite water resources for short-term food sufficiency. The GRI's design choices, including adopting an equal weighting scheme and a linear additive aggregation approach, promote structural flexibility that enables the modification, application, and implementation of the index in other semi- to hyper-arid regions with a high level of dependency on groundwater resources.

Systematic identification and analysis of frequent gene fusion events in metabolic pathways.

BACKGROUND: Gene fusions are the most powerful type of in silico-derived functional associations. However, many fusion compilations were made when <100 genomes were available, and algorithms for identifying fusions need updating to handle the current avalanche of sequenced genomes. The availability of a large fusion dataset would help probe functional associations and enable systematic analysis of where and why fusion events occur. RESULTS: Here we present a systematic analysis of fusions in prokaryotes. We manually generated two training sets: (i) 121 fusions in the model organism Escherichia coli; (ii) 131 fusions found in B vitamin metabolism. These sets were used to develop a fusion prediction algorithm that captured the training set fusions with only 7 % false negatives and 50 % false positives, a substantial improvement over existing approaches. This algorithm was then applied to identify 3.8 million potential fusions across 11,473 genomes. The results of the analysis are available in a searchable database at http://modelseed.org/projects/fusions/ . A functional analysis identified 3,000 reactions associated with frequent fusion events and revealed areas of metabolism where fusions are particularly prevalent. CONCLUSIONS: Customary definitions of fusions were shown to be ambiguous, and a stricter one was proposed. Exploring the genes participating in fusion events showed that they most commonly encode transporters, regulators, and metabolic enzymes. The major rationales for fusions between metabolic genes appear to be overcoming pathway bottlenecks, avoiding toxicity, controlling competing pathways, and facilitating expression and assembly of protein complexes. Finally, our fusion dataset provides powerful clues to decipher the biological activities of domains of unknown function.

Evaluating Didactic Methods for Training Medical Students in the Use of Bedside Ultrasound for Clinical Practice at a Faculty of Medicine in Romania.

OBJECTIVES: Medical students' time is limited, so efficiency in medical education is valued. This research project aimed to determine the most effective means to teach bedside ultrasound to medical students in a 1-week training course. We hypothesized that the best method would include a combination of podcasts and hands-on teaching; therefore, there would be a statistically significant difference among the various methods of teaching. METHODS: Medical students were randomly assigned to 3 groups. All groups attended a 50-minute hands-on bedside ultrasound training session. Students in the first group attended a 50-minute live lecture before the hands-on session, whereas students in the second group watched a podcast that covered the same material as the live lecture. Students in the third group served as the control and only attended the hands-on sessions. Five topics were covered during the course: (1) introduction to ultrasound, (2) pulmonary ultrasound, (3) cardiac ultrasound, (4) hepatobiliary ultrasound, and (5) focused assessment with sonography for trauma. Students completed a 20-question pre- and post-training quiz that covered basic ultrasound principles. Students also conducted a focused assessment with sonography for trauma examination for the practical portion of their evaluation. RESULTS: Students' pre- to post-training quiz scores increased from 33.6% to 72.6% correct in the lecture group (n = 21; P < .0001), from 40.7% to 75.5% correct in the podcast group (n = 20; P< .0001), and from 37.8% to 70.0% correct in the control group (n = 23; P< .0001). Data analysis of written and practical examination scores showed no significant differences among the groups [F(2,61) = 0.885; P = .418; F(2,60) = 1.739; P = .184, respectively]. CONCLUSIONS: These results suggest that all 3 methods are equally effective in teaching novice medical students basic ultrasound knowledge and skills.

High throughput screening using acoustic droplet ejection to combine protein crystals and chemical libraries on crystallization plates at high density.

We describe a high throughput method for screening up to 1728 distinct chemicals with protein crystals on a single microplate. Acoustic droplet ejection (ADE) was used to co-position 2.5nL of protein, precipitant, and chemicals on a MiTeGen in situ-1 crystallization plate™ for screening by co-crystallization or soaking. ADE-transferred droplets follow a precise trajectory which allows all components to be transferred through small apertures in the microplate lid. The apertures were large enough for 2.5nL droplets to pass through them, but small enough so that they did not disrupt the internal environment created by the mother liquor. Using this system, thermolysin and trypsin crystals were efficiently screened for binding to a heavy-metal mini-library. Fluorescence and X-ray diffraction were used to confirm that each chemical in the heavy-metal library was correctly paired with the intended protein crystal. A fragment mini-library was screened to observe two known lysozyme ligands using both co-crystallization and soaking. A similar approach was used to identify multiple, novel thaumatin binding sites for ascorbic acid. This technology pushes towards a faster, automated, and more flexible strategy for high throughput screening of chemical libraries (such as fragment libraries) using as little as 2.5nL of each component.

Solvent minimization induces preferential orientation and crystal clustering in serial micro-crystallography on micro-meshes, in situ plates and on a movable crystal conveyor belt.

X-ray diffraction data were obtained at the National Synchrotron Light Source from insulin and lysozyme crystals that were densely deposited on three types of surfaces suitable for serial micro-crystallography: MiTeGen MicroMeshes™, Greiner Bio-One Ltd in situ micro-plates, and a moving kapton crystal conveyor belt that is used to deliver crystals directly into the X-ray beam. 6° wedges of data were taken from ∼100 crystals mounted on each material, and these individual data sets were merged to form nine complete data sets (six from insulin crystals and three from lysozyme crystals). Insulin crystals have a parallelepiped habit with an extended flat face that preferentially aligned with the mounting surfaces, impacting the data collection strategy and the design of the serial crystallography apparatus. Lysozyme crystals had a cuboidal habit and showed no preferential orientation. Preferential orientation occluded regions of reciprocal space when the X-ray beam was incident normal to the data-collection medium surface, requiring a second pass of data collection with the apparatus inclined away from the orthogonal. In addition, crystals measuring less than 20 µm were observed to clump together into clusters of crystals. Clustering required that the X-ray beam be adjusted to match the crystal size to prevent overlapping diffraction patterns. No additional problems were encountered with the serial crystallography strategy of combining small randomly oriented wedges of data from a large number of specimens. High-quality data able to support a realistic molecular replacement solution were readily obtained from both crystal types using all three serial crystallography strategies.

A linear relationship between crystal size and fragment binding time observed crystallographically: implications for fragment library screening using acoustic droplet ejection.

High throughput screening technologies such as acoustic droplet ejection (ADE) greatly increase the rate at which X-ray diffraction data can be acquired from crystals. One promising high throughput screening application of ADE is to rapidly combine protein crystals with fragment libraries. In this approach, each fragment soaks into a protein crystal either directly on data collection media or on a moving conveyor belt which then delivers the crystals to the X-ray beam. By simultaneously handling multiple crystals combined with fragment specimens, these techniques relax the automounter duty-cycle bottleneck that currently prevents optimal exploitation of third generation synchrotrons. Two factors limit the speed and scope of projects that are suitable for fragment screening using techniques such as ADE. Firstly, in applications where the high throughput screening apparatus is located inside the X-ray station (such as the conveyor belt system described above), the speed of data acquisition is limited by the time required for each fragment to soak into its protein crystal. Secondly, in applications where crystals are combined with fragments directly on data acquisition media (including both of the ADE methods described above), the maximum time that fragments have to soak into crystals is limited by evaporative dehydration of the protein crystals during the fragment soak. Here we demonstrate that both of these problems can be minimized by using small crystals, because the soak time required for a fragment hit to attain high occupancy depends approximately linearly on crystal size.

Green roof adoption in atlanta, georgia: the effects of building characteristics and subsidies on net private, public, and social benefits.

This research draws on and expands previous studies that have quantified the costs and benefits associated with conventional roofs versus green roofs. Using parameters from those studies to define alternative scenarios, we estimate from a private, public, and social perspective the costs and benefits of installing and maintaining an extensive green roof in Atlanta, GA. Results indicate net private benefits are a decreasing function of roof size and vary considerably across scenarios. In contrast, net public benefits are highly stable across scenarios, ranging from $32.49 to $32.90 m(-2). In addition, we evaluate two alternative subsidy regimes: (i) a general subsidy provided to every building that adopts a green roof and (ii) a targeted subsidy provided only to buildings for which net private benefits are negative but net public benefits are positive. In 6 of the 12 general subsidy scenarios the optimal public policy is not to offer a subsidy; in 5 scenarios the optimal subsidy rate is between $20 and $27 m(-2); and in 1 scenario the optimal rate is $5 m(-2). The optimal rate with a targeted subsidy is between $20 and $27 m(-2) in 11 scenarios and no subsidy is optimal in the twelfth. In most scenarios, a significant portion of net public benefits are generated by buildings for which net private benefits are positive. This suggests a policy focused on information dissemination and technical assistance may be more cost-effective than direct subsidy payments.

Environmental impacts from pesticide use: a case study of soil fumigation in Florida tomato production.

The search for alternative fumigants has been ongoing since the 1992 Parties of the Montreal Protocol classified methyl bromide as a Class I controlled substance with an ozone depletion potential (ODP) of 0.7 and destined it for phase-out. This paper focuses on the hazards from fumigants proposed as alternatives for pre-plant soil fumigation in tomato production. We use the Environmental Impact Quotient (EIQ) developed by Kovach et al. to estimate the hazards from methyl bromide and the proposed alternative fumigants to workers, consumers, beneficial arthropods, birds, fish, and bees. Our findings indicate that iodomethane 98/2 has the lowest EIQ index value and field use rating, and is the alternative with the lowest relative risk. Among environmental categories, workers and beneficial arthropods experience the highest relative risks from the proposed tomato fumigants, and fish and consumers the least risks.

Emergency medical services-based community stroke education: pilot results from a novel approach.

BACKGROUND AND PURPOSE: Although previous studies using mass media have demonstrated successful public stroke awareness campaigns, they may have been too costly for smaller communities to implement. The goal of this study was to investigate if a novel emergency medical services (EMS) -sponsored community awareness campaign could increase public stroke awareness. METHODS: This was a pre- and postintervention study with 2 phases conducted between August 2005 and July 2007. During Phase I, strategic placement of stroke education media by EMS personnel was implemented in one county over a 2-year period. Five random-digit, standardized phone surveys measuring stroke awareness were conducted with county residents to assess the campaign's impact. In Phase II, EMS interventions and random-digit measurements were conducted in 4 additional counties with 4 counties randomly selected as controls. RESULTS: A pattern of increasing stroke knowledge after exposure to the EMS intervention followed by declines in the absence of the intervention was observed during Phase I. EMS interventions also demonstrated a positive effect on the stroke knowledge of residents who lived in counties exposed to the intervention during Phase II with a statistically significant (P<0.05) increase observed in the proportion of respondents that named 2 stroke risk factors and 3 symptoms in comparison to either no changes or declines in the control counties. No evidence of a positive impact on knowledge of calling 911 for stroke was observed. CONCLUSIONS: Results of this study suggest that the public's knowledge of stroke signs and symptoms was increased using communitywide EMS-based programs. Additional studies are needed to determine optimal methods for educating the public regarding the need to call 911 for stroke and to confirm these results in other locales.

Farm-level irrigation and the marginal cost of water use: evidence from Georgia.

We create a proxy for the cost of irrigation water in Georgia from a sample of Georgia irrigators by investigating the marginal cost of pumping groundwater. We then combine this proxy with agronomic and climatic variables to estimate the response of agricultural water use to differences in the marginal cost of irrigation. The results show that pumping costs are a significant determinant of water use, and imply that agricultural water use would be moderately affected by institutional changes that would explicitly price water.