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Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.
The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.
The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.
Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
OBJECTIVES/GOALS: We compared the validity of an International Classification of Diseases, Clinical Modification (ICD) algorithm for identifying high-grade cervical intraepithelial neoplasia and adenocarcinoma in situ (together referred to as CIN2+) from ICD 9th revision (ICD-9) and 10th revision (ICD-10) codes. METHODS/STUDY POPULATION: Using Tennessee Medicaid data, we identified cervical diagnostic procedures in 2008-2017 among females aged 18-39 years in Davidson County, TN. Gold-standard cases were pathology-confirmed CIN2+ diagnoses validated by HPV-IMPACT, a population-based surveillance project in catchment areas of five US states. Procedures in the ICD transition year (2015) were excluded to account for implementation lag. We pre-grouped diagnosis and procedure codes by theme. We performed feature selection using least absolute shrinkage and selection operator (LASSO) logistic regression with 10-fold cross validation and validated models by ICD-9 era (2008-2014, N = 6594) and ICD-10 era (2016-2017, N = 1270). RESULTS/ANTICIPATED RESULTS: Of 7864 cervical diagnostic procedures, 880 (11%) were true CIN2+ cases. LASSO logistic regression selected the strongest features of case status: Having codes for a CIN2+ tissue diagnosis, non-specific CIN tissue diagnosis, high-grade squamous intraepithelial lesion, receiving a cervical treatment procedure, and receiving a cervical/vaginal biopsy. Features of non-case status were codes for a CIN1 tissue diagnosis, Pap test, and HPV DNA test. The ICD-9 vs ICD-10 algorithms predicted case status with 68% vs 63% sensitivity, 95% vs 94% specificity, 63% vs 64% positive predictive value, 96% vs 94% negative predictive value, 92% vs 89% accuracy, and C-indices of 0.95 vs 0.92, respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Overall, the algorithm’s validity for identifying CIN2+ case status was similar between coding versions. ICD-9 had slightly better discriminative ability. Results support a prior study concluding that ICD-10 implementation has not substantially improved the quality of administrative data from ICD-9.
OBJECTIVES/GOALS: Allopregnanolone (ALLO), a modulator of GABAA receptors, may be useful as a treatment for human and canine benzodiazepine-refractory status epilepticus (SE). Our objective was to develop a phamacokinetic-pharmacodynamic (PKPD) model relating ALLO plasma concentrations to electroencephalographic (EEG) effects in dogs. METHODS/STUDY POPULATION: Four healthy dogs and one dog with epilepsy that had implanted intracranial electrodes were utilized. ALLO doses ranging from 1-6 mg/kg were administered IV over 5 min. EEG data were collected during four IM doses (1-2 mg/kg). Blood samples were collected up to 6 hr following dosing. ALLO concentrations were measured using HPLC-MS/MS. Power density was determined in EEG bands using a custom algorithm. A two-compartment link PKPD model was developed to describe the relation between ALLO plasma concentration and change in EEG power in the alpha, beta, delta and theta bands. RESULTS/ANTICIPATED RESULTS: ALLO caused a rapid increase in absolute power density in all EEG bands measured (1-4, >4 – 8, >8 – 12, >12 – 25, and >25 – 100 Hz). The onset of effect was rapid (1-3 min) and demonstrated by frequency band and dose analysis. Concentration-EEG data were best fit by a two-compartment PK model and sigmoidal Emax PD indirect link model. The beta frequency band was most sensitive, showing increases in power at the lowest ALLO concentrations. The EC50 concentration for the beta frequency was ~270 ng/mL. The EC50 values for effects on the other frequency bands were ~500-700 ng /mL. In conclusion, IV ALLO causes a rapid effect on EEG that can be used to determine minimal plasma concentrations associated with target engagement. DISCUSSION/SIGNIFICANCE OF IMPACT: Dose selection for future clinical trials will use the effective concentrations determined here in conjunction with studies in animal status epilepticus models. Studies are planned in client owned dogs with epilepsy to evaluate clinical efficacy in dogs and as nonclinical proof-of-concept evidence supporting translational studies in people. CONFLICT OF INTEREST DESCRIPTION: Michael Rogawski and Dorota Zolkowska are named as inventors on patent applications claiming use of neuroactive steroids including allopregnanolone and ganaxolone in the treatment of status epilepticus.
We describe an ultra-wide-bandwidth, low-frequency receiver recently installed on the Parkes radio telescope. The receiver system provides continuous frequency coverage from 704 to 4032 MHz. For much of the band (
), the system temperature is approximately 22 K and the receiver system remains in a linear regime even in the presence of strong mobile phone transmissions. We discuss the scientific and technical aspects of the new receiver, including its astronomical objectives, as well as the feed, receiver, digitiser, and signal processor design. We describe the pipeline routines that form the archive-ready data products and how those data files can be accessed from the archives. The system performance is quantified, including the system noise and linearity, beam shape, antenna efficiency, polarisation calibration, and timing stability.
Mycoprotein is a food high in both dietary fibre and non-animal-derived protein. Global mycoprotein consumption is increasing, although its effect on human health has not yet been systematically reviewed. This study aims to systematically review the effects of mycoprotein on glycaemic control and energy intake in humans. A literature search of randomised controlled trials was performed in PubMed, Embase, Web of Science, Google Scholar and hand search. A total of twenty-one studies were identified of which only five studies, totalling 122 participants, met the inclusion criteria. All five studies were acute studies of which one reported outcomes on glycaemia and insulinaemia, two reported on energy intake and two reported on all of these outcomes. Data were extracted, and risk-of-bias assessment was then conducted. The results did not show a clear effect of acute mycoprotein on blood glucose levels, but it showed a decrease in insulin levels. Acute mycoprotein intake also showed to decrease energy intake at an ad libitum meal and post-24 h in healthy lean, overweight and obese humans. In conclusion, the acute ingestion of mycoprotein reduces energy intake and insulinaemia, whereas its impact on glycaemia is currently unclear. However, evidence comes from a very limited number of heterogeneous studies. Further well-controlled studies are needed to elucidate the short- and long-term effects of mycoprotein intake on glycaemic control and energy intake, as well as the mechanisms underpinning these effects.
Triage at mass gatherings in Australia is commonly performed by staff members with first aid training. There have been no evaluations of the performance of first aid staff with respect to diagnostic accuracy or identification of presentations requiring ambulance transport to hospital.
It was hypothesized that triage decisions by first aid staff would be considered correct in at least 61% of presentations.
A retrospective audit of 1,048 presentations to a single supplier of event health care services in Australia was conducted. The presentations were assessed based on the first measured set of physiological parameters, and the primary triage decision was classified as “expected” if the primary and secondary triage classifications were the same or “not expected” if they differed. The performance of the two triage systems was compared using area under the receiver operating characteristic curve (AUROC) analysis.
The expected decision was made by first aid staff in 674 (71%) of presentations. Under-triage occurred in 131 (14%) presentations and over-triage in 142 (15%) presentations. The primary triage strategy had an AUROC of 0.7644, while the secondary triage strategy had an AUROC of 0.6280, which was significantly different (P = .0199).
The results support the continued use of first aid trained staff members in triage roles at Australian mass gatherings. Triage tools should be simple, and the addition of physiological variables to improve the sensitivity of triage tools is not recommended because such an approach does not improve the discriminatory capacity of the tools.
In many materials development projects, scientists and research heads make decisions to guide the project direction. For example, scientists may decide which processing steps to use, what elements to include in their material selection, or from what suppliers to source their materials. Research heads may decide whether to invest development effort in reducing the environmental impact or production cost of a material. When making these decisions, it would be helpful to know how those decisions affect the achievable performance of the materials under consideration. Often, these decisions are complicated by trade-offs in performance between competing properties. This paper presents an approach for visualizing and evaluating design spaces, where a design space is defined as the set of possible materials under consideration given specified constraints. This design space visualization approach is applied to two case studies with environmental impact motivations: one in biodegradability for solvents, and the other in sustainable materials sourcing for Li-ion batteries. The results demonstrate how this visualization approach can enable data-driven, quantitative decisions for project direction.
Plastics generally play a very important role in a plethora of industries, fields and our everyday lives. In spite of their cheapness, availability and important contributions to lives, they however, pose a serious threat to the environment due to their mostly non-biodegradable nature. Recycling into useful products can reduce the amount of plastic waste. Thermal degradation (Pyrolysis) of plastics is becoming an increasingly important recycling method for the conversion of plastic materials into valuable chemicals and oil products. In this work, waste Polyethylene terephthalate (PET) water bottles were thermally converted into useful gaseous and liquid products. A simple pyrolysis reactor system has been used for the conversions with the liquid product yield of 65 % at a temperature range of 400°C to 550°C. The chemical analysis of the pyrolytic oil showed the presence of functional groups such as alkanes, alkenes, alcohols, ethers, carboxylic acids, esters, and phenyl ring substitution bands. The main constituents were 1-Tetradecene, 1-Pentadecene, Cetene, Hexadecane, 1-Heptadecene, Heptadecane, Octadecane, Nonadecane, Eicosane, Tetratetracontane, 1-Undecene, 1-Decene). The results are promising and can be maximized by additional techniques such as hydrogenation and hydrodeoxygenation to obtain value-added products.
SDG 15 requires the maintenance of life on land and endorses priorities already established through international conventions and agreements. The scale, and complexity, of tropical forest loss and biodiversity decline versus the limited resources for conservation and forestry pose many challenges. The main innovation of SDG 15 is that decision makers will see this goal as one to integrate with other SDGs; the risk is that short-term priorities and a ‘business as usual’ approach will undermine this. We examine these opportunities and challenges, the factors that impinge upon them and how they may play out over the next decade. There will be trade-offs between SDG 15 and other SDGs resulting from competition for land, but there are also synergies and opportunities that require recognition. We encourage conservation and development professionals to engage with those responsible for all the Agenda 2030 targets to ensure that SDG 15 is a priority in all SDG related processes.
Reducing agricultural nonpoint pollution has been an environmental policy issue since the early 1980s. We discuss the evolution and results of federal and state policy, the contributions of applied economic research to improving the effectiveness and efficiency of water pollution control policies for agriculture, elements of policy reforms that are consistent with the Clean Water Act, and the outlook for needed policy innovation.
This paper summarizes a multi-state, multi-year study assessing the potential for local agriculture in northern New England. While largely rural, this region's agricultural sector differs greatly from the rest of the United States, and demand for locally produced food has been increasing. To assess this unique economic landscape, researchers and Cooperative Extension at the Universities of Maine, New Hampshire, and Vermont investigated four key areas: (1) local food capacities, (2) constraints to agricultural expansion, (3) consumer preferences for local and organic produce, and (4) the role of intermediaries as alternative local food outlets. The project included input from local farmers, Extension members, restaurants, and the general public. We present the four research areas in a sequential, overlapping fashion. The timing of our research was such that each step in the process informed the next and can be used as a template for assessing a region's potential for local agricultural production.
Chapter 1 discusses the terminology of the name Third Intermediate Period and demonstrates the views within previous archaeological thought and theory, showig which ideas have shaped the discussions and approaches to Third Intermediate Period archaeology, history, and culture. Chapter 1 also provides a discussion of the complex and disputed chronology for the Third Intermediate Period, outlining those areas that are agreed upon and those areas which are still debated.
Chapter 5 discusses the evidence presented in the preceding four chapters and its overall significance for the understanding of the development of Egypt during the Third Intermediate Period. The chapter discusses a series of interconnected characteristics identified within Third Intermediate Period culture and society which relate to the political and economic power of regions, the nucleation of both settlements and people, self-sufficiency at a collective and individual level, defence, both physical and spiritual, regionality in terms of settlement development and material culture, and finally elite emulation through objects. These characteristics are also discussed in association with the themes of continuity and change/transition compared with the previous New Kingdom, and also within aspects of the (Egyptian) north and (Libyan) south socio-cultural and socio-geographical divide.
Chapter 2 establishes the theoretical and archaeological context for the study of landscape and settlements in the Third Intermediate Period. It discusses the approaches to and problems inherent in Egyptian settlement studies regarding landscape reconstruction, the preservation of ancient sites, and defining the concept of ‘site’. The chapter constructs a framework for the understanding of settlement archaeology in the Third Intermediate Period through the analysis of a dataset made up of Third Intermediate Period textual and archaeological material from landscapes and settlements. It further outlines the archaeological theory regarding landscape archaeology in order to establish a methodology for the most effective way of approaching Egyptian settlement patterns and defining the concept of what is a ‘site’ in Egyptian settlement archaeology. The comprehensive record of survey, excavation reports, and artefact/textual source analysis compiled in Appendix 1 is used in Chapter 2 to evaluate the potential for conducting landscape archaeology to see whether settlement patterns are visible, the extent to which they are different from the New Kingdom, and the factors which may have influenced these patterns with due regard to the limitations of the data.
Chapter 4 demonstrates links back to Ramesside object preferences, and to precursors of Late Period object typologies. The material culture of everyday life and social practices of the people living at that time demonstrate the Third Intermediate Period as a distinctly defined cultural element within Egyptian society and Egyptology. There were changes in artefact usages and material culture, and implications for understanding characteristics of the object world of the period, and the lifecycles of the Third Intermediate Period population. The domestic material culture also demonstrates aspects of regionality in relation to the political fragmentation of the country. The ceramics of the period identify continuity or changes in storage, dining, and drinking cultures. Alongside ceramics, Chapter 4 also includes objects of personal adornment, tools, weapons, and re-used and salvaged stone. The artefacts and object-world of the settlements allow exploration of the social status of the population, their religious beliefs, the extent of elite emulation and self-sufficiency regarding elite object replication, the extent of object re-use and recycling, and the creation and availability of materials for object manufacture.