PP215 An Evaluation Of The Scottish Medicine Consortium Detailed Advice Document

IntroductionThe Scottish Medicines Consortium (SMC) conducts early health technology assessment (HTA) of new medicines. The advice is implemented at the local level by 14 Health Board Area Drug and Therapeutics Committees (ADTCs). The primary output is a published document, the Detailed Advice Document (DAD), which aims to describe the strengths and weaknesses of the evidence considered and the rationale for the decision. We examined how the DAD is being used to determine areas for improvement.MethodsWe conducted semi-structured interviews with a purposive sample of SMC and ADTC members and formulary pharmacists, who are one of the key audiences. Interviews were recorded and transcribed using Microsoft Teams and coded in NVivo. The results were assessed via thematic analysis, which included major themes such as the structure and content of the DAD and its usefulness in supporting implementation of the advice from an ADTC perspective.ResultsFollowing initial interviews (n = 7), some early themes have emerged. The DAD is a valued tool describing the assessment of a medicine's clinical and cost effectiveness. The current length of the DADs and the technical language used can limit the accessibility of information, and there have been suggestions on how to improve the structure and content. Additional interviews are still being completed and full interview results (available early 2021) will be analyzed to identify key themes.ConclusionsThe DAD is the primary output of SMC's HTA process, which includes decisions on whether a medicine can be routinely prescribed in the National Health Service Scotland. DADs have increased in length over the years, reflecting the increasing complexity of new medicines and a corresponding increase in the size of pharmaceutical company submissions. The interviews conducted to date suggest that the DADs are highly regarded and support implementation of new medicines advice by the ADTC. The findings of this evaluation will lead to an action plan for improvement.

Engagement markers in research project websites: Promoting interactivity and dialogicity

Scholars are currently not only required to produce primary output, i.e. peer-reviewed research articles, chapters or books, which constitutes certified and legitimised knowledge (Puschmann 2015), but also to disseminate such output, which is frequently carried out digitally and in English. In this context it is the aim of this paper to gain insights into scholars’ digital discursive practices by analysing academic websites of research projects funded under the European H2020 programme. More specifically, it explores the ways in which a potentially wide, blurred audience is addressed by means of engagement markers, particularly, reader pronouns, questions, and directives, including imperatives, obligation modals and adjectival phrases expressing necessity. Results indicate that the frequency of use of engagement markers varies across websites and that it may affect their degree of potential interactivity. They further show that some engagement markers are more common than others and that they tend to display specific rhetorical purposes. Differences on their use and function when compared to their use in RA writing are also shown. It is concluded that these interpersonality features have an important role in the potential promotion of dialogicity in this digital medium, and crafting an effective professional identity of the research teams.

The evaluation of effect Gammarana intervention to reducing stunting during the Covid-19 pandemic: Protocol evaluation of stunting intervention in Enrekang District

Background: Evaluation of large-scale stunting interventions in Indonesia has never been carried out, because it found limited sensitive and specific interventions that were carried out massively at the village level. The provincial government of South Sulawesi Indonesia in 2020 has implemented a stunting intervention model called Gammarana. The purpose of this evaluation is to analyze the impact of Gammarana on changes in stunting at the project site. Location project as many as 30 villages with a population estimated 60,000. Design and Methods: Evaluation in this study using a retrospective method and internal and external audit to document potential, then validated after the field visit Gammarana first phase in 2020. Basic Logic Model evaluation model with 22 indicators (input, process, secondary output and primary output). Proving the effect of Gammarana on changes in stunting by comparing the phenomena in the comparison village.Results: The comparison villages were set as equal and comparable in 13 indicators that could disturb the study conclusions. The result of the initial condition is that the conditions of the two villages of Gammarana and Villages Comparison are seen as the same in various characteristics, so that whatever the results of this evaluation study are believed to be the impact of Gammarana Project.Conclusions: this protocol eligible to evaluation of Gammarana Project Intervention in Enrekang District, South Sulawesi Indonesia.

SamQL: a structured query language and filtering tool for the SAM/BAM file format

Background The Sequence Alignment/Map Format Specification (SAM) is one of the most widely adopted file formats in bioinformatics and many researchers use it daily. Several tools, including most high-throughput sequencing read aligners, use it as their primary output and many more tools have been developed to process it. However, despite its flexibility, SAM encoded files can often be difficult to query and understand even for experienced bioinformaticians. As genomic data are rapidly growing, structured, and efficient queries on data that are encoded in SAM/BAM files are becoming increasingly important. Existing tools are very limited in their query capabilities or are not efficient. Critically, new tools that address these shortcomings, should not be able to support existing large datasets but should also do so without requiring massive data transformations and file infrastructure reorganizations. Results Here we introduce SamQL, an SQL-like query language for the SAM format with intuitive syntax that supports complex and efficient queries on top of SAM/BAM files and that can replace commonly used Bash one-liners employed by many bioinformaticians. SamQL has high expressive power with no upper limit on query size and when parallelized, outperforms other substantially less expressive software. Conclusions SamQL is a complete query language that we envision as a step to a structured database engine for genomics. SamQL is written in Go, and is freely available as standalone program and as an open-source library under an MIT license, https://github.com/maragkakislab/samql/.

Analysis and Design for Output Voltage Regulation in Constant-on-Time-Controlled Fly-Buck Converter

Fly-buck converter is a multi-output converter with the structure of a synchronous buck converter structure on the primary side and a flyback converter structure on the secondary side, and can be utilized in various applications due to its many advantages. In terms of control, the primary side of the fly-buck converter has the same structure as a synchronous buck converter, allowing the constant-on-time (COT) control to be applied to the fly-buck converter. However, due to the inherent energy transfer principle, the primary-side output voltage regulation of COT controlled fly-buck converters may be poor, which can deteriorate the overall converter performance. Therefore, the primary output capacitor must be carefully designed to improve the voltage regulation characteristics. In this paper, a theoretical analysis of the output voltage regulation in COT controlled fly-buck converter is conducted, and based on this, a design guideline for the primary output capacitor considering the output voltage regulation is presented. The validity of the analysis and design guidelines was verified using a 5 W prototype of the COT controlled fly-buck converter for telecommunication auxiliary power supply.

Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia

Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes seemingly critical for malignant growth. As such, there is considerable interest in targeting mitochondrial metabolism in cancer. However, notwithstanding the few drugs targeting mutant dehydrogenase activity, nearly all hopeful 'mito-therapeutics' cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? Such information is particularly critical for the subset of human cancers, including acute myeloid leukemia (AML), in which alterations in mitochondrial metabolism are implicated in various aspects of cancer biology (e.g., clonal expansion and chemoresistance). Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in various hematological cell types, with a specific focus on OXPHOS dynamics in AML. Consistent with prior reports, clonal cell expansion, characteristic of leukemia, was universally associated with a hyper-metabolic phenotype which included increases in basal and maximal glycolytic and respiratory flux. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic limitations in oxidative ATP synthesis (i.e., OXPHOS). Remarkably, by performing experiments across a physiological span of ATP free energy (i.e, ΔGATP), we provide direct evidence that, rather than contributing to cellular ΔGATP, leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of OXPHOS kinetics proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Taken together, these findings argue against ATP being the primary output of mitochondria in leukemia and provide proof-of-principle that restoring, rather than disrupting, OXPHOS and/or cellular ΔGATP in cancer may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

Diffusion Tensor Imaging: A Promising New Technique for Accurate Identification of the Stria Medullaris and Habenula

The Stria Medullaris (SM) is a white-matter tract that contains afferent fibres that connect the cognitive-emotional areas in the forebrain to the Habenula (Hb). The Hb plays an important role in behavioral responses to reward, stress, anxiety, pain, and sleep through its action on neuromodulator systems. The Fasciculus Retroflexus (FR) forms the primary output of the Hb to the midbrain. The SM, Hb, and FR are part of a special pathway between the forebrain and the midbrain known as the Dorsal Diencephalic Conduction system (DDC). Hb dysfunction is accompanied by different types of neuropsychiatric disorders, such as schizophrenia, depression, and Treatment-Resistant Depression (TRD). Due to difficulties in the imaging assessment of the SM and HB in vivo, they had not been a focus of clinical studies until the invention of Diffusion Tensor Imaging (DTI), which has revolutionized the imaging and investigation of the SM and Hb. DTI has facilitated the imaging of the SM and Hb and has provided insights into their properties through the investigation of their monoamine dysregulation. DTI is a well-established technique for mapping brain microstructure and white matter tracts; it provides indirect information about the microstructural architecture and integrity of white matter in vivo, based on water diffusion properties in the intra- and extracellular space, such as Axial Diffusivity (AD), Radial Diffusivity (RD), mean diffusivity, and Fractional Anisotropy (FA). Neurosurgeons have recognized the potential value of DTI in the direct anatomical targeting of the SM and Hb prior to Deep Brain Stimulation (DBS) surgery for the treatment of certain neuropsychiatric conditions, such as TRD. DTI is the only non-invasive method that offers the possibility of visualization in vivo of the white-matter tracts and nuclei in the human brain. This review study summarizes the use of DTI as a promising new imaging method for accurate identification of the SM and Hb, with special emphasis on direct anatomical targeting of the SM and Hb prior to DBS surgery.

Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia.

Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes seemingly critical for malignant growth. As such, there is considerable interest in targeting mitochondrial metabolism in cancer. However, notwithstanding the few drugs targeting mutant dehydrogenase activity, nearly all hopeful ‘mito-therapeutics’ cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? Such information is particularly critical for the subset of human cancers, including acute myeloid leukemia (AML), in which alterations in mitochondrial metabolism are implicated in various aspects of cancer biology (e.g., clonal expansion and chemoresistance). Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in various hematological cell types, with a specific focus on OXPHOS dynamics in AML. Consistent with prior reports, clonal cell expansion, characteristic of leukemia, was universally associated with a hyper-metabolic phenotype which included increases in basal and maximal glycolytic and respiratory flux. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic limitations in oxidative ATP synthesis (i.e., OXPHOS). Remarkably, by performing experiments across a physiological span of ATP free energy (i.e, ΔGATP), we provide direct evidence that, rather than contributing to cellular ΔGATP, leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of OXPHOS kinetics proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Taken together, these findings argue against ATP being the primary output of mitochondria in leukemia and provide proof-of-principle that restoring, rather than disrupting, OXPHOS and/or cellular ΔGATP in cancer may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

Definition of Reference Models for Power, Mass, Working Width, and Price for Tillage Implements

Farm machinery selection, operation and management directly impact crop cultivation processes and outputs. A priori quantification of technical and financial needs allows definition of proportionate distribution and management of available resources and simplification of selection process. Appropriate planning, association and adjustment of the power unit and implement are required for soil cultivation. Consideration of functional parameters of the implement, their proper estimation and operation directly impact the soil structure, productivity and return on investment. Thus, a modelling approach was implemented for the definition of possible parameter-price relations for tillage equipment. The performed analysis allowed us to investigate the main relevant parameters, quantify their impact, and elaborate forecasting models for price, power, mass and working width. The significant relevance of the technical parameters and adjustment issues were outlined for each tillage implement group. For harrows and cultivators, the dependencies between studied parameters expressed better predictive qualities, especially for price-mass relation (R² > 0.8). While for ploughs power and mass relation had a primary output (R² = 0.7). The prediction features of the models provided reliable results for the estimation of the indicative values of the price and parameters of the implements.

Rethinking Streets for Physical Distancing

This report summarizes the primary output of this project, a book of COVID-era street reconfiguration case studies called Rethinking Streets During COVID-19: An Evidence-Based Guide to 25 Quick Redesigns for Physical Distancing, Public Use, and Spatial Equity. COVID-era needs have accelerated the process that many communities use to make street transformations due to: a need to remain physically distanced from others outside our immediate household; a need for more outdoor space close to home in every part of every community to access and enjoy; a need for more space to provide efficient mobility for essential workers in particular; and a need for more space for local businesses as they try to remain open safely. This project is the third in a series of NITC-supported case study books on best practices in street reconfigurations for more active, sustainable, and in this case, COVID-supportive uses. The full, 154-page book is available for free download from the National Institute for Transportation and Communities (NITC).