The AI-driven Drug Design (AIDD) platform: an interactive multi-parameter optimization system integrating molecular evolution with physiologically based pharmacokinetic simulations.

Computer-aided drug design has advanced rapidly in recent years, and multiple instances of in silico designed molecules advancing to the clinic have demonstrated the contribution of this field to medicine. Properly designed and implemented platforms can drastically reduce drug development timelines and costs. While such efforts were initially focused primarily on target affinity/activity, it is now appreciated that other parameters are equally important in the successful development of a drug and its progression to the clinic, including pharmacokinetic properties as well as absorption, distribution, metabolic, excretion and toxicological (ADMET) properties. In the last decade, several programs have been developed that incorporate these properties into the drug design and optimization process and to varying degrees, allowing for multi-parameter optimization. Here, we introduce the Artificial Intelligence-driven Drug Design (AIDD) platform, which automates the drug design process by integrating high-throughput physiologically-based pharmacokinetic simulations (powered by GastroPlus) and ADMET predictions (powered by ADMET Predictor) with an advanced evolutionary algorithm that is quite different than current generative models. AIDD uses these and other estimates in iteratively performing multi-objective optimizations to produce novel molecules that are active and lead-like. Here we describe the AIDD workflow and details of the methodologies involved therein. We use a dataset of triazolopyrimidine inhibitors of the dihydroorotate dehydrogenase from Plasmodium falciparum to illustrate how AIDD generates novel sets of molecules.

Prediction of physicochemical and pharmacokinetic properties of botanical constituents by computational models.

Botanicals contain complex mixtures of chemicals most of which lack pharmacokinetic data in humans. Since physicochemical and pharmacokinetic properties dictate the in vivo exposure of botanical constituents, these parameters greatly impact the pharmacological and toxicological effects of botanicals in consumer products. This study sought to use computational (i.e., in silico) models, including quantitative structure-activity relationships (QSAR) and physiologically based pharmacokinetic (PBPK) modeling, to predict properties of botanical constituents. One hundred and three major constituents (e.g., withanolides, mitragynine, and yohimbine) in 13 botanicals (e.g., ashwagandha, kratom, and yohimbe) were investigated. The predicted properties included biopharmaceutical classification system (BCS) classes based on aqueous solubility and permeability, oral absorption, liver microsomal clearance, oral bioavailability, and others. Over half of these constituents fell into BCS classes I and II at dose levels no greater than 100 mg per day, indicating high permeability and absorption (%Fa > 75%) in the gastrointestinal tract. However, some constituents such as glycosides in ashwagandha and Asian ginseng showed low bioavailability after oral administration due to poor absorption (BCS classes III and IV, %Fa < 40%). These in silico results fill data gaps for botanical constituents and could guide future safety studies. For example, the predicted human plasma concentrations may help select concentrations for in vitro toxicity testing. Additionally, the in silico data could be used in tiered or batteries of assays to assess the safety of botanical products. For example, highly absorbed botanical constituents indicate potential high exposure in the body, which could lead to toxic effects.

How and where does "care" fit within seminal life-course approaches? A narrative review and critical analysis.

AIMS: To map the concepts of the caring life-course theory that are used in life-course approaches from different disciplines; establish whether there is a common recognition of, or language used, to describe care in those life-course approaches; and identify the role and contribution of care to the life-course literature. DESIGN: This discursive paper uses a narrative review process to explore points of convergence and divergence between life-course approaches and the caring life-course theory. METHODS: Categories for analysis were developed deductively and inductively, focusing on the constructs of fundamental care, capacity and capability, care network, care transition, care trajectory and care biography. RESULTS: We identified four disciplinary perspectives: (1) life-course sociology; (2) life-course epidemiology; (3) lifespan developmental psychology; and (4) life-course health development. While six core constructs of the caring life-course theory were described, either explicitly or implicitly, in existing life-course approaches, no single approach fully describes the role and contribution of care across the lifespan. CONCLUSION: Life-course approaches have largely neglected the contribution and role of care in informing the life-course discourse. This review highlights the significance of care beyond traditional healthcare settings and recognizes it as a fundamental human need for well-being and development, which can contribute to existing life-course literature. IMPLICATION FOR THE PROFESSION AND/OR PATIENT CARE: There is a need to understand care as a complex system and embrace a whole-system, life-course approach to enable nurses and other healthcare professionals to provide high-quality, patient-centred care. IMPACT: Incorporating care within a life-course approach provides opportunities to integrate and deliver care centred around the person, their life transitions, trajectories and care networks, including informal carers and healthcare professionals. NO PATIENT OR PUBLIC CONTRIBUTION: Patients or members of the public were not involved in this study as it is a discursive paper based on the relevant literature.

From Promise to Practice: How Health Researchers Understand and Promote Transdisciplinary Collaboration.

There is an increasing emphasis on transdisciplinary research to address the complex challenges faced by health systems. However, research has not adequately explored how members of transdisciplinary research teams perceive, understand, and promote transdisciplinary collaboration. As such, there is a need to investigate collaborative behaviors, knowledge, and the impacts of transdisciplinary research. To address this gap, we conducted a longitudinal realist evaluation of transdisciplinary collaboration within a 5-year National Health and Medical Research Council-funded Center of Research Excellence in Transdisciplinary Frailty Research. The current study aimed to explore researchers' perceptions and promotion of transdisciplinary research specifically within the context of frailty research using qualitative methods. Participants described transdisciplinary research as a collaborative and integrative approach that involves individuals from various disciplines working together to tackle complex research problems. However, participants often used terms like interdisciplinary and multidisciplinary interchangeably, indicating that a shared understanding of transdisciplinary research is needed. Barriers to transdisciplinary collaboration included time constraints, geographical distance, and entrenched collaboration patterns. To overcome these challenges, participants suggested implementing strategies such as creating a shared vision and goals, establishing appropriate collaboration systems and structures, and role modeling collaborative behaviors, values, and attitudes. Our findings underscore the need for practical knowledge in developing transdisciplinary collaboration and leadership skills across different career stages. In the absence of formal training, sustained and immersive programs that connect researchers with peers, educators, and role models from various disciplines and provide experiential learning opportunities, may be valuable in fostering successful transdisciplinary collaboration.

Understanding the enablers to implementing sustainable health and well-being programs for older adults in rural Australia: A scoping review.

INTRODUCTION: Supporting the health and well-being of older Australians necessitates the implementation of effective and sustainable community-based interventions. Rural settings, however, pose unique challenges to intervention implementation and sustainability, with limited research exploring strategies employed to overcome these complexities. OBJECTIVE: To identify enabling strategies that support the sustainable implementation of community-based health and well-being interventions for older adults in rural Australia. DESIGN: A scoping review, following methods by Arksey and O'Malley and enhanced by elements of the Joanna Briggs Institute methodology for scoping reviews and Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), was conducted. An electronic search of seven databases was completed in April 2023. A thematic analysis was applied to provide a comprehensive and contextualised understanding of the phenomenon of interest. FINDINGS: Of 1277 records screened, 15 studies were identified and included for review. Five themes identified key enablers for rural implementation: (1) Co-designing for the local context; (2) Embedding local champions; (3) Leveraging existing local resources; (4) Maintaining impact beyond the end of the funded period and (5) Flexibility in funding models. DISCUSSION: The sustainable implementation of interventions requires active community involvement and consultation through all stages of program design and delivery to effectively meet the health and well-being needs of older rural-dwelling Australians. CONCLUSION: Our findings advocate for clear implementation guidelines to support the design, delivery and adaptation of community-based programs that appropriately reflect the unique contextual needs and strengths of rural communities.

'I wasn't made to feel like a nut case after all': A qualitative story completion study exploring healthcare recipient and carer perceptions of good professional caregiving relationships.

BACKGROUND: Professional caregiving relationships are central to quality healthcare but are not always developed to a consistently high standard in clinical practice. Existing literature on what constitutes high-quality relationships and how they should be developed is plagued by dyadic conceptualisations; discipline, context and condition-specific research; and the absence of healthcare recipient and informal carer voices. This study aimed to address these issues by exploring how healthcare recipients and carers conceptualise good professional caregiving relationships regardless of discipline, care setting and clinical condition. DESIGN: A qualitative story completion approach was used. Participants completed a story in response to a hypothetical stem that described a healthcare recipient (and, in some instances, carer) developing a good relationship with a new healthcare provider. Stories were analysed using reflexive thematic analysis. PARTICIPANTS: Participants were 35 healthcare recipients and 37 carers (n = 72 total). RESULTS: Participants' stories were shaped by an overarching discourse that seeking help from new providers can elicit a range of unwanted emotions for both recipients and carers (e.g., anxiety, fear, dread). These unwanted emotions were experienced in relation to recipients' presenting health problems as well as their anticipated interactions with providers. Specifically, recipient and carer characters were fearful that providers would dismiss their concerns and judge them for deciding to seek help. Good relationships were seen to develop when healthcare providers worked to relieve or minimise these unwanted emotions, ensuring healthcare recipients and carers felt comfortable and at ease with the provider and the encounter. Participants positioned healthcare providers as primarily responsible for relieving recipients' and carers' unwanted emotions, which was achieved via four approaches: (1) easing into the encounter, (2) demonstrating interest in and understanding of recipients' presenting problems, (3) validating recipients' presenting problems and (4) enabling and respecting recipient choice. Participants' stories also routinely oriented to temporality, positioning relationships within recipients' and carers' wider care networks and biographical and temporal contexts. CONCLUSION: The findings expand our understanding of professional caregiving relationships beyond dyadic, static conceptualisations. Specifically, the findings suggest that high-quality relationships might be achieved via a set of core healthcare provider behaviours that can be employed across disciplinary, context and condition-specific boundaries. In turn, this provides a basis to support interprofessional education and multidisciplinary healthcare delivery, enabling different healthcare disciplines, specialties, and teams to work from the same understanding of what is required to develop high-quality relationships. PATIENT OR PUBLIC CONTRIBUTION: The findings are based on stories from 72 healthcare recipient and carer participants, providing rich insight into their conceptualisations of high-quality professional caregiving relationships.

My Wellbeing Journal: Development of a communication and goal-setting tool to improve care for older adults with chronic conditions and multimorbidity.

BACKGROUND: Chronic conditions and multimorbidity, the presence of two or more chronic conditions, are increasingly common in older adults. Effective management of chronic conditions and multimorbidity in older adults requires a collaborative and person-centred approach that considers the individual's goals, preferences and priorities. However, ensuring high-quality personalised care for older adults with multimorbidity can be challenging due to the complexity of their care needs, limited time and a lack of patient preparation to discuss their personal goals and preferences with their healthcare team. OBJECTIVE: To codesign a communication and goal-setting tool, My Wellbeing Journal, to support personalised care planning for older adults with chronic conditions and multimorbidity. DESIGN: We drew on an experience-based codesign approach to develop My Wellbeing Journal. This article reports on the final end-user feedback, which was collected via an online survey with older adults and their carers. SETTING AND PARTICIPANTS: Older adults with chronic conditions, multimorbidity and informal carers living in Australia. Personalised care planning was considered in the context of primary care. RESULTS: A total of 88 participants completed the online survey. The survey focused on participants' feedback on the tool in terms of effectiveness, efficiency, satisfaction and errors encountered. This feedback resulted in modifications to My Wellbeing Journal, which can be used during clinical encounters to facilitate communication, goal setting and progress tracking. DISCUSSION AND CONCLUSIONS: Clinicians and carers can use the tool to guide discussions with older adults about their care planning and help them set realistic goals that are meaningful to them. The findings of this study could be used to inform the development of recommendations for healthcare providers to implement person-centred, goal-oriented care for older adults with chronic conditions and multimorbidity. PATIENT OR PUBLIC CONTRIBUTION: Older adults living with chronic conditions and multimorbidity and their carers have contributed to the development of a tool that has the potential to significantly enhance the experience of personalised care planning. Their direct involvement as collaborators has ensured that the tool is optimised to meet the standards of effectiveness and usability.

How transdisciplinary research teams learn to do knowledge translation (KT), and how KT in turn impacts transdisciplinary research: a realist evaluation and longitudinal case study.

BACKGROUND: Transdisciplinary research and knowledge translation are increasingly regarded as key concepts underpinning applied research across the health and social sciences, due to their presumed potential in addressing complex, "wicked" problems and improving the use of research in practice and policy, respectively. Despite sharing an impact mandate, the relationship between transdisciplinary research collaboration and knowledge translation remains unclear. In response, we examined the relationship between transdisciplinary collaboration and knowledge translation to generate these understandings with a view towards maximizing the impact of collaborative efforts. METHODS: We undertook a realist evaluation and longitudinal case study of a 5-year National Health and Medical Research Council-funded Centre of Research Excellence in Transdisciplinary Frailty Research. Data were collected between February 2017 and March 2020 over three rounds of theory development, refinement and testing using interviews, observation, document review and visual elicitation as data sources. The Human Research Ethics Committee of the University of Adelaide approved this study. RESULTS: Iterative analysis of narrative interviews and visual data led to the development of three overarching programme theories explicating the reciprocal relationship between KT understandings and transdisciplinary team process. These programme theories revolve around the concept of a network, which we define in alignment with extant theoretical literature on network mechanisms and complex networks as graphically representable networks of agents/people (nodes) joined by social relationships (links). Our findings demonstrate that under the right contextual conditions, transdisciplinary team members respond through an improved ability to (1) navigate the network, (2) negotiate the network and (3) mobilize the network. CONCLUSIONS: This research demonstrates the reciprocity and mutually supportive relationship between transdisciplinary research and knowledge translation. Our findings suggest that embedding a collaborative knowledge translation framework and providing resources such as facilitation and distributed leadership within a transdisciplinary team can improve collaboration and support transdisciplinary research objectives.

Prevalence and determinants of physical frailty among people living in residential aged care facilities: a large-scale retrospective audit.

BACKGROUND: Physical frailty is associated with increased risk of falls, hospitalisation and mortality. There is a dearth of information on physical frailty of older adults living in residential aged care. This study aimed to describe physical frailty in aged care residents and investigate possible determinants of frailty. METHOD: A retrospective audit of resident records was undertaken across 14 residential aged care facilities. Data were extracted on all consenting residents who had completed measures relating to frailty (Short Physical Performance Battery SPPB; grip strength). All data of the first record of measures were extracted, resident characteristics, and the time from admission to assessment. Summary statistics were completed. Differences between sub-groups were explored (Mann-Whitney U, Kruskall-Wallis Ranked tests). Associations between variables were explored with Chi-squared and Pearson correlations. Determinants of physical frailty were determined with linear regression analyses. Alpha (2-sided) was 0.05. RESULTS: Data were extracted for 1241 residents (67% female), with a mean age of 86.0 (7.6) years. Males had a significantly lower time from admission to assessment of frailty (p ≤ 0.001). The average SPPB score was 4.1 (3.3), 75% of residents were frail and 19% pre-frail. Bivariate analyses indicated no significant relationships between grip strength and SPPB score, but significant differences for grip strength, where males were significantly stronger (males 20.2 ± 8.3 kg; females 12.4 ± 5.4 kg; p ≤ 0.001). There was a significant positive relationship between SPPB total score and grip strength, gender (p ≤ 0.001), and marital status (p = 0.049) and a negative relationship between time from admission to assessment and SPPB total score (p ≤ 0.001). There were significant negative relationships between gender (p ≤ 0.001) and age (p ≤ 0.001), and time from admission to assessment (p ≤ 0.001) with grip strength. CONCLUSION: Older adults living in residential aged care have a high level of physical frailty which may lead to increased risk of adverse outcomes. Time in the residential aged care setting and age appear to predict physical frailty. There is a need for a consistent battery of measures to continually monitor frailty and programs to address the high levels of frailty in residential aged care.

Application of Caring Life-Course Theory to explore care needs in women with pregnancy-related pelvic girdle pain.

AIMS: To describe the care needs of women with pregnancy-related pelvic girdle pain based on the Caring Life-Course Theory. DESIGN: A descriptive qualitative research design. METHODS: Data were collected between November 2019 and February 2021 from 20 purposively selected pregnant women with pelvic girdle pain aged between 22 and 39 years in antenatal care at a tertiary hospital in Australia. Individual semi-structured interviews were recorded via a digital audio recorder and transcribed verbatim. Qualitative content analysis method was used to analyse the data. FINDINGS: Five broad themes were identified: pain is an added burden to pregnancy; knowledge is power to own what happens to me; engaging in self-help; care from others is useful; and pain deserves more attention from healthcare professionals. CONCLUSION: Caring Life-Course Theory presented a useful and applicable scaffold for describing care needs of pregnant women with pelvic girdle pain. The study revealed experiencing pelvic girdle pain led to additional care needs during pregnancy, highlighting the importance of self-management strategies and an appreciation of care from others to assist women in limiting the effects of the pain. Participants identified the need for more information and attention from healthcare professionals to be able to better manage their condition. IMPACT: This study presents a comprehensive picture of the change in care needs triggered by experiencing pelvic girdle pain during pregnancy. The findings have the potential to facilitate better care provision by considering novel methods of delivery, such as information and communication technology, whilst acknowledging the value placed on credible and trusted sources. Knowledge acquired through this study may be used by nurses and midwives, along with other healthcare professionals, to enhance the provision of comprehensive care that is acceptable to women with pelvic girdle pain during pregnancy.

Towards a unifying caring life-course theory for better self-care and caring solutions: A discussion paper.

AIM: To present the first iteration of the caring life-course theory. BACKGROUND: Despite requiring care from birth to death, a person's universal or fundamental care needs and the subsequent care provision, either by self or others, has yet to be presented within a life-course perspective. Accurately describing the care people require across their lifespan enables us to identify who, what type, how and where this care should be provided. This novel perspective can help to legitimise a person's care needs and the support they require from wider care systems and contexts. DESIGN: Discussion paper outlines theory development. We adopted an inductive approach to theory development, drawing upon existing literature and the team's diverse experiences. Our theoretical insights were refined through a series of collaborative meetings to define the theory's constructs, until theoretical saturation was reached. DISCUSSION: Fourteen constructs are identified as essential to the theory. We propose it is possible, using these constructs, to generate caring life-course trajectories and predict divergences in these trajectories. The novel contribution of the theory is the interplay between understanding a person's care needs and provision within the context of their lifespan and personal histories, termed their care biography, and understanding a person's care needs and provision at specific points in time within a given care network and socio-political context. IMPACT FOR NURSING: The caring life-course theory can provide a roadmap to inform nursing and other care industry sectors, providing opportunities to integrate and deliver care from the perspective of the person and their care history, trajectories and networks, with those of professional care teams. It can help to shape health, social and economic policy and involve individuals, families and communities in more constructive ways of talking about the importance of care for improved quality of life and healthy societies.

"You Are By No Means Alone": A Netnographic Study of Self-Care Support in an Online Community for Older Adults.

Online peer-to-peer communities provide environments in which people with similar health concerns can interact and exchange information that can support self-care of long-term conditions. However, current theories have not adequately accounted for how self-care support is enacted in online communities. We conducted an observational netnography to identify and analyze posts in a publicly accessible online community (discussion forum boards) designed for older people. A Straussian grounded theory approach was used to examine 659 posts in health-related message boards. Self-care support involved the construction of three interrelated identities: (1) the support seeking self, in which members described problems and requested information; (2) the empathizing self, in which they described similar experiences and offered support; and (3) the influencing self, in which they provided information or advice. Online communities appear to be an important source of peer support and information and may be a cost-effective approach to supplement standard care.

Impact of COVID-19 on Hospital Admissions for COPD Exacerbation: Lessons for Future Care.

Background and Objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Acute exacerbations (AECOPD) are common and often triggered by viral infection. During the COVID-19 pandemic social restrictions, including 'shielding' and 'lockdowns', were mandated. Multiple, worldwide studies report a reduction in AECOPD admissions during this period. This study aims to assess the effect of the pandemic and Lockdown on the rates of admission with AECOPD and severity of hospitalised exacerbations in the North-East of England. Materials and Methods: Data were extracted for patients presenting with a diagnosis of AECOPD or respiratory failure secondary to AECOPD during the 'COVID-19 period' (26/3/20-31/12/20) and a date-matched control period from the year previous. We present descriptive statistics and regression analysis of the effects of the COVID-19 period on the rates of hospital admission. Results: Compared to the matched control period, the COVID-19 period was associated with fewer AECOPD admissions (COVID-19 = 719, control = 1257; rate ratio 0.57, p < 0.001) and shorter length of stay (COVID-19 = 3.9 ± 0.2, control = 4.78 ± 0.2 days; p = 0.002), with similar in-hospital plus 30-day post-discharge mortality. Demographics were similar between periods. Only six patients had a positive COVID-19 PCR test. Conclusion: During the COVID-19 period there was a substantial reduction in AECOPD admissions, but no increase in overall severity of exacerbations or mortality. Rather than fear driving delayed hospital presentation, physical and behavioural measures taken during this period to limit transmission of COVID-19 are likely to have reduced transmission of other respiratory viruses. This has important implications for control of future AECOPD.

Understanding consumer perceptions of frailty screening to inform knowledge translation and health service improvements.

BACKGROUND AND OBJECTIVES: despite growing support for the clinical application of frailty, including regular frailty screening for older adults, little is known about how older adults perceive frailty screening. The purpose of this study was to examine older adults' perspectives on frailty screening to inform knowledge translation and service improvements for older adults with frailty. RESEARCH DESIGN: interpretive descriptive qualitative design. PARTICIPANTS: a total of 39 non-frail (18%), pre-frail (33%) and frail or very frail (49%) South Australian older adults aged 62-99 years, sampled from community, assisted living and residential aged care settings. METHODS: seven focus groups were conducted and analysed by two independent investigators using inductive thematic analysis. RESULTS: three themes were identified. First, older adults question the necessity and logic of an objective frailty measure. Second, older adults believe any efforts at frailty screening need to culminate in an action. Third, older adults emphasise that frailty screening needs to be conducted sensitively given negative perceptions of the term frailty and the potential adverse effects of frailty labelling. DISCUSSION AND IMPLICATIONS: previous screening experiences and underlying beliefs about the nature of frailty as inevitable shaped openness to, and acceptance of, frailty screening. Findings correspond with previous research illuminating the lack of public awareness of frailty and the nascent stage of frailty screening implementation. Incorporating consumer perspectives, along with perspectives of other stakeholder groups when considering implementing frailty screening, is likely to impact uptake and optimise suitability-important considerations in person-centred care provision.

Re-thinking reablement strategies for older adults in residential aged care: a scoping review.

BACKGROUND: The number of older adults in residential aged care is increasing. Aged care residents have been shown to spend most of the day sedentary and have many co-morbidities. This review aimed to systematically explore the effectiveness of reablement strategies in residential aged care for older adults' physical function, quality of life and mental health, the features of effective interventions and feasibility (compliance, acceptability, adverse events and cost effectiveness). METHOD: This scoping review was undertaken according to PRISMA guidelines (extension for scoping reviews). Five e-databases (Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and CINAHL) were searched from 2010 onwards. Randomised controlled trials investigating reablement strategies addressing physical deconditioning for older adults (mean age ≥ 65 yrs) in residential aged care on physical function, quality of life or mental health were included. Feasibility of the interventions (compliance, acceptability, satisfaction, adverse events and cost effectiveness) was explored. RESULTS: Five thousand six hundred thirty-one citations were retrieved, and 63 studies included. Sample sizes ranged from 15 to 322 and intervention duration from one to 12 months. Exercise sessions were most often conducted two to three times per week (44 studies) and physiotherapist-led (27 studies). Interventions were predominately multi-component (28 studies, combinations of strength, balance, aerobic, functional exercises). Five interventions used technology. 60% of studies measuring physical function reported significant improvement in the intervention versus control, 40% of studies measuring quality of life reported significant improvements in favour of the intervention, and 26% of studies measuring mental health reported significant intervention benefits. Over half of the studies measured compliance and adverse events, four measured acceptability and none reported cost effectiveness. CONCLUSIONS: There has been a research surge investigating reablement strategies in residential aged care with wide variability in the types and features of strategies and outcome measures. Few studies have measured acceptability, or cost effectiveness. Exploration of core outcomes, mapping stakeholders and co-designing a scalable intervention is warranted. TRIAL REGISTRATION: Prospectively registered review protocol (Open Science Framework: DOI https://doi.org/10.17605/OSF.IO/7NX9M ).

Characterization of size-specific effects during dual-energy CT material decomposition of non-iodine materials.

PURPOSE: The dual-energy CT (DECT) LiverVNC application class in the Siemens Syngo.via software has been used to perform non-iodine material decompositions. However, the LiverVNC application is designed with an optional size-specific calibration based on iodine measurements. This work investigates the effects of this iodine-based size-specific calibration on non-iodine material decomposition and benchmarks alternative methods for size-specific calibrations. METHODS: Calcium quantification was performed with split-filter and sequential-scanning DECT techniques on the Siemens SOMATOM Definition Edge CT scanner. Images were acquired of the Gammex MECT abdomen and head phantom containing calcium inserts with concentrations ranging from 50-300 mgCa/ml. Several workflows were explored investigating the effects of size-specific dual-energy ratios (DERs) and the beam hardening correction (BHC) function in the LiverVNC application. Effects of image noise were also investigated by varying CTDIvol and using iterative reconstruction (ADMIRE). RESULTS: With the default BHC activated, Syngo.via underestimated the calcium concentrations in the abdomen for sequential-scanning acquisitions, leaving residual calcium in the virtual non-contrast images and underestimating calcium in the enhancement images for all DERs. Activation of the BHC with split-filter images resulted in a calcium over- or underestimation depending on the DER. With the BHC inactivated, the use of a single DER led to an under- or overestimate of calcium concentration depending on phantom size and DECT modality. Optimal results were found with BHC inactivated using size-specific DERs. CTDIvol levels and ADMIRE had no significant effect on results. CONCLUSION: When performing non-iodine material decomposition in the LiverVNC application class, it is important to understand the implications of the BHC function and to account for patient size appropriately. The BHC in the LiverVNC application is specific to iodine and leads to inaccurate quantification of other materials. The inaccuracies can be overcome by deactivating the BHC function and using size-specific DERs, which provided the most accurate calcium quantification.

Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones.

There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24-48 h before PfDHODH inhibition would be expected to do so.

Feasibility and acceptability of commonly used screening instruments to identify frailty among community-dwelling older people: a mixed methods study.

BACKGROUND: Frailty exposes older people to an elevated risk of a range of negative outcomes. Emerging evidence that frailty can be effectively treated within community settings has stimulated calls for more proactive screening within primary care. Assessing feasibility is a critical preliminary step in assessing the efficacy of interventions such as screening. However, few studies have explored the feasibility and acceptability of administering frailty screening instruments within general practice, and even fewer have incorporated patient perspectives. Our study had three objectives: To 1) assess overall feasibility of the instruments (completion time and rate); 2) assess patient acceptability towards the instruments; and 3) assess the feasibility and acceptability of the instruments to administering nurses. METHODS: The feasibility and acceptability of several frailty screening instruments (PRISMA-7, Edmonton Frail Scale, FRAIL Scale Questionnaire, Gait Speed, Groningen Frailty Indicator, Reported Edmonton Frail Scale and Kihon Checklist) was explored within the context of a larger diagnostic test accuracy (DTA) study. Completion time and rate was collected for all participants (N = 243). A sub-sample of patients (n = 30) rated each instrument for ease of completion and provided comment on perceived acceptability. Lastly, five of six administering nurses involved in the DTA study participated in semi-structured face-to-face interviews, rating the instruments against several feasibility and acceptability criteria (time, space, equipment, skill required to implement, acceptability to patients and nurses, ease of scoring) and providing comment on their responses. RESULTS: The PRISMA-7 returned the highest overall feasibility and acceptability, requiring minimal space, equipment, skills and time to implement, and returning the fastest completion rate and highest patient and nurse acceptability rating. All screening instruments were faster to implement than the two reference standards (Fried's Frailty Phenotype and Frailty Index). Self-administered instruments were subject to lower rates of completion than nurse-administered instruments. CONCLUSIONS: This study has demonstrated that a number of commonly used frailty screening instruments are potentially feasible for implementation within general practice. Ultimately, more research is needed to determine how contextual factors, such as differences in individual patient and clinician preferences, setting and system factors, impact on the feasibility of screening in practice.

Orthopaedic surgeons' perceptions of frailty and frailty screening.

BACKGROUND: Over the past decade, there has been significant growth in the awareness and understanding of fragility among orthopaedic surgeons in the context of osteoporotic fractures and with it, improvements in the recognition and management of fragility fractures. Emerging as a major clinical and research focus in aged care is the concept of frailty and its associations with fragility, sarcopenia, falls and rehabilitation. Currently, research is lacking on how orthopaedic surgeons perceive frailty and the role of frailty screening. A baseline understanding of these perceptions is needed to inform integration of frailty identification and management for patient optimization in orthopaedic practices, as well as research and education efforts of patients and healthcare professionals in orthopaedic contexts. METHODS: We used an exploratory design guided by qualitative description to conduct 15 semi-structured telephone and in-person interviews across three orthopaedic surgeon subgroups (Registrars, Junior Consultants, and Senior Consultants). Data collection and analysis occurred iteratively and was guided by thematic saturation. RESULTS: Orthopaedic surgeons have a disparate understanding of frailty. Between colleagues, frailty is often referred to non-specifically to suggest a general state of risk to the patient. Frailty screening is regarded positively but its specific utility in orthopaedic environments is questioned. Easy-to-administer frailty screening tools that are not exclusive assessments of functional status are viewed most satisfactorily. However these tools are rarely used. CONCLUSIONS: There is little understanding among orthopaedic surgeons of frailty as a phenotype. Beliefs around modifiability of frailty were dissimilar as were the impact of related risk factors, such a cognitive status, chronic disease, social isolation, and environmental influences. This in turn may significantly impact on the occurrence and treatment outcomes of fragility fracture, a common orthopaedic problem in older populations. This study highlights need for knowledge translation efforts (e.g. education) to achieve cohesive understanding of frailty among health professionals.

Total keratometry in intraocular lens power calculations in eyes with previous laser refractive surgery.

IMPORTANCE: Intraocular lens (IOL) calculations in post-refractive cases remain a concern. Our study identifies improved options for surgeons. BACKGROUND: To evaluate and compare the prediction accuracy of IOL power calculation methods after previous laser refractive surgery using standard keratometry (SK), measured posterior corneal astigmatism (PCA) and total keratometry (TK). DESIGN: Retrospective consecutive cohort. PARTICIPANTS: A total of 50 consecutive patients (72 eyes) at a private institution who underwent cataract surgery with prior laser refractive procedures. METHODS: Methods using SK included ASCRS mean, Barrett True-K no history, Haigis-L and Shammas IOL formulae. Barrett True-K using posterior values (True K TK), Haigis and Holladay 1 Double-K methods using TK were also assessed. Post-surgery refraction was undertaken at minimum 3 weeks following surgery. MAIN OUTCOME MEASURES: Arithmetic and absolute IOL refractive prediction errors, variances in mean arithmetic IOL prediction error, and percentage of eyes within ±0.25D, ±0.50D, ±0.75D and ±1.00D of refractive prediction errors were compared. RESULTS: The Barrett True-K (TK) provided the lowest mean refractive prediction error (RPE) and variance for both prior myopes and hyperopes undergoing cataract surgery. The Barrett True-K (TK) exhibited the highest percentages of eyes within ±0.50D, ±0.75D and ±1.00D of the RPE compared to other formulae for prior myopic patients. CONCLUSIONS AND RELEVANCE: Accuracy of IOL power calculations in post-laser eyes can be improved by the addition of posterior corneal values as measured by the IOLMaster 700. The use of total keratometry may supplement outcomes when no prior refraction history is known.