Background Careful development of interventions using principles of co-production is now recognized as an important step for clinical trial development, but practical guidance on how to do this in practice is lacking. This paper aims (1) provide practical guidance for researchers to co-produce interventions ready for clinical trial by describing the 4-stage process we followed, the challenges experienced and practical tips for researchers wanting to co-produce an intervention for a clinical trial; (2) describe, as an exemplar, the development of our intervention package. Method We used an Integrated Knowledge Translation (IKT) approach to co-produce a telehealth-delivered exercise program for people with stroke. The 4-stage process comprised of (1) a start-up planning phase with the co-production team. (2) Content development with knowledge user informants. (3) Design of an intervention protocol. (4) Protocol refinement. Results and reflections The four stages of intervention development involved an 11-member co-production team and 32 knowledge user informants. Challenges faced included balancing conflicting demands of different knowledge user informant groups, achieving shared power and collaborative decision making, and optimising knowledge user input. Components incorporated into the telehealth-delivered exercise program through working with knowledge user informants included: increased training for intervention therapists; increased options to tailor the intervention to participant’s needs and preferences; and re-naming of the program. Key practical tips include ways to minimise the power differential between researchers and consumers, and ensure adequate preparation of the co-production team. Conclusion Careful planning and a structured process can facilitate co-production of complex interventions ready for clinical trial. Graphical Abstract
Background Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs. Methods We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography. Results CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model. Conclusions Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.
This short communication paper aimed to compile the main determinants of inequality in dental services by distinguishing between access, utilisation, and provision of dental services. Recent findings integrated, and a dedicated conceptual framework entitled “Triangle of inequality in dental services” has been suggested. These can contribute a rich knowledge in this area and open a new window for policymakers and researchers to seek applied interventions to decrease inequality and improve access and utilisation in communities. This paper aims to synthesise the available evidence and add value to the scope. It highlights a dedicated concept for inequality in dental services beyond other areas of public health.
Recombinant protein approaches offer major promise for safe and effective vaccine prevention of SARS-CoV-2 infection. We developed a recombinant spike protein vaccine (called NARUVAX-C19) and characterized its ability when formulated with a nanoemulsion adjuvant to induce anti-spike antibody and T-cell responses and provide protection including against viral transmission in rodent. In mice, NARUVAX-C19 vaccine administered intramuscularly twice at 21-day interval elicited balanced Th1/Th2 humoral and T-cell responses with high titers of neutralizing antibodies against wild-type (D614G) and delta (B.1.617.2) variants. In Syrian hamsters, NARUVAX-C19 provided complete protection against wild-type (D614G) infection and prevented its transmission to naïve animals ( n = 2/group) placed in the same cage as challenged animals ( n = 6/group). The results contrasted with only weak protection seen with a monomeric spike receptor-binding domain (RBD) vaccine even when formulated with the same adjuvant. These encouraging results warrant the ongoing development of this COVID-19 vaccine candidate.
Background Understanding how species biology may facilitate resilience to climate change remains a critical factor in detecting and protecting species at risk of extinction. Many studies have focused on the role of particular ecological traits in driving species responses, but less so on demographic history and levels of standing genetic variation. Additionally, spatial variation in the interaction of demographic and adaptive factors may further complicate prediction of species responses to environmental change. We used environmental and genomic datasets to reconstruct the phylogeographic histories of two ecologically similar and largely co-distributed freshwater fishes, the southern ( Nannoperca australis ) and Yarra ( N. obscura ) pygmy perches, to assess the degree of concordance in their responses to Plio-Pleistocene climatic changes. We described contemporary genetic diversity, phylogenetic histories, demographic histories, and historical species distributions across both species, and statistically evaluated the degree of concordance in co-occurring populations. Results Marked differences in contemporary genetic diversity, historical distribution changes and historical migration were observed across the species, with a distinct lack of genetic diversity and historical range expansion suggested for N. obscura . Although several co-occurring populations within a shared climatic refugium demonstrated concordant demographic histories, idiosyncratic population size changes were found at the range edges of the more spatially restricted species. Discordant responses between species were associated with low standing genetic variation in peripheral populations. This might have hindered adaptive potential, as documented in recent demographic declines and population extinctions for the two species. Conclusion Our results highlight both the role of spatial scale in the degree of concordance in species responses to climate change, and the importance of standing genetic variation in facilitating range shifts. Even when ecological traits are similar between species, long-term genetic diversity and historical population demography may lead to discordant responses to ongoing and future climate change.
Prostate cancer is a complex disease affecting millions of men globally. Radiotherapy (RT) is a common treatment modality although treatment efficacy is dependent upon several features within the tumour microenvironment (TME), especially hypoxia. A hypoxic TME heightens radioresistance and thus disease recurrence and treatment failure continues to pose important challenges. However, the TME evolves under the influence of factors in systemic circulation and cellular crosstalk, underscoring its potential to be acutely and therapeutically modified. Early preclinical evidence suggests exercise may affect tumour growth and some of the benefits drawn, could act to radiosensitise tumours to treatment. Intracellular perturbations in skeletal muscle reactive oxygen species (ROS) stimulate the production of numerous factors that can exert autocrine, paracrine, and endocrine effects on the prostate. However, findings supporting this notion are limited and the associated mechanisms are poorly understood. In light of this preclinical evidence, we propose systemic changes in redox signalling with exercise activate redox-sensitive factors within the TME and improve tumour hypoxia and treatment outcomes, when combined with RT. To this end, we suggest a connection between exercise, ROS and tumour growth kinetics, highlighting the potential of exercise to sensitise tumour cells to RT, and improve treatment efficacy.
Background Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent childhood neurodevelopmental disorder. It shares some genetic risk with Autism Spectrum Disorder (ASD), and the conditions often occur together. Both are potentially associated with abnormal glutamate and GABA neurotransmission, which can be modelled by measuring the synaptic activity in the retina with an electroretinogram (ERG). Reduction of retinal responses in ASD has been reported, but little is known about retinal activity in ADHD. In this study, we compared the light-adapted ERGs of individuals with ADHD, ASD and controls to investigate whether retinal responses differ between these neurodevelopmental conditions. Methods Full field light-adapted ERGs were recorded from 15 ADHD, 57 ASD (without ADHD) and 59 control participants, aged from 5.4 to 27.3 years old. A Troland protocol was used with a random series of nine flash strengths from −0.367 to 1.204 log photopic cd.s.m ⁻² . The time-to-peak and amplitude of the a- and b-waves and the parameters of the Photopic Negative Response (PhNR) were compared amongst the three groups of participants, using generalised estimating equations. Results Statistically significant elevations of the ERG b-wave amplitudes, PhNR responses and faster timings of the b-wave time-to-peak were found in those with ADHD compared with both the control and ASD groups. The greatest elevation in the b-wave amplitudes associated with ADHD were observed at 1.204 log phot cd.s.m ⁻² flash strength ( p < .0001), at which the b-wave amplitude in ASD was significantly lower than that in the controls. Using this measure, ADHD could be distinguished from ASD with an area under the curve of 0.88. Conclusions The ERG b-wave amplitude appears to be a distinctive differential feature for both ADHD and ASD, which produced a reversed pattern of b-wave responses. These findings imply imbalances between glutamate and GABA neurotransmission which primarily regulate the b-wave formation. Abnormalities in the b-wave amplitude could provisionally serve as a biomarker for both neurodevelopmental conditions.
Purpose To evaluate the measurement properties of the Oxford Hip Score (OHS), EQ-5D-5L utility index and EQ-5D-5L visual analogue scale (EQ-VAS) in patients undergoing elective total hip arthroplasty in Australia. Methods In this prospective multi-centre study, the OHS and EQ-5D-5L were collected preoperatively, six weeks (6w) and six months (6m) postoperatively. The OHS, EQ-VAS and EQ-5D-5L index were evaluated for concurrent validity, predictive validity (Spearman's Rho of predicted and observed values from a generalised linear regression model (GLM)), and responsiveness (effect size (ES) and standard response mean (SRM)). Results 362 patients were included in this analysis for 6w and 269 for 6m. The EQ-5D-5L index showed good concurrent validity with the OHS (r = 0.71 preoperatively, 0.61 at 6w and 0.59 at 6m). Predictive validity for EQ-5D-5L index was similar to OHS when regressed (GLM). Responsiveness was good at 6w (EQ-5D-5L index ES 1.53, SRM 1.40; OHS ES 2.16, SRM 1.51) and 6m (EQ-5D-5L index ES 1.88, SRM 1.70; OHS ES 3.12, SRM 2.24). The EQ-VAS returned poorer results, at 6w an ES of 0.75 (moderate) and SRM 0.8. At 6m the EQ-VAS had an ES of 0.92 and SRM of 1.00. It, however, had greater predictive validity. Conclusions The EQ-5D-5L index and the OHS demonstrate strong concurrent validity. The EQ-5D-5L index demonstrated similar predictive validity at 6w and 6m, and both PROMs had adequate responsiveness. The EQ-VAS should be used routinely together with the EQ-5D-5L index. The EQ-5D-5L is suitable to quantify health-related quality of life in Australian hip arthroplasty patients.
During Australia's unprecedented bushfires in 2019-2020, misinformation blaming arson surfaced on Twitter using #ArsonEmergency. The extent to which bots and trolls were responsible for disseminating and amplifying this misinformation has received media scrutiny and academic research. Here, we study Twitter communities spreading this misinformation during the newsworthy event, and investigate the role of online communities using a natural experiment approach-before and after reporting of bots promoting the hashtag was broadcast by the mainstream media. Few bots were found, but the most bot-like accounts were social bots, which present as genuine humans, and trolling behaviour was evident. Further, we distilled meaningful quantitative differences between two polarised communities in the Twitter discussion, resulting in the following insights. First, Supporters of the arson narrative promoted misinformation by engaging others directly with replies and mentions using hashtags and links to external sources. In response, Opposers retweeted fact-based articles and official information. Second, Supporters were embedded throughout their interaction networks, but Opposers obtained high centrality more efficiently despite their peripheral positions. By the last phase, Opposers and unaffiliated accounts appeared to coordinate, potentially reaching a broader audience. Finally, the introduction of the bot report changed the discussion dynamic: Opposers only responded immediately, while Supporters countered strongly for days, but new unaffiliated accounts drawn into the discussion shifted the dominant narrative from arson misinformation to factual and official information. This foiled Supporters' efforts, highlighting the value of exposing misinformation. We speculate that the communication strategies observed here could inform counter-strategies in other misinformation-related discussions. Supplementary information: The online version contains supplementary material available at 10.1007/s13278-022-00892-x.
Excessive physical demand at work has traditionally been connected with adverse health outcomes, but excessive sitting is now also being recognised as an occupational hazard and emerging work-related risk. Traditional preventive occupational health and ergonomics programs are useful but limited through reliance on individual behaviour change and time-diversion from productive work. A new ‘Goldilocks Work Paradigm’ aims to optimise health and productivity by using movements of productive tasks. Using rail driving as a specific case of a highly sedentary and inflexible working environment, we construct a conceptual framework for designing better jobs, arguing that a theoretical amalgamation of the new Goldilocks Work Paradigm with System Thinking, Participatory Ergonomics, and a Risk Management Framework, is needed, for establishing a unified, strategic approach—a ‘just right’ job design model. We extend this by outlining a practical process of designing better jobs with tools that can be used to achieve it.
This paper presents an adaptive robust optimization approach to optimal operation of multi-layout energy hubs under uncertainty. In the first step, the multi-layout energy hub concept is presented and discussed comprehensively followed by its required energy management model, but in the deterministic form. In the next step, an adaptive robust optimization approach is developed for the energy management model of multi-layout energy hubs. The uncertainties of energy hub load as well as upstream energy market prices are considered through bounded intervals using polyhedral uncertainty sets. The proposed adaptive-robust multi-layout EHS optimizer (ARMEO) is developed as a tri-level min-max-min optimization problem which cannot be solved directly. To do so, column-and-constraint (C&C) technique is used to recast the tri-level model into a "min" master problem and a "max-min" sub-problem. However, the "max-min" sub-problem is still a bi-level model and cannot be solved directly. To cope, block coordinate descent (BCD) methodology is applied to the sub-problem to iteratively solve the "max-min" sub-problem. An industrial-based case study is conducted to show the effectiveness of the proposed model in 1) managing multi-layout energy hubs, and 2) provide immunized operational solutions against uncertainties. Based on the results, it is observed that the ARMEO model is subject to a higher operation cost (compared to deterministic model), however, the obtained operating solutions are immunized against the uncertainties. Moreover, it has been shown that the proposed multi-layout EHS model can provide reasonable operating solutions for all layouts of the system as a whole.
Sexual dimorphism occurs where different sexes of the same species display differences in characteristics not limited to reproduction. For the nematode Caenorhabditis elegans , in which the complete neuroanatomy has been solved for both hermaphrodites and males, sexually dimorphic features have been observed both in terms of the number of neurons and in synaptic connectivity. In addition, male behaviours, such as food-leaving to prioritise searching for mates, have been attributed to neuropeptides released from sex-shared or sex-specific neurons. In this study, we show that the lury-1 neuropeptide gene shows a sexually dimorphic expression pattern; being expressed in pharyngeal neurons in both sexes but displaying additional expression in tail neurons only in the male. We also show that lury-1 mutant animals show sex differences in feeding behaviours, with pharyngeal pumping elevated in hermaphrodites but reduced in males. LURY-1 also modulates male mating efficiency, influencing motor events during contact with a hermaphrodite. Our findings indicate sex-specific roles of this peptide in feeding and reproduction in C. elegans , providing further insight into neuromodulatory control of sexually dimorphic behaviours.
Objective Investigate associations of objective and subjective indicators of sleep impairment and disorders with low muscle strength (LMS) in different age groups and genders using data from a population-based cohort study. Methods Polysomnographic and subjective sleep data from participants (aged 40–80 years) of the HypnoLaus study (Lausanne, Switzerland) were cross-sectionally analyzed. Indicators of sleep impairment and disorders were based on pre-defined cutoffs. LMS was defined according to the diagnosis of sarcopenia (grip strength <27 kg for men and <16 kg for women). Results obtained by multivariate logistic regression were controlled for confounders. Results 1902 participants (mean [SD] age, 57.4 [10.5] years; 968 [50.9 %] female) were enrolled. Objective short (<6.2 h) and long sleep durations (>8.5 h) were associated with LMS (OR = 1.74, 95 % CI = 1.07–2.82; OR = 6.66, 95 % CI = 3.45–12.87, respectively). Increased nighttime wakefulness >90 min and severe obstructive apnea (OSA) (AHI > 30) were associated with LMS (OR = 1.60, 95 % CI = 1.01–2.56; OR = 2.36, 95 % CI = 1.29–4.31, respectively). In adults aged over 60 years, these associations persisted, and reduced sleep efficiency was associated with LMS (aOR = 1.81, 95 % CI 1.05–3.13). Objective long sleep duration was associated with LMS in both genders and severe OSA predicted LMS among women (aOR = 2.64, 95 % CI 1.11–6.24). Conclusions Markers of early sarcopenia are affected by long sleep duration from middle age onwards in both genders. Older adults are more susceptible to the effects of other indicators of inappropriate sleep duration and quality. The findings support a potential role of sarcopenia in age-related OSA. The intricate relationships between sleep and muscle health are potential targets of public health interventions and clinical research on preventive and therapeutic strategies against the increasing morbimortality observed with ageing.
Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is often associated with symptoms that can significantly impact quality of life and daily functioning. Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom. However, up to two-third of patients also complain of dyspnea as a predominant self-reported symptom. In clinical practice it is often challenging to ascertain whether dyspnea represents an AF-related symptom or a symptom of concomitant cardiovascular and non-cardiovascular comorbidities, since common AF comorbidities such as heart failure and chronic obstructive pulmonary disease share similar symptoms. In addition, therapeutic approaches specifically targeting dyspnea have not been well validated. Thus, assessing and treating dyspnea can be difficult. This review describes the latest knowledge on the burden and pathophysiology of dyspnea in AF patients. We discuss the role of heart rhythm control interventions as well as the management of AF risk factors and comorbidities with the goal to achieve maximal relief of dyspnea. Given the different and often complex mechanistic pathways leading to dyspnea, dyspneic AF patients will likely profit from an integrated multidisciplinary approach to tackle all factors and mechanisms involved. Therefore, we propose an interdisciplinary and integrated care pathway for the work-up of dyspnea in AF patients.
3D printing of concrete is commonly viewed as a promising way to manufacture novel structural sections with numerous benefits. This process, however, relies upon a specific set of timely parameters that can have significant impact on the long-term performance and durability of the printed sections, especially since they are potentially expected to be exposed to the outside environments. In that respect, this article provides a critical review of the durability properties of 3D printed concrete (3DPC) sections, including the effect of printing parameters, mixture proportions, and key materials on shrinkage behavior, porosity and pore connectivity, freeze thawing, fire, chemical, and acid resistance. Based on this review, it is found that the thermo-durability properties of 3D printed concrete sections are highly sensitive to the shrinkage potential and printing time interval, which can significantly alter the porosity and pore connectivity of the printed concrete, especially at interlayer bonding regions. Suggestions for improving the durability of 3D printed concrete sections exposed to the various environments are also provided in the final part of this review.
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