Autonomous electric vehicles promise to improve traffic safety, increase fuel efficiency and reduce congestion in future intelligent transportation systems. Ecological driving characteristics are first studied to concentrate on energy consumption, the ability to quickly pass its destination, etc. of autonomous electric vehicle plans (AEVPs) to maximize total energy efficiency benefits. To realize this goal, an optimal control model is developed to provide ecological driving suggestions to AEVPs. The Radau pseudospectral method (RPM) is adopted to put the optimal control model into nonlinear programs (NLP), and multiobjective optimization, including safety, economy and fast mobility, is considered, which conditions and constraints such as vehicle dynamics, traffic rules, and energy consumption. To enhance optimal model applicability, two ecological driving procedures are proposed. One procedure is that two-phase trajectory optimization and ecological driving states, such as velocity and acceleration, for the leading vehicle are developed according to RPM characteristics, while the other provides a set of targeted driving states to the following vehicles. The objective of the procedure is to minimize the total energy consumption of AEVPs, while travel comfort and safety are integrated into the schematization by optimization functions. Numerical experiments illustrate significance when ecological driving strategy for AEVPs considers energy consumption characteristics, thereby ensuring total energy consumption efficiency for AEVPs. EVs will be common transportation in future.The automotive industry has developed electric vehicles to reduce the dependency on petroleum fuels, improve energy efficiency and promote sustainable transportation. Many governments have plans to accelerate the market shares of electric vehicles (EVs); therefore, EVs have experienced huge market penetration over the past decade. The U.S. EIA projects that over 30 million (24%), passenger cars on U.S. roads will be electricity powered by 20402. EEVs mainly mean that energy consumption needs to be considered to cover travel activities due to battery technology limitations, combined with vehicle powertrains, vehicle dynamics, tire models, etc. Meanwhile, surrounding vehicle states and road information can be collected by connecting vehicle technologies to determine innovative driving state control and trajectory planning. Edwin proposed an approach to estimate the potential of eco-driving for reducing energy consumption3. Maria introduced the Pontryagin maximum principle to optimize the calculated battery consumption, and connected vehicle technology was used to transmit with other vehicles4. Hu proposed an optimal controller by using emerging connected technology to minimize the fuel efficiency for hybrid electric vehicles, including road topography and dynamic speed limits5. Therefore, ecological driving is an effective integrated strategy that includes vehicle dynamics control, energy consumption calculation, vehicle driving state collection and connected vehicle technology. In particular, for electric vehicles, regenerative braking can recharge a portion of energy to the battery during deceleration. Existing study results demonstrate that regenerative braking could increase the EV driving range by 8–25%6.Ecological electric vehicles (EEVs) are a new concept that adapts the driving strategy to an energy-aware anticipative driving strategy and have high potential to improve the safety and efficiency of the transportation network7. Vehicle platoons are mainly used to control a suitable safety distance to reduce air resistance and energy consumption by installing sensors such as radar, lidar or machine vision. Recently, connected vehicle technologies have been applied to platoons that can enable vehicles to drive a much closer distance upon information obtained from neighboring vehicles. Many studies mainly design optimal control models to obtain speed advisories for minimizing fuel consumption. Gong developed cooperative platoon control for a platoon mixed with connected and autonomous vehicles and human-driven vehicles by using the model predictive control optimal method8. Jia builds a cooperative driving model by using connected vehicle technologies for studying time-delay communication9. Luo introduced a mixed-integer linear program to minimize the total fuel consumed with multiple speed options10. Li proposed a Lyapunov technique to study trajectory tracking control for connected vehicle platoons by considering the position error and velocity difference11. The above studies generally concentrate on algorithm theories, optimal models and fuel energy consumption for human-driving vehicle platoons. However, fuel consumption calculations for vehicle platoons should be taken into consideration; in combination with vehicle dynamics and road information, the driving states of leading vehicles are usually assumed or ignored so that the total fuel energy consumption cannot be accurately calculated. In fact, regarding energy-efficient vehicle platoons, the driving states of leading vehicles are important, especially for electric vehicle platoons under congested traffic conditions; therefore, multiobjective optimization, including safety, economic and fast mobility, should be calculated in ecological driving studies. Lorenzo introduced nonlinear model predictive control to develop an ecological driving of electric vehicles to minimize energy consumption12. Makoto proposed adaptive neural networks to design electric vehicle platoons13. Guo introduced an adaptive backstepping sliding mode of a high-level law to study the coordinated control method for autonomous electric vehicle platoons14. Several studies have developed innovative control algorithms, stability analysis and parts of fuel energy consumption. However, the total fuel energy consumption minimization of electric vehicle platoons should be researched due to the energy consumption characteristics of multivehicle platoons.A platoon is another energy-efficient vehicle driving control solution that can save battery fuel. Sun shows that the average reduction in fuel consumption for platoons can reach up to 10%6. Riccardo proposed a mixed-integer linear program methodology for the optimization of charging with a vehicle-to-grid for a shared autonomous electric vehicle15. Chen developed a passive fault-tolerant path following the control method of an autonomous distributed electric vehicle when a vehicle steering system is fault16. Yi proposed a data-driven method to formulate a grid stochastic energy consumption model of electric vehicles17. Zhang developed a novel tracking control method of intelligent electric vehicles to realize path tracking based on lane detection and sliding mode control methods18. Victor designs a static decision model to involve autonomous electrical vehicles19. Li proposed a potential field method to achieve the trajectory control of autonomous electric vehicles with in-wheel motors20. Doan proposed the Pontryagin maximum principle for the optimal allocation of wireless power transfer systems21. The above studies mainly focus on performance optimization, algorithm theories, path-following methods and charging methods, etc., while fuel consumption energy has not been considered in the process of trajectory planning for autonomous electric vehicles. In fact, energy consumption is a vital factor for autonomous electric vehicles because limited energy should be used to ensure that autonomous electric vehicles arrive at the terminal position.Recently, the majority of EV tasks have mainly focused on battery technology limitations and charging infrastructure problems, while the driving efficiency of EVs should be studied in an intelligent transportation system environment. Autonomous electric vehicles, combined with connectivity, are considered a major issue supporting a more efficient and clearer transportation system. Gao thinks that adopting connected and automated vehicle technologies can promote energy efficiency via eco-driving functions in optimizing EV performance effectively22. Zhao developed V2 V communication to realize autonomous electric vehicle platoons, and thus vehicle interruptions were successfully designed23. He develops an optimal control model as a foundation to provide ecological driving to mixed gasoline vehicles and EVs, and speed advisory and acceleration-based advisory strategies are used to study energy consumption1. Bian studied a multiple-predecessor following strategy to reduce time headway via vehicle-to-vehicle (V2 V) communication, and a constant time headway policy was proposed for general communication topologies24. Qi designed a cooperative system in which vehicles and infrastructure are tightly integrated by using wireless communications25. In addition, the impact of driving behavior, vehicle dynamics and data-driven energy consumption are also integrated into the framework. The above studies on AEVPs have been chiefly embodied in V2 V systems, optimal control models and algorithm innovation. In fact, ecological driving for AEVPs is a local minimum problem due to constraints imposed by neighboring vehicles. Therefore, to ensure the minimum total energy consumption of AEVPs, the ecological driving states of leading vehicles and following vehicles should be jointly studied. Especially importantly, ecological trajectories of leading vehicles should be designed to ensure effective vehicle tracking according to specific traffic environments.Another energy-efficient trajectory plan for autonomous electric vehicles is platooning, which shows good potential for fuel economy. As autonomous electric vehicle platoons (AEVPs) travel on roads, different energy consumption characteristics and constraints for different vehicles can be allocated through new technologies, such as vehicle-to-vehicle (V2 V) and vehicle-to-infrastructure (V2I) communications or algorithm innovation. In this way, if trajectory planning and ecological driving states of leading vehicles can be effectively designed, the following vehicles can realize safety, energy-efficient trajectory tracking and ecological driving states. In fact, many studies mostly focus on the driving states of the following vehicles, and the driving states of the leading vehicle are ignored so that the predictive driving states of the leading vehicle cannot be adjusted according to the specific driving environment. Therefore, the total energy consumption for AEVPs could not be truly realized. Choi proposes RFID tags to supply lines and estimate the position of vehicles, and connecting technologies are used to calculate distances between vehicles26. Hu introduced an improved artificial potential method for path planning considering vehicle velocity to prevent unnecessary lane changing behavior27. Song proposed an improved A* graph, and a new path smoothing process with three types of path smoothers was developed to improve path performance28. Mohamed introduced the RRT algorithm to split planning into two efficient phases to reduce its computational time combined with the robustness of parametric vector valued splines. Other methods of motion planning have also been developed in recent years29. Wu developed differential dynamic programming for a novel path planner combined with kinematic feasibility30. Li proposed a novel integrated local trajectory planning and tracking control framework for motion planning of autonomous vehicles31. The above studies are mainly focused on motion planning algorithms to realize specific driving behaviors. However, these algorithms only generate instantaneous commands, and the generated trajectories are not smooth or ignore vehicle dynamics and traffic rule safety constraints. Guo introduced a model predictive control method to design path-following schemes for autonomous vehicles, and a differential evolution algorithm was adopted32. Makoto developed nonlinear model predictive control for autonomous vehicle motion planning, which can solve nonlinear vehicle dynamics and environmental conditions33. Bian presents a systematic approach to connected vehicles at unsignalized intersections without global coordination, and a distributed observation algorithm is introduced to achieve trajectory planning34. Indeed, safety requirements for autonomous vehicles are to ensure vehicle dynamics safety, especially when vehicles are at high speeds. Meanwhile, tire mechanics and rollover should be taken into consideration. However, autonomous vehicles are complicated engineering artifacts, so many problems in motion planning cannot be solved by simply relying on model predictive control methods. For example, multiphase trajectories for autonomous vehicles should be planned according to specific constraints for specific traffic scenes, the immersed local optimal problem should be solved to realize global optimization, and terminal states of autonomous vehicles should be defined according to specific road traffic environments. Sometimes we want to compute a trajectory from its current position to the destination as fast or as energy efficient as possible35. Therefore, to achieve the requirements of autonomous vehicles, another trajectory planning method should be developed. The pseudospectral method was applied in the field of aerosols in the early stage. Few papers have been published using the pseudospectral method to solve motion planning for autonomous vehicles. Michael introduced a pseudospectral optimal control algorithm for motion planning of small unmanned ground vehicles36. The pseudospectral algorithm is a direct approach in which numerical optimal control techniques are used to solve the motion planning of robots, and the abovementioned problems can be solved by the pseudospectral method. The pseudospectral algorithm is an effective optimal control method for autonomous vehicles.Motion planning aims to plan motion trajectories in a short future horizon to find collision-free trajectories under static and dynamic obstacles. The majority of existing studies in motion planning algorithms of autonomous vehicles are found in the robotics field. There exist three category methods. First, the sampling-based method means that the state space is discretized or randomly sampled in lattices, such as the A* graph and RRT algorithm. Second, the decomposed method means that the planning problem is decomposed into two easier subproblems. Third, the motion planning problem is transferred into a mathematical programming-based method, such as model predictive controlThis study aims to address the ecological driving on multiphase trajectories and multiobjective optimization for AEVPs by using the pseudospectral method and V2V communication technologies to minimize the total fuel consumption of AEVPs. Ecological driving means that the constraints of vehicle dynamics, traffic rules, energy consumption minimization, and the ability to quickly pass trajectories of electric vehicles should be taken into consideration when trajectory planning and driving states of AEVPs are designed in this paper. The first strategy shows that the pseudospectral method is used to design ecological driving on trajectory planning and driving states of the leading electric vehicle to ensure ecological driving of the leading vehicle. The second strategy shows that the following electric vehicles should track the planned multistage trajectories, and the driving states of the leading vehicle can be transmitted to following electric vehicles by V2 V communication technologies under the conditions of ensuring the minimum total platoon energy consumption. In addition, a multiobjective optimal model including safety, economic and fast mobility mainly involves two parts: the minimum of total energy consumption and the ability to quickly pass its destination to realize ecological autonomous driving.The remainder of the paper is organized as follows. “Autonomous electric vehicles are researched in this paper to improve energy efficiency, promote sustainable transportation and realize green mobility, especially as ecological driving on AEVPs and reducing overall fuel consumption are helpful to realize high-quality green mobility. Autonomous electric vehicle applications are mostly focused on vehicle system models to improve efficiency through optimal powertrain operations. Vehicle dynamics models, longitudinal vehicle kinematics models, platoon dynamics models and energy consumption models are involved in system models. Longitudinal vehicle kinematics models are used to calculate the energy consumption of AEVPs, and vehicle dynamics models are used to design motion planning and driving states for the leading vehicle according to specific traffic scenes. System models are crucial to ecological driving for AEVPs.Longitudinal vehicle kinematics models of AEVs include traction force, ground resistance and wind resistance. Newton’s second law is adopted to build longitudinal models, as follows:In the above equation, Electric vehicle is assumed to front-wheel drive. The traction force can be expressed as:The total resistive forces are aerodynamic drag The desired distance between vehicles is defined as follows:38. Pseudospectral algorithms can be categorized into the Gauss pseudospectral method (GPM), Legendre pseudospectral method (LPM) and Radau pseudospectral method (RPM). Pseudospectral methods have attracted much attention because of their exponential convergence rates for problems with smooth and well-behaved solutions39. In RPM, the Legendre–Gauss-Radau (LGR) collocation method is adopted to discretize the optimal control problem. In this study, RPM is proposed to develop ecological driving for AEVPs because it has the advantage of exponential convergence, and state interpolation, such as terminal points and constraints, is included. It also has the advantages of fast convergence, lower sensitivity to initial values and multistage trajectory optimization and can obtain higher accuracy results with less computational cost. Accordingly, an optimal control model based on RPM is studied to minimize the total energy consumption of AEVPs to realize ecological driving. In addition, for a platoon, the optimal model needs energy-optimal acceleration. Therefore, putting nonlinear optimal control problems into a nonlinear programming problem (NLP) to realize total energy consumption minimization of AEVPs is an important method. The specific procedure using RPM is as follows:Pseudospectral algorithms are direct methods in the numerical method field and can also be named global optimization algorithms, usually Lagrange interpolation is used to put a series of optimal problems into discretization and realize the global solution, while the real optimum sometimes cannot be obtained. Generally, direct methods transcribe the continuous optimal control problem to nonlinear programs (NLPs) based on the discretization methodFirst, time regions. To apply the RPM algorithm, the time region to achieve the optimal control problem is If the ecological driving process of AEVPs has been divided into K phases that have consisted of K mesh intervals, the time region in every phase should be transmitted into Second, discretion state variables and control variables. The RPM principle shows that Lagrange interpolation is used to put a series of optimal problems into discretization by building Lagrange polynomials to approximate states Third, Dynamical differential equation conversion. Equation  is derivForth, Objective function. Through the above three steps, the optimization function can be calculated as follows:Ecological driving for AEVPs needs to take into consideration boundary conditions to make AEVPs safely, effectively and ecologically track trajectory and driving states. A multiobjective optimization model also needs to consider the constraints and conditions. The boundary conditions and constraints include the driving states of the leading vehicle and following vehicles, initial boundary conditions and terminal boundary conditions. Initial boundary conditions are initial state variables at the beginning of vehicles, and terminal boundary conditions are the conditions that need to be satisfied at the end of trajectory. Two phase trajectories for AEVPs are studied, and multiobjective state constraints are set up according to specific traffic scenes.In the first phase, the trajectory and driving states of the conditions and constraints of the leading vehicle should be set up as follows:The initial states of the leading vehicle at the beginning include the vehicle position, velocity, heading angle, and front wheel angle as follows:The terminal states of the leading vehicle at the end in the first phase can be set up as follows:The leading vehicle should obey traffic rules, and driving states should be restrained in specific ranges to ensure AEVP ecological driving according to specific traffic scenes. Therefore, the state constraints for the leading vehicle are:Control variables should obey vehicle dynamics, and their constraints are:In the second phase, the initial states of the leading vehicle at the beginning are equal to the terminal states of the leading vehicle in the first phase according to the principle of RPM:The terminal states of the leading vehicle at the end in the second phase can be set up as follows:The state constraints of the leading vehicle in the second phase are:Initial states of following vehicle The terminal states of vehicle The constraints of driving states for following vehicle 2, energy efficient speed planning for optimal control problem40.Meanwhile, nonlinear optimal control problems are converted into NLP to solve the abovementioned objectives. For a platoon approaching road section that is prone to traffic accidents, the optimal control model needs energy-optimal acceleration, as follows:The function of the proposed optimal control model is to minimize the total energy consumption of AEVPs to realize ecological driving and achieve automatic driving. Therefore, the objective of the optimal model is to minimize total energy consumption, comfort, safety and the ability to quickly pass its destination, which shows exponential convergence and high efficiency. Multi-objective optimization could arrive at a good effect, for example, when total energy consumption is calculated, vehicle safety is needed to considered to ensure the suitable speed planning, and the vehicle comfort is also considered, because the relation between velocity planning and vehicle comfort is demanded to balance. Many scholars are studied optimal relation such as optimal control for a semi-autonomous ecological driver assistance systemSubject to:Combined with Eqs. , 18), , , 22), , , and 2525 and coIn the above optimal model, Eq.  is the tEquation  represenWhen AEVPs are driving on road scenes that are prone to traffic accidents, the leading vehicle may drive at different energy-optimal speeds to ensure that the platoon can traverse traffic scenes safely. Therefore, the leading vehicle can be divided into two states at two different velocities. Equation  can be rThe objective function  is formuThis section describes numerical experiments to demonstrate the ecological driving of AEVPs. Two phases of experiments can be studied in this paper. Two obstacles on roads are stochastically set up and marked in red under the road environment. The obstacles can be expressed by using the P-norm as follows:When the value p is larger, the rectangular shape is closer to the vehicle. According to the above additions, the obstacle constraints can be set as follows:(i)The initial conditions for the leading vehicle and the following vehicle can be defined as follows:(ii)The terminal conditions for the leading vehicle and the following vehicle can be defined as follows:The experiments can be divided into two phases, and the average traffic speed of AEVPs is assumed to be Ecological driving study results for AEVPs are shown in the following graphics.Figure (i)The initial conditions for the leading vehicle and the following vehicle can be defined as follows:(ii)The terminal conditions for the leading vehicle and the following vehicle can be defined as follows:In the second phase, the leading vehicle drives at an acceleration state, and some important parameters can be set up in the following form:Figure (i)The initial conditions for the leading vehicle and the following vehicles can be defined as follows:(ii)The terminal conditions for the leading vehicle and the following vehicles can be defined as follows:In the second phase, the initial conditions for the leading vehicle and the following vehicle are equal to the terminal conditions in the first phase.(iii)The terminal conditions can be defined as follows:The ecological driving study results for AEVPs are shown in the following graphics.Suppose that the platoon consists of three vehicles, and the average traffic speed of AEVPs is assumed Figure This section describes a comparative analysis of RPM in realizing multiphase trajectories and multiobjective optimization for AEVPs. As trajectory planning is based on the optimal control method, the model predictive control method (MPC) is another trajectory planning method for autonomous electric vehicles. To reflect the advantage of the RPM method, the comparative analysis is studied. Trajectory planning based on MPC and vehicle velocity are set as Figure entclass1pt{minimaAEVPs is a major research hotspot in future. This paper proposes an optimal control model for ecological driving to minimize the energy consumption of AEVPs. To enhance ecological driving efficiency, the proposed optimal control model develops NLP problems by using the RPM algorithm. NLP problems easily solve such propositions because they contain some decision variables and constraints. By solving the NLP formulation, the ecological driving states and trajectory of the leading vehicle can be obtained, and a sequence of driving states, such as acceleration and velocity, can be suggested to the following vehicles for automated vehicle platoons. Numerical experiments illustrate ecological driving strategies for AEVPs and demonstrate the benefits of connected and autonomous vehicle technologies in realizing energy efficiency and ecological driving of platoons. Numerical experiments also show that regarding energy consumption efficiency, connected and autonomous vehicle systems with platoons can effectively realize total energy consumption efficiency. Meanwhile, the multiphase trajectories of autonomous vehicles by the RPM algorithm can be further investigated during some complicated traffic scenes through complex communication topology. For example, when AEVPs drive at unsignalized intersections, so many autonomous vehicles come from different directions. To ensure that AEVPs safely drive, the complex communication topology can be used to transfer vehicle state information to the surrounding vehicles to plan multiphase trajectory planning, which can be helpful to realize specific driving states during different driving phases. Combined with complex communication topology, multiphase trajectory planning by the RPM method can be used to solve so many complicated road traffic scenes, such as tunnel traffic scenes, road traffic in severe weather, and bridge traffic that has the features of wet and slippery roads.


Research on adherence interventions in rheumatology is limited by methodological issues, particularly heterogeneous outcomes. We aimed to describe researchers’ experiences with conducting interventional studies targeting medication adherence in rheumatology and their perspectives on establishing core outcomes.Semi-structured interviews using audio conference were conducted with researchers who had conducted an adherence study of any design in the past 10 years. Data collection and thematic analysis were performed iteratively, until saturation.We interviewed 13 researchers, most of whom worked in academia and specialized in epidemiology and/or health services research. We identified three themes: 1) improving measurement of adherence ; 2) challenges in designing and appraising adherence intervention studies ; and 3) advancing outcome assessment in adherence intervention studies .Uniquely gathering perspectives from international adherence researchers, our findings led to researcher-informed recommendations for improving adherence research including specifying the targeted adherence phase in designing interventions and studies and providing a glossary of terms to promote consistency in reporting. We also identified recommendations for developing a core domain set for interventional studies targeting medication adherence including involvement of patients, clinicians, and other stakeholders and methodological and practical considerations to establish rigor and support uptake.The online version contains supplementary material available at 10.1186/s41927-021-00193-4. Medication non-adherence in rheumatic diseases - as high as 90% in gout, 70% in rheumatoid arthritis (RA), and 43% in systemic lupus erythematosus (SLE) , 2 - hasWe conducted an international qualitative study as part of the OMERACT-Adherence Working Group.Researchers were eligible if they were English-speaking and had conducted an interventional study targeting medication adherence in the past 10 years using any design . We drew from our collegial and professional networks internationally to identify potential participants. We utilized purposive sampling  to colleThe first author (SS), a PhD candidate, who is a pharmacist with a graduate degree in qualitative research, conducted the semi-structured interviews through audio conference from August 2019 to January 2020, without the presence of non-participants. The interviewer had no prior relationship with the participants. The interview guide  researchers from seven countries  participated in the study (Table We identified three themes: 1) improving measurement of adherence; 2) challenges in designing and appraising adherence intervention studies; and 3) advancing outcome assessment in adherence intervention studies. We describe each theme and corresponding categories in detail as follows and provide illustrative participant quotations in Table This theme captured participants’ perspectives on the measurement of adherence, which is not just limited to interventional studies of medication adherence but also applies to all types of studies in the field, including descriptive studies that quantify the extent of adherence (or non-adherence) in a patient population and analytic studies that evaluate the association between adherence (or non-adherence) and outcome(s). Participants indicated limitations to the measurement of adherence and shared insights and recommendations for addressing them.both interventions as well as studies to evaluate these. It was indicated by the majority that adherence research has been significantly hindered by confusion, conflation, and omission of the three phases of adherence . Participants provided examples - some studies only measure adherence for the period in which a patient is on therapy, with study follow-up terminating at the time when the drug is stopped, thus reflecting poor medication taking only at the implementation phase, while in other studies, patients are followed after therapy discontinuation, capturing poor medication taking during the implementation phase, as well as non-persistence with therapy. In citing prior works that have called for standardized definitions for phases of adherence, participants highlighted that efforts should go beyond use of terminologies but also in research practice with respect to explicit specification and measurement of these phases of adherence.Participants collectively called for consideration and better specification of the targeted phase of adherence in designing no single perfect adherence measure” using multiple measures would overcome specific limitations and allow triangulation of information captured by various sources.Participants indicated their preference for using multiple adherence measures in their studies, specifically a combination of objective measures which are not reliant on memory or affected by social desirability bias, combined with subjective measures which provide more details on constructs underlying poor adherence. Such recommendations stem from noted limitations of adherence measures relating to issues of sensitivity, specificity, and reproducibility. With pharmacy refill or claims data, participants listed limitations of lacking information on prescribing rationalization, being limited to selected populations (e.g. those with insurance coverage) or jurisdictions (e.g. those with resources and infrastructure), and failing to capture whether medications are actually taken. Other adherence measures discussed were pill counts and electronic monitoring, which were considered logistically prohibitive , and vulnerable to bias given that measures requiring patients’ involvement may serve as interventions themselves. Participants also discussed self-reported measures of adherence through interviews or questionnaires and noted that interviews were time-consuming, not always feasible in the clinic setting, and may overestimate adherence. Questionnaires on the other hand may not reflect actual medication taking behaviour, lack of validation, and have poor wording that may make it difficult to understand by patients. As participants indicated having “good adherence” in interventional studies of medication adherence. The conventional threshold of “taking 80% of doses as prescribed” is widely used to categorize patients as adherent or non-adherent and/or determine the effect of an intervention. A problem of using this threshold was that it did not distinguish between “forgiving” versus “non-forgiving” medications, that is, medications for which missing a small number of doses do not have significant clinical consequences versus one which can have severe consequences if not taken as prescribed. Consideration of clinically meaningful thresholds when designing adherence research studies was recommended instead of the current “one-size-fits-all approach” to better understand how much improvement in adherence is needed or necessary, how to translate improvements in adherence into clinical benefits, and whether the intervention is cost-effective.Participants indicated the need to address the absence of a medication-specific and disease-specific clinically meaningful thresholds for “This theme encapsulates key challenges with conducting adherence intervention studies as described from first-hand experiences by participants and extends to challenges with respect to evaluating/appraising adherence intervention studies.gold standard” for outcomes leading to very little comparability between studies. Participants described outcomes they have measured and reported in their respective adherence intervention studies. “Adherence outcomes” included barriers to adherence , related constructs pertaining to medication taking  and adherence itself (measured through varying methods such as self-report and pharmacy refill records). “Clinical outcomes” included condition-specific biological markers (e.g. serum uric acid level in gout), disease severity , adverse events, and healthcare utilization . Other outcomes described by participants represented psychological and psychosocial constructs including mental health , quality of life, and patient satisfaction. Finally, some participants reported measuring outcomes related to the intervention itself . Indeed, with such wide range of outcomes, participants indicated confusion on outcomes selection for intervention studies. Related to this, participants indicated the need to consider study participant burden and fatigue with respect to having too many outcomes to report.An important challenge with conducting interventional studies of medication adherence identified by participants was the lack of a “Another key challenge identified was study recruitment to achieve adequate statistical power. Participants highlighted this particular issue for several reasons. First, differences between intervention and comparison groups (effect sizes) are usually small, thus requiring bigger sample size (higher power) to be detected. Second, patients and funders were thought to be interested in changes in clinical outcomes rather than improvements in adherence, which may require an even bigger sample size, especially if power and sample size calculations are aimed at adherence as primary outcomes and clinical outcomes are considered as secondary outcomes. Third, individuals who participate in research studies are those who are more likely to be adherent, making it harder to detect additional effects of interventions. Indeed, non-adherent patients who are the population of interest for intervention studies and who may benefit the most were felt to be the hardest to recruit. Related to these issues of recruitment and sampling, participants indicated lack of consensus on whether sampling should be random or specifically targeted at non-adherent patients. In the case of targeted recruitment, participants were unsure of guidance on the best approach for screening potential participants and deciding who is non-adherent.Participants indicated that challenges with adherence intervention studies are not confined to conducting studies themselves but also extend to evaluating/appraising published studies. A significant contributor to the latter challenge was poor reporting, that is description of adherence interventions, in published studies that limit the ability to understand their design. Participants indicated that very few authors describe how interventions have been conceptualized; for example, whether established frameworks  were used , 15. ParThis theme captures rationale for standardizing outcome assessment in adherence intervention studies and provided priorities and preferences for what outcomes should be included in a core domain set. It additionally captures challenges in developing and implementing a core domain set.cheaper”.Participants noted the heterogeneity that has limited adherence intervention research and unanimously agreed on the importance of standardizing approaches to outcomes selection. According to participants, such standardization would make trials comparable, facilitate meta-analysis, allow combination of efforts internationally, and strengthen the evidence base  on what intervention works. With this, participants recognized the value of having a recommended core domain set for adherence intervention studies. Participants believed that a core domain set will improve not just interventional studies but all adherence research in general by adding rigor, offering clarity with regards to appropriate application of adherence measures, and promoting standardized use and reporting of outcomes. Having a core domain set was also believed to have positive impacts on clinical practice since it would inform clinicians on how best to support their patients with medication taking and reduce the many missed opportunities that currently exist in clinical practice due to inadequate evidence. Furthermore, participants indicated that a core domain set may improve quality of care at organizational levels by informing outcomes that should be measured in routine data collection for quality assurance purposes. One participant speculated that having a core domain set may actually reduce the number of outcomes that need to be measured to prove the effectiveness of an intervention, hence making the evaluation of interventions more feasible and “between rheumatic diseases and from other conditions, for example, cardiovascular disease); 2) culture of the target group (important when measuring the experience with the intervention); 3) research elements such as study objectives  and study design ; 4) logistical factors including feasibility of implementing the outcome and funding availability (if researchers can afford to measure a certain outcome); and 5) intervention design . Finally, in no particular order, participants’ preferences for the types of outcomes in interventional studies targeting medication adherence included: 1) objective measures of adherence with attention to specific phases ; 2) subjective measures of constructs that explain reasons for non-adherence (e.g. medication beliefs); 3) intervention-specific outcomes (outcomes that measure what the intervention was designed to target); 4) health outcomes which include composite, surrogate or direct clinical outcomes and side effects; 5) psychosocial outcomes that may be influenced by adherence ; and 6) economic outcomes  that provide information on the cost-benefit of the intervention.Participants indicated a number of considerations for including outcomes in a core domain set, as well as shared preferences for types outcomes. The consideration of outcomes to be included in a domain set was believed to depend on: 1) the therapeutic area of focus , there were concerns around poor uptake. For example, the majority of participants were concerned that introduction of a core domain set might inhibit adherence research by recommending outcomes that may not be feasible or costly to measure. Some participants suggested that perhaps it would be better to provide guidelines around outcomes selection considerations as opposed to prescribing a list of outcomes to be measured. Some also believed that guidelines to standardize measurement methods might be more useful and practical than the recommendation of the core domain set since the same outcome can be measured using very different methods, providing different results. Participants questioned the appropriate extent to which the recommended core domain set should be imposed, that is, whether it should remain as a set of guidelines or be mandated under specific circumstances such as a requirement for funding or inclusion in a meta-analysis. Transparency in the benefits and consequences of following the recommendations was considered necessary to allow researchers to make an informed decision about whether or not to include the recommended outcomes in their study.Participants highlighted that conducting adherence intervention studies often involves collaborations across diverse fields and interests – including patients and caregivers, psychologists, clinicians, regulators, clinical trialists, and epidemiologists. While lending strength to research, this was also noted as a challenge as each discipline has a different conceptual understanding of adherence. Participants anticipated that different groups will have different expectations from outcomes within a core domain set. It was, therefore, considered desirable for the core domain set to represent and reflect the priorities of different stakeholders. It was also recommended to provide a complementary glossary (terminology definition) with the recommended core domain set considering the diverse, heterogeneity and inconsistency of the terminology in adherence literature, and the significant disagreements between researchers in basic terminology and concepts in the field.Participants felt that patients would be mostly interested in whether the intervention is going to help with their disease or interfere with their ability to undertake activities of daily living, quality of life , enriched the interviews and insights gained. Altogether, thematic analysis led to the identification of three themes – improving measurement of adherence, challenges in designing and appraising adherence intervention studies, and advancing outcome assessment in adherence intervention studies. These themes have implications for informing recommendations for improving adherence research – including specifying the targeted adherence phase in designing adherence interventions and studies, using multiple measures of adherence, applying clinically meaningful thresholds for determining adherence/non-adherence, and providing a glossary to define key terms so as to continue promoting consistency in reporting of adherence research studies. Also, an implication of our study are identified researcher-recommendations for developing a core domain set for interventional studies targeting medication adherence including the involvement of patients, clinicians, decision makers and other stakeholders to represent respective priorities as well as methodological and practical considerations to establish rigor and support future uptake. While our findings have direct implications in rheumatology where we particularly focused our inquiry, we anticipate their applications in other chronic conditions.This was an international qualitative study in which we interviewed 13 adherence researchers about their perspective in conducting adherence studies. Though we were particularly interested in Challenges in conducting and appraising adherence intervention studies were discussed at length by participants. This is not surprising considering that adherence research is a relatively new field, with the World Health Organization definition of adherence published less than two decades ago . Our stuAn entire theme was identified around complexity of measuring adherence as an outcome for studies of interventions targeting medication adherence reflecting the multidimensional construct of adherence. The lack of a gold standard adherence measure and the many limitations of the current measures were particularly discussed. Our findings are in line with current knowledge about diversity of adherence measures and expands the findings of our aforementioned 2019 systematic review on the scope of outcomes in studies of adherence intervention in rheumatology, we found 115 unique measurements of adherence using 37 different instruments . This inStudy findings have direct implications for informing our OMERACT Adherence Working Group’s efforts towards development of a core domain set for studies targeting adherence among patients with rheumatic diseases . The comStrengths of our study included collaborative development of the interview guide with Working Group members, interview pilot testing, purposive sampling for diversity of perspectives with member checking, investigator triangulation, and member checking. Limitations include interviewing only English speaking researchers and utilization of audio conferencing, which may have been associated with loss of non-verbal cues . On balaOverall, adherence intervention research in rheumatology has been hindered by lack of standardization and guidance on terminology, measurement and outcome selection , 8. UniqAdditional file 1. Interview guide.Additional file 2. The COREQ checklist.


Cancer cells often adapt their lipid metabolism to accommodate the increased fatty acid demand for membrane biogenesis and energy production. Upregulation of fatty acid uptake from the environment of cancer cells has also been reported as an alternative mechanism. To investigate the role of lipids in tumor onset and progression and to identify potential diagnostic biomarkers, lipids are ideally imaged directly within the intact tumor tissue in a label-free way. In this study, we investigated lipid accumulation and distribution in living zebrafish larvae developing a tumor by means of coherent anti-Stokes Raman scattering microscopy. Quantitative textural features based on radiomics revealed higher lipid accumulation in oncogene-expressing larvae compared to healthy ones. This high lipid accumulation could reflect an altered lipid metabolism in the hyperproliferating oncogene-expressing cells. Cancer is the second leading cause of death responsible for about 1 out of 6 deaths worldwide. According to the World Health Organization one defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries and then invade adjoining parts of the body and spread to other organs WHO, . These aC. elegans  has gained popularity over the last years and has been established as an in vivo cancer model offering many benefits. Zebrafish are small, easy, and cheap to house. Moreover, this small fresh water fish shares approximately 81% of human disease related genes  and second harmonic generation (SHG) imaging have been used for imaging zebrafish  and coherent anti-Stokes Raman scattering (CARS). In SRS, the signal is obtained by an increased intensity on the Stokes beam (stimulated Raman gain) or a decreased intensity on the pump beam (stimulated Raman loss), and thus SRS requires modulation schemes and lock-in or tuned amplifier detection approaches . CRS allows the use of the spectral focusing method to add a frequency dimension to the microscopic image allowing for fast and easy switching of the vibrational excitation frequency by means of chirped laser pulses  has emerged as powerful imaging tool offering a unique opportunity to image metabolism by tracking specific endogenous molecules of interest  up to 120 hpf and monitored changes that occur in the lipid content of an emerging tumor.In this paper, we performed hyperspectral CARS microscopy to investigate lipid metabolism in a zebrafish cancer model. The CARS microscope, based on a compact and cost effective femtosecond Ti:sapphire laser with an inherently synchronized high power Yb fiber amplifier for Stokes generation as described in Andreana et al. , was useD. rerio) were maintained at standard conditions  Tg(UAS:EGFP-Hsa.HRAS_G12V)io6 were used to target oncogene expression to the central nervous system . The volume containing the zebrafish larvae was then released into a sterilized glass bottom dish forming a semi-spherical volume  was added to the medium at 24 hpf. For imaging, zebrafish were manually dechorionated and larvae showing a healthy or strong RAS-mediated phenotype were selected and transferred to a small water tank. Before imaging, zebrafish larvae were anesthetized in 100 mg/L tricaine . Subsequently, larvae were transferred into a pipette with 250 l volume  to fix tl volume . The endl volume . This coIn vivo imaging of 120 hpf zebrafish larvae stained with Nile red, following the protocol as in Minchin and Rawls  fluorescence imaging has been used to countercheck the signal of the label-free contrast by means of CARS microscopy. Indeed, its potential as fluorescent lipid stain has been exploited for many years , we used mean and standard deviation to obtain the intensity levels of the selected ROI in the images. The mean provides measures of the overall lightness/darkness of the ROI, while the standard deviation describes its overall contrast. These measures are associated to the amount of lipid detected in a specific region. The identified ROI for these measurements corresponded to a single dorsal myotome of the zebrafish larvae  in RAS+ and RAS- larvae was performed and 120 hpf larvae were imaged by confocal microscopy to show triglycerides content. The comparative results of Nile red showing similar phentotype than the CARS images are shown in Additionally, we performed independent The CARS images from the longitudinal study from 72 to 120 hpf are shown in The observed lipid content in the CARS images has been investigated by means of mean and standard deviation of the intensity distribution within a single image and radiomic analysis as described in section 2.5. First, mean and standard deviations on a normalized ROI have been calculated. Results are highlighted in Second, for objective evaluation radiomics analysis has been performed. Dependence variance is a gray level dependence matrix (GLDM) metrics, which characterizes the gray value dependence size in the image. (i) Dependence is defined as the number of connected pixels that are dependent (similar) to a center pixel, meaning in case of more homogeneous textures this dependency is higher. (ii) Normalized non-uniformity measures the similarity of run lengths in the image. (iii) Run length refers to the number of consecutive pixels having the same values in the image. Lower non-uniformity value indicates that the run length similarities are lower, which corresponds to more heterogeneous patterns. Short run emphasis describes the distribution of short run lengths. Higher short run emphasis value indicates more fine textures. These three identified significant radiomic features had a negative correlation coefficient, implying that in case of RAS+ larvae these values are all decreased compared to RAS- larvae. This finding correlates with visual assessment, where RAS- cases represent a more balanced pattern, composed of small but homogeneous subregions. Overall, these findings indicate that the lower the dependence variance (surrounding pixels are different than center pixel), the lower the run length similarities (high variation in homogeneous subgroup sizes), and the lower the short run length emphasis , the more likely a tissue is malignant. For the distribution and correlation of these prominent features, see The results shown give an objective evaluation that hyperproliferative cells accumulate higher amounts of lipids compared to untransformed cells in our animal model from early stages on. Indeed, under non-pathological cellular conditions there is a balance between lipid production and the amount used. Recent studies have suggested that cancer cells with RAS mutations exhibit altered metabolism including an enhanced lipid synthesis (Oba et al., in vivo imaging of lipids in zebrafish larvae from 72 to 120 hpf has been performed by means of hyperspectral CARS microscopy. Lipid distribution was investigated in oncogene-expressing and healthy larvae by means of standard statistical tools and more advanced tools like radiomics. It was shown that multiple radiomic features have a significant negative correlation with the cancer state of zebrafish larvae. However, due to the small sample size for the radiomic analysis, further investigation with a larger cohort is needed in order to determine whether the discovered relation holds true in a more representative cohort. It has been demonstrated that CARS microscopy can be used to track lipid content in living larvae revealing increased lipids in tumor-developing zebrafish larvae. This trend has been confirmed by Nile Red staining experiments. Our results indicate that CARS microscopy is a suitable method to investigate lipid metabolism in living zebrafish larvae during development and tumor formation. We anticipate that using hyperspectral CARS microscopy will allow for detailed characterization of lipid metabolism alterations during tumorigenesis. Furthermore, we envision that our CARS microscopy approach can be implemented in label-free high throughput via radiomics automated screening platforms to identify compounds with anti-tumor effects by targeting lipid metabolism in zebrafish, which could ultimately be translated to clinical applications. Our platform could help to better understand mechanisms underlying cancer development. While the data and the analysis presented in this paper are preliminary and further investigation with a larger number of samples is required, our proposed approach based on the combination of radiomic analysis and label-free CARS microscopy has high potential for an improved understanding of lipid metabolism and for high throughput in vivo zebrafish drug screening.Label-free The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Ethical review and approval was not required for the animal study because in this study zebrafish larvae from 72 to 120 h-post-fertilization have been investigated which do not require any ethic approval.MA and AU collected and analyzed the CARS data. CS collected and analyzed the Nile red data. CPS and LP performed the radiomic feature analysis. CS and MD generated the zebrafish model and provided the zebrafish larva. MA, AU, CS, and MD wrote the manuscript. RL, WD, MD, and AU coordinated and supervised the experiments. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The targeted and conditional activation of pharmaceuticals is an increasingly important feature in modern personalized medicine. Nucleic acid nanoparticles show tremendous potential in this exploit due to their programmability and biocompatibility. Among the most powerful nucleic acid specific treatments is RNA interference-based therapeutics. RNA interference is a naturally occurring phenomenon in which specific genes are effectively silenced. Recently we have developed two different strategies based on customized multivalent nucleic acid nanoparticles with the ability to conditionally activate RNA interference in diseased cells as well as elicit detectable fluorescent responses.,2 These  Specifically, RNA has garnered attention through research exploiting its plethora of functionalities in sensing and treating various diseases. RNA interference (RNAi) which is the effective termination of specific protein production, serves as an important aspect of RNA therapeutics –13. RNAi occurs naturally through various pathways but can be taken advantage of synthetically using a number of designed RNA strands . The ability to simultaneously deliver and activate multiple functionalities (including but not limited to RNAi) would prove immensely beneficial to personalized medicine. Additionally, predicting the structure, folding, and tertiary interactions of RNA would greatly benefit and accelerate the design of therapeutics.Nucleic acid nanoparticles have become increasingly attractive in therapeutic research due to their high customizability and various functionalities while retaining biocompatibility and ease in production via introduction of split cognate strands –16. Each strand contributes half of a designed DS RNA duplex, which upon re-association and further dicing forms a functional therapeutic. The initially prepared non-functional DNA-RNA hybrids contain either ssDNA or, as in the highlighted work , ssRNA over-hangs of different lengths, called toeholds . This in silico approach supplemented in vitro experiments to confirm RNA structures and interactions.The previously mentioned functionality operates using DNA-RNA hybrids. An additional scheme has also been exploited using RNA-RNA interactions .[1] In tin vivo.The conditionally activated RNA nanoparticles, published back-to-back in Nano Letters , 2, offe. In a bacterial system, designed riboswitches that are responsive to temperature and binding of a ligand were recently shown to be able to regulate both transcriptional and translational efficiency . Such approaches are not necessarily in competition, but instead have different uses. The two aforementioned approaches are well suited for designing reporter genes or gene circuits but require the de novo design of genomic regions upstream of the translation start site of a gene. The conditional activation of RNA interference (the focus of this research highlight) on the other hand, is based on comparatively short synthetic noncoding RNAs that function in the context of human cancer cells and are thus closer to traditional small molecule therapeutics. Not only will it be interesting to compare these different novel tools for the “smart” control of gene expression: exciting opportunities abound to combine such approaches, leading to systems that allow ever more complex control of the cellular machinery by operating on different levels simultaneously.There are other approaches of designed RNA constructs that can switch between different conformations. For example, riboregulators have been developed, that enable protein translation conditional to the binding of a trigger RNA Overall, published techniques can be used in conjunction with pre-existing nucleic acid nanostructures thus increasing the control over the formulation and co-delivery of pharmaceuticals and biosensors for the treatment and detection of a large variety of diseases.


Current Issues in Molecular Biology (ISSN 1467-3045) was launched in 1999 and has published international and multidisciplinary articles on all aspects of molecular biology spanning from basic mechanisms to applications in fields primarily, but not exclusively, relevant to microbiology and virology. Current Issues in Molecular Biology, published by Caister Academic Press [Current Issues in Molecular Biology will be published by MDPI [ogy ISSN 467-3045  by MDPI .Current Issues in Molecular Biology, as it excellently complements the portfolio of MDPI journals [International Journal of Molecular Sciences [We are delighted to take over the publication of journals , provideSciences  and streCurrent Issues in Molecular Biology will publish papers which provide fundamental mechanistic and functional insights into molecular biology, in both eukaryotes and prokaryotes. MDPI will publish three issues in 2021, and four quarterly issues as of 2022. Current Issues in Molecular Biology!We look forward to publishing your work in


The COVID-19 pandemic has had a significant impact on patient lifestyles with new measures designed to reduce transmission of the virus drastically transforming life as we know it. Public health interventions — alongside advances in medical treatments, vaccine technology, and gene sequencing — have drastically reduced the impact of the pandemic across the world. Yet there has been relatively little focus on the potential role of physical activity (PA) in reducing disease burden during the pandemic. We discuss the latest evidence related to the role of exercise or physical pre-rehabilitation before infection and consider whether this may be an overlooked public health strategy.’hands, face, spaceandfresh air‘ appear prominently on all government briefings but exercise, once famously quoted as being the ‘miracle cure’ by the Academy of Medical Royal Colleges, is conspicuously absent. Despite the evidence supporting the physical and mental health benefits of exercise at a population level, there remains a void of information regarding how people can engage in PA safely during the pandemic and a lack specific targeted PA interventions for high-risk patient cohorts.As we progress through the second year of the pandemic, there has been a renewed focus on adjustments that individuals and society will have to make as we continually adapt to life with COVID-19. Key public health messages regarding the importance of  Physical deconditioning and low exercise capacity (cardiorespiratory fitness) are also associated with many adverse health outcomes such as premature death and increased cardiometabolic disease risk in adult and paediatric populations. Considering this, it has been proposed that structured interventions supporting PA may help to improve health outcomes for all patients and ameliorate the potential negative consequences of lockdown measures.During the last year, social distancing measures, home working practices, and restricted access to leisure and exercise facilities have had a major impact on individuals' opportunities to stay physically active. Several studies have reported that loneliness, physical inactivity, and weight gain have increased during the COVID-19 pandemic. The proposed benefits of PA are two-fold: acutely reducing hospitalisation and mortality, while reducing the risk of developing long-term cardiometabolic consequences . Furthermore, widening access to PA may reduce inequalities in COVID-19 outcomes observed in populations at higher risk from physical inactivity and metabolic disease, namely those from Black, Asian, and minority ethnic (BAME) groups.The presence of pre-existing cardiometabolic diseases, obesity, and lower PA levels have all been associated with worsening COVID-19 outcomes; a recent study reported that physically inactive patients are at increased risk of hospitalisation (odds ratio 2.26) compared to those meeting PA guidelines. A recent meta-analysis has also reported that regular exercise is associated with a higher antibody response to vaccinations and highlighted a potential link between regular PA and improved adaptive immunity to infectious diseases.It is predicted that COVID-19 is likely to have a significant burden on healthcare systems worldwide for many years to come, with the prospect of future pandemics. Any efforts to physically pre-habilitate people are likely to be of benefit. In the first instance, PA, — alongside interventions to promote healthy diets, working, and educational policies — could reverse the trend of rising rates of obesity. Exercise can also improve patients’ immune function, metabolic profile, and cardiorespiratory fitness, raising their baseline physiological reserve and ability to respond to acute infection. The role of exercise for health benefits in the general population is highlighted in the UK Chief Medical Officers’ and World Health Organization guidelines  where rehabilitation and structured exercise have been shown to reduce disease severity, reduce healthcare utilisation, and improve patients’ quality of life.idelines , which rBox 1It is recommended that:All adults should partake in regular physical activity.Adults should do at least 150–300 minute of moderate-intensity aerobic physical activity or 75 min–50 minutes of vigorous intensity of aerobic physical activity, or a combination of moderate and vigorous intensity activity throughout the week for an increase in health benefits.Adults should also do muscle-strengthening activities at moderate or greater intensity that involve all major muscle groups on 2 or more days a week, as these provide additional health benefits.Sedentary behaviour:Adults should limit the amount of time spent being sedentary. Replacing sedentary time with physical activity of any intensity (including light intensity).A greater awareness of these programmes could help to promote PA in high-risk groups, or be adapted to pre-habilitate patients to provide similar benefits during the pandemic. Sustained efforts to promote PA must be initiated across society so that interventions go beyond the niche of specialised secondary care pathways and integrate into primary care. Access to remote or telehealth-based exercise initiatives, alongside social prescribing and active policies in work and school environments, may help patients to become more active.Evidence-based PA promotion programmes, when integrated into local sports or community facilities, have been shown to increase participation in exercise and encourage positive behaviours change.Low levels of physical activity and cardiometabolic risk factors are associated with worsening health outcomes from COVID-19. Public health initiatives designed to promote PA and reverse the trends of rising physical inactivity and obesity levels in the population could improve outcomes for individuals during the pandemic. In order for this to be successful, PA interventions based upon existing rehabilitation programmes will need to be repurposed and delivered at scale to help all patients stay active during the pandemic.


To identify ethical values guiding decision making in resetting non-COVID-19 paediatric surgery and maternity services in the National Health Service (NHS).A rapid review of academic and grey literature sources from 29 April to 31 December 2020, covering non-urgent, non-COVID-19 healthcare. Sources were thematically synthesised against an adapted version of the UK Government’s Pandemic Flu Ethical Framework to identify underpinning ethical principles. The strength of normative engagement and the quality of the sources were also assessed.NHS maternity and paediatric surgery services in England.Searches conducted 8 September–12 October 2020, and updated in March 2021, identified 48 sources meeting the inclusion criteria. Themes that arose include: staff safety; collaborative working – including mutual dependencies across the healthcare system; reciprocity; and inclusivity in service recovery, for example, by addressing inequalities in service access. Embedded in the theme of staff and patient safety is embracing new ways of working, such as the rapid roll out of telemedicine. On assessment, many sources did not explicitly consider how ethical principles might be applied or balanced against one another. Weaknesses in the policy sources included a lack of public and user involvement and the absence of monitoring and evaluation criteria.ethics-lite, with sources mentioning principles in passing rather than explicitly applying them. This leaves decision makers and healthcare professionals without an operationalisable ethical framework to apply to difficult reset decisions and risks inconsistencies in decision making. We recommend further research to confirm or refine the usefulness of the reset phase ethical framework developed through our analysis.Our findings suggest that relationality is a prominent ethical principle informing resetting NHS non-COVID-19 paediatric surgery and maternity services. Sources explicitly highlight the ethical importance of seeking to minimise disruption to caring and dependent relationships, while simultaneously attending to public safety. Engagement with ethical principles was  The first review to identify the ethical principles guiding decision making in maternity and paediatric services as England’s National Health System delivers non-urgent, non-COVID-19 healthcare during the pandemic.We conducted a rigorous rapid review of sources from policy, academic and grey literature databases.Our approach to qualitative synthesis and appraisal of sources against the Appraisal of Guidelines for Research and Evaluation II (AGREE-II) tool identified areas where ethical guidance and policies lack clarity and fail to implement patient and public involvement.Our coding framework is based on the 2017 UK Government Pandemic Flu Ethical Framework, adapted according to two policy sources that met our inclusion criteria, presenting possible methodological tensions.An initial Reset Phase Ethical Framework has arisen out of our inductive qualitative synthesis of sources for others to apply and refine.must resume alongside the capacity for subsequent waves of COVID-19.The COVID-19 pandemic is causing far-reaching consequences for health systems worldwide. In England, the response to the sudden demand for critical care services was to reorient clinical capacity. Many non-urgent services were suspended, and staff and resources were redeployed to acute care.Our review asked: which ethical values (explicitly or implicitly) guided decision making in non-COVID-19 paediatric surgery  and maternity services  during the initial NHS reset in England? We focused on maternity and paediatric services because professional and patient organisations have highlighted adverse impacts on these areas due to measures to respond to COVID-19 infections,15 16The pandemic, with emerging evidence and uncertain outcomes, rapid adjustments to healthcare policies and practices—both for the acute and now the reset phase—and uncertainties around personal risk, has created a particularly challenging decision-making context. The ethical values guiding the resumption of non-COVID-19 health services are likely to differ from the everyday ethical frameworks relied on prior to the pandemic. The acute phase of the UK’s response to the pandemic has been guided by the Pandemic Flu Ethical framework,We adopted a rapid review methodology appropriate to addressing urgent demands for synthesised evidence,10.1136/bmjopen-2021-049214.supp1Supplementary dataWe included sources that: (A) were developed to guide non-COVID-19 paediatric surgery and maternity services, or (B) discussed the application of ethical values to paediatric surgery and maternity services in England during the reset phase. The reset phase commenced on 29 April 2020, the day NHS services were instructed to prepare delivery of non-COVID-19 surgical services,Resume all non-urgent services incorporating revised COVID-19 infection prevention and control measures.Prepare for, and manage, second or recurrent waves of COVID-19 infections.Embrace opportunities to reconfigure health services .Accordingly, our inclusion criteria were: sources published after 29 April 2020, relating to non-COVID-19 paediatric and maternity services in the NHS in England, discussing decision making with implicit or explicit reference to ethics and written in English. A cut-off date of 31 December 2020 was introduced when conducting the updated searches in March 2021, as this is when the Health Foundation COVID-19 policy tracker ended. We took an inclusive approach to data sources that met the inclusion criteria if they were national (UK wide and applicable to England), NHS Trust or local policies and directives; guidance or statements from professional bodies; working papers or committee reports; evidence reviews; primary qualitative or quantitative research; peer-reviewed commentaries; or grey literature discussing experiences of paediatric or maternity services in England during the reset phase.Searches were conducted between 8 September and 12 October 2020 by AC and PB, and updated between 10 and 21 March 2021 by AC. For academic sources, we searched the bibliographic databases PubMed and PubMed LitCOVID, and clearing houses of COVID-19 related research, including the EPPI Centre Living Map of COVID-19 evidenceWe developed a search strategy see , which wHow we make decisions’ and ‘Our policies and procedures’. Included documents were read in full and coded against the coding framework by CR  taken. Where a source met multiple screening categories, all were identified. This categorisation approach sought to provide an initial sense of the depth of sources to inform full-text analysis. Grey literature screening was conducted in a shared Excel spread sheet and for academic sources using Rayyan software.37Third phase of the NHS response to Covid’, a letter issued by the NHS Chief Executive and Chief Operating Officer to all NHS Trusts,Five Principles for the next phase of the Covid response’, developed by a coalition of UK health and social care charities.In order to conduct a thematic synthesis of sources, we developed a coding framework for the reset phase. This was based on the Pandemic Flu Ethical FrameworkOur approach raises a methodological tension as our coding framework draws on two sources relevant to the review but which were excluded from it. It was, however, justified given the lack of an overarching ethical framework tailored to the reset phase and the need for a coding framework that reflects the ethical specificities of this phase. We will consider this further in the Discussion.Alongside our thematic synthesis, we assessed the extent to which ethical principles were identified, operationalised and balanced against one another using a 1–3 scale where: (1) ethical principle(s) inferred or mentioned but not clearly applied; (2) ethical principle(s) identified and application described; and (3) ethical principle(s) operationalised, that is, discussed in-depth, including balancing against other principles. This scoring system was an adaptation of our protocol: we had intended to apply the ‘review of reasons’ approach,Policy sources  were appraised for quality using an adapted version of the AGREE-II instrumentAs this was a rapid review, there was no patient or public involvement.We present the results of searches, screening, the characteristics of included sources and the data analysis. We also separately present a case study example of the publication scheme review from one NHS Trust. No FOIA responses providing relevant materials were received.Academic and grey literature searches identified 19 405 sources . After removing duplicates, 18 766 results were screened, with 18 316 excluded as not relevant. Four hundred and fifty sources were assessed for eligibility by title and abstract or, where necessary, full-text screening. Of these, 360 were excluded as being outside the review scope, and on full-text review a further 39 sources were excluded. Therefore, searches identified 48 sources for analysis see .45safety of NHS staff was most frequently coded, with recovering the operation of healthcare and embracing new ways of working explicitly identified slightly less frequently. Staff safety was understood broadly, encompassing Personal Proective Equipment (PPE), testing and isolation protocols, the importance of staff well-being (including leave) and the importance of ongoing staff training.unvoiced concerns’post-Covid assessment Services’.62All sources explicitly referenced or applied the principle of recognising harms and balancing these against possible benefits. The subdomain of contact, connections, and interactions with patients’ while accounting for individual needs and circumstances.Respect was a frequently explicitly considered principle, encompassing keeping people informed and respecting personal decisions about care, including acknowledging patients’ right to express views on matters affecting them both directly and through organisations such as the Maternity Voices Partnership.turning on the tap at one end will not necessarily release the flow at the other — there are multiple taps which need to be released in a sequential fashion’.Maternity staff cannot be replaced by other staff groups due to their specialist skill set and protecting this workforce from unnecessary risk is therefore crucial to ensure that maternity care can be sustained’62Collaborative working was explicitly referenced, recognising the codependency of elements of the health service: ‘… it is important to consider the needs of surgical patients on an equal footing with those receiving care for COVID-19 and other medical diseases’.timely and safe discharge’ to maximise the capacity to respond to ongoing waves of COVID-19 infections.5 59Inclusivity in service delivery was emphasised under the principle of fairness. Barriers to maternity care such as English language abilities, immigration status and individualised factors—including risk of domestic abuse or history of human trafficking–were identified.Under the principle of reciprocity, the subdomain of everyone taking actions to protect healthcare workers and patients was explicitly emphasised. Notably, this recognised the increased risks and burdens faced by healthcare staff and those at increased risk of COVID-19 infection and poor outcomes, such as members of BAME communities.62 64The analysis led to iterative inductive evolution of the coding framework, adding subcategories identified in italics in Scoring sources for their practical usefulness to healthcare professionals highlights that nearly half explicitly identified key ethical principles but failed to offer advice about how they might be used in decision making (22 scored 1). Broad statements about core principles were often made, such as respect for patients and minimising harms that were frequently mentioned in relation to infection prevention and control. Nineteen sources scored 2 for clearly identifying ethical principles and suggesting how they might be applied; for example, by identifying decision-making support tools eg, ref . Seven sWe present initial findings from one NHS Trust publication scheme review see . As withOur pragmatic rapid review identified the ethical principles referenced in published academic and grey literature and decision-making guidance informing the resetting of NHS paediatric surgery and maternity services. A key review outcome is a reset phase ethical framework inductively developed based on the sources reviewed . Our resRelationality was reflected in numerous ways, anchored in the individual and organisational mutual dependencies and responsibilities that have been starkly highlighted by the COVID-19 pandemic. The ethical importance of attending to the adverse impact of the COVID-19 on caring and dependent relationships, seeking to minimise disruption to these as much as possible to meet the needs of patients and family or carers while simultaneously attending to public safety is one example. In our review, the relational context of decision making was prominent, reflecting family and caring relationships inherent to our areas of focus: birthing partners in maternity care, and parents or carers in paediatric services.jarring and unwelcome’ (p. 871) shift in ethical framing that clinicians must negotiate.how they ought to be operationalised must be clear. Guidance lacking this dimension leave healthcare professionals without a coherent ethical framework to support decision making,Research in psychology has demonstrated that when people are working in stressful situations under pressure of time, with access to extensive yet conflicting information from multiple sources, and when outcomes are uncertain, they tend to make more decisions based on intuition, gut feelings, or heuristics (rules of thumb) rather than on rational thinking ’ (p. 2).73 78Our assessment of the level of engagement with ethical principles found them to be ‘ethics-lite’. While key principles were referenced, sometimes only in passing, many sources failed to operationalise them. We define operationalisation as applying ethical principles to specific situations, considering how predictable ethical dilemmas might be managed or offering suggestions as to how, in practice, ethical principles might be balanced against one another. This is especially important when the ethical approach moves between individual-focussed clinical care and wider public health measures, which is recognised to produce a ‘equal concern and respect as the underpinning principle,fairness, chiefly that everyone matters equally and is weighted equally, has emerged as an underpinning principle. However, our review demonstrates that the NHS operational context in the reset is ethically distinct. The underpinning principle of fairness must be balanced across considerations such as the impact of delayed care; constraints of infection prevention and control measures; broad mutual interdependencies between healthcare providers, patients and the public; and uncertain COVID-19 risks—exacerbated by inequalities and intersectionalities—for healthcare providers and patients. These considerations foreground complex, layered configurations of interdependencies and relationships embedded within healthcare provision in the reset. Ethical frameworks may assist decision makers to navigate this challenging decision-making context. Consequently, in contrast to the UK Chief Medical Officers advice not to produce updated ethical guidance for the COVID-19 pandemic,urgently requires a tailored approach.Our reset ethical framework, inductively developed through this review, offers a useful starting point. Additional research is required to confirm or further refine its congruence with the decision-making processes of individual Trusts and healthcare providers, embedded within their regional and systemic relationships and to areas of healthcare beyond paediatric surgery and maternity services. This forms part of our ongoing research activities. Recognising the importance of our review finding that ethical frameworks should be operationalisable, we briefly explain how our reset ethical framework could be applied in practice. The Pandemic Flu Ethical Framework emphasises the NHS is accountable to the public, communities and patients that it serves’.90Appraising sources against the AGREE-II tool identified a lack of monitoring and auditing systems for rapidly adjusted policies and practice guidance, which is concerning given the reported impacts on some areas of patient care. It also showed a lack of public involvement beyond, at best, patient representatives,Our review maintained methodological rigour by including a systematic search strategy where possible and double screening and double coding 25% of sources. Team discussions to develop the coding framework and reflect on emerging findings were also ongoing throughout. We adopted an inclusive approach to grey literature and academic sources, ensuring the relevance of our review to healthcare policy and practice. This was complemented by the publication scheme review, which indicated the application of guidelines to situated Trust-level decision making. However, methodological limitations remain, chiefly that the rapidity of the review rapidity necessarily limited its scope and depthThis review has sought to render explicit the ethical values underpinning decision making specific to the reset phase, yielding important learning for healthcare policy makers and Trust decision makers. Our findings suggest that some key ethical and legal duties—such as involvement–have been immediate casualties of the time-pressured decision-making context. We accept that there may be significant logistical barriers to achieving meaningful engagement and that compromises during a crisis may be required.how health services resets will continue to be necessary. We are supporting this process by publishing our proposed reset ethics framework here. This has been inductively developed based on the sources included in this review. We continue to refine this framework through our ongoing empirical and conceptual research.This review adds to the rapidly evolving evidence on England’s health systems’ response to the COVID-19 pandemic, focusing on the normative foundations underpinning the resetting of NHS health services in maternity and paediatric surgery services, alongside a continuing response to the demands of COVID-19. It is important that the government and professional bodies continue to engage with the difficult ethical decisions this requires, and we recommend increased public involvement in this process to build solidarity in supporting the required responses. Our review has found that to date, guidance developed for this period are ethics lite and fail to provide an operationalisable ethical framework for decision makers and healthcare professionals. Addressing this is an important priority as the NHS in England moves further into the reset period, where difficult ethical decisions about


Emotional blunting is frequently reported by patients with major depressive disorder (MDD) and has been identified as one of the most prominent side effects of antidepressants leading to medication discontinuation. However, antidepressant-induced emotional blunting remains largely unexplored—there lacks a clinical definition of this condition, and no agreeing conclusion has been reached regarding its etiology. Current research suggests that the onset of diminished emotional response may be related to antidepressant dose, with higher doses being more likely to induce emotional blunting. Consequently, most clinicians either reduce the dose or switch to another drug when treating this symptom. Overall, more comprehensive clinical assessments or interviews specifically designed to evaluate antidepressant-induced emotional blunting in MDD patients are in need to elucidate the neuropsychological mechanisms behind this increasingly prevalent symptom. Depressive disorders have been estimated to be the third leading cause of years lived with disability for all ages worldwide, and the global prevalence of MDD has significantly increased over the last few decades . The WHOMost evidence-based clinical practice guidelines recommend antidepressants as the first treatment step for MDD , 10. FroEmotional blunting is also considered a potential side effect of antidepressants, in particular SSRI antidepressants, and has been reported in multiple case reports and clinical studies. It was estimated that about 40–60% of patients who suffered from MDD and were treated with either SSRIs or serotonin-noradrenaline reuptake inhibitors (SNRIs) had experienced some degrees of emotional blunting , 21. In Emotional blunting is a condition present in many psychiatric disorders, including depression, schizophrenia  and postMany patients diagnosed with MDD and treated with SSRIs described a restriction or diminution in the intensity or frequency of emotions common in everyday living and essential for daily functioning , 25. ForDespite lacking a clinically preferred scale and a clear clinical definition for antidepressant-induced emotional blunting , a few qA more recently developed instrument is the Oxford Questionnaire on the Emotional Side-effects of Antidepressants . It is One limitation with all current psychometric assessments on antidepressant-induced emotional blunting is that there is no clinical definition or a standard measure of emotional blunting, making it difficult to test the accuracy of these evaluations . MoreoveA substantial amount of subjective evidence suggests that emotional blunting is induced by antidepressants and is different from the emotional states experienced during depressive episodes , 31. ForSome researchers argue that emotional blunting is not only a simple side effect of antidepressants but also a residual symptom of depression. They believe that emotional blunting is a symptom of depression that is not measured in conventional scales and is often incompletely treated with SSRIs . In one A later study was conducted among 17 healthy volunteers who received either 7 days of bupropion, a norepinephrine-dopamine reuptake inhibitor, or placebo . ContrarNevertheless, emotional blunting is a relatively subjective symptom, and studies directly measuring emotional blunting in the form of interviews or questionnaires should also be conducted to determine whether the symptom occurs in healthy controls taking antidepressants. In all, although most studies agree that antidepressant treatment induces emotional blunting in patients with MDD, a few studies suggest that the numbing of emotions could also be a residual symptom of MDD due to incomplete treatment.The first antidepressants were discovered by chance more than 60 years ago and were later found to promote serotonin (5-HT) or noradrenaline (NA) function in the central nervous system –43. Almovia serotoninergic effects  systems that project to the prefrontal cortex , 53. As As mentioned earlier, almost all current explanations for antidepressant-induced emotional blunting in patients with MDD revolve around SSRIs and the neurotransmitter serotonin. However, patients taking other types of antidepressants have also reported blunted emotions as a side effect of antidepressant use . Thus, fOn the one hand, antidepressants successfully reduced the emotional distress patients experienced during their depressive episodes; on the other hand, unwanted outcomes like reduced sociability and emotional detachment from family urge managements targeting the emotional side effect of antidepressants. The first option to consider is reducing the dosage or discontinuing the medication , 53. Som2c antagonist, while vortioxetine is often classified as a serotonin modulator and stimulator .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


V mimicus in a 56-year-old male, who was transferred from an outside hospital to the inpatient burn unit after sustaining traumatic and burn injuries in a firework explosion accident. The patient underwent surgical treatment and antibiotics with good improvement. Although rare, our case study will help to underscore the important role of V mimicus as a human pathogen.Burns are one of the most common and devastating forms of trauma. Burns are a significant problem with high associated morbidity and mortality worldwide. Burn wound infection is a serious complication, which plays an important role in increasing the overall fatality rate in burn patients. In this study, we report a case of the polymicrobial burn wound infection involving  Streptococcus pyogenes was the predominant pathogen implicated in burn wound infections and was a significant cause of death in severely burned patients Staphylococcus aureus becomes a common cause of early burn wound infections Pseudomonas aeruginosa represents a major concern in burn patient care settings [V mimicus soft tissue infection in a burn patient with multiple traumatic injuries.Burns are the fourth most common type of trauma worldwide and contribute significantly to the burden of death and disability settings ,8. Here V mimicus and Aeromonas hydrophilia, and the antibiotic regimen was narrowed to cefepime only. Vancomycin and metronidazole were discontinued. After wound cultures from a secondary surgical debridement of the right leg again grew V mimicus and now Pseudomonas stutzeri, the patient elected to undergo a right above-knee amputation for source control of acute osteomyelitis and soft tissue necrosis. Subsequent wound cultures from above the right knee amputation site grew Candida albicans. The patient was started on fluconazole as there were operative plans for a right latissimus dorsi flap. He was eventually discharged to a skilled nursing facility on fluconazole and cefepime for six weeks total from when he first cleared his wound cultures. This patient was fitted with a prothesis and made a full recovery with good return of functional performance status post-amputation.A 56-year-old male with a medical history of polysubstance abuse and hypertension was transferred from an outside hospital to the inpatient burn unit after sustaining traumatic and burn injuries in a firework explosion accident one week prior. Upon admission, he was afebrile and hemodynamically stable . His complicated injury complex included first and second-degree burns to the face, right upper, and right lower extremities; right deltoid wound with exposed humerus suggest picture reference of the abdominal wall, leg and shoulder; right lower extremity open wounds status post debridement now with vacuum-assisted closures; foreign objects in the scrotum, left medial thigh, and medial forearm status post scrotal repair with staples; and, a right open tibial-fibular fracture status post open reduction internal fixation (ORIF) with overlying wound and exposed hardware . He had Vibrio species are water microorganisms commonly found in marine or brackish water environments. Among currently described Vibrio species, Vibrio cholerae, Vibrio vulnificus, and Vibrio parahaemolyticus are most frequently associated with human illnesses [V cholerae is the etiological agent of cholera, a severe diarrhea. Non-cholera Vibrio species such as V vulnificus, and V parahaemolyticus, cause vibriosis, a group of infections with different clinical manifestations depending on the pathogen species, route of infection, and host susceptibility V mimicus was identified in 1983, and it has been recognized as an uncommon cause of gastroenteritis occurring after recent ingestion of seafood and in acute otitis media after exposure to seawater V mimicus are nonhalophilic and can live in fresh water. A large foodborne outbreak caused by V mimicus involving 306 people was related to the ingestion of dishes containing freshwater fish and seafood in Chiang Mai, Thailand V mimicus infection among four persons associated with crayfish consumption was reported in Washington State, USA V mimicus was identified by Vitek 2, which is a fully automated system that performs bacterial identification using fluorescence-based technology. Microscopic examination of a gram-stained smear confirmed that this bacterium is gram negative bacillus. On sheep blood agar, V mimicus is beta hemolytic, and on MacConkey agar is non-lactose fermenting (V mimicus and wound) search in PubMed did not identify any other previously reported cases. Burn infections can occur at the healthcare facility, but commonly at the time of burn. Environmental pathogens as fungi and water-borne bacteria are highly likely to occur at the burn environment even if it took days or weeks to manifest. The patient's infection was likely acquired at the burn site due to contamination of burn with stream water. The choice of ORIF in a burn heavily contaminated wound is likely suboptimal. Open well-drained wounds with external fixators as needed is likely a better option for avoiding aggressive severe infections as Vibrio species.llnesses ,10. Humarmenting . PolymicV mimicus in a burn patient with multiple traumatic injuries. Although rare, our case study will help to underscore the important role of V mimicus as a human pathogen.In summary, we present the case of burn wound infection associated with TP, MY and AY: designed the study and wrote the manuscript.Approval from the ethical committee was not required due to the nature of this case report. Abiding by the Declaration of Helsinki, patient anonymity was guaranteed.