Conventional seismic rehabilitation methods may not be suitable for some buildings owing to their high cost and time-consuming foundation work. In recent years, viscoelastic dampers (VEDs) have been widely used in many mid- and high-rise buildings. This study introduces a viscoelastic passive control system called rotary rubber braced damper (RRBD). The RRBD is an economical, lightweight, and easy-to-assemble device. A finite element model considering nonlinearity, large deformation, and material damage is developed to conduct a parametric study on different damper sizes under pushover cyclic loading. The fundamental characteristics of this VED system are clarified by analyzing building structures under cyclic loading. The result show excellent energy absorption and stable hysteresis loops in all specimens. Additionally, by using a sinusoidal shaking table test, the effectiveness of the RRBD to manage the response displacement and acceleration of steel frames is considered. The RRBD functioned at early stages of lateral displacement, indicating that the system is effective for all levels of vibration. Moreover, the proposed damper shows significantly better performance in terms of the column compression force resulting from the brace action compared to chevron bracing (CB). In the last three decades, structural control systems have been greatly improved to confront natural hazards such as wind and earthquakes ,2. ThreeBy carrying out a review of bracing systems prior to presenting the proposed system has put the idea into perspective. Braced frames are designed to resist both gravity and lateral loads in beam bending and column compression, and axial compression and tension, respectively. Numerous braced frame types exist including K-bracing, V-bracing, X-bracing, CB and single diagonal . In ordeThe nonlinear cyclic response of the brace dictates the dissipation of seismic energy in a Chevron braced frame (CBF). Cyclic axial force deformation behavior of a brace is asymmetrical in tension and compression and buckling effects often result in significant strength and stiffness deterioration . TherefoThere is a concurrent determination of structural members, such as beams, braces and columns, during the design of bracing system dampers. This allows the frame to be designed with prior knowledge of the high axial forces generated by the braces. Conversely, a braced seismic protection design should consider how the brace attachment to the initial frames can be affected. When CB systems are used to protect frames from seismic activity, column failure can be induced following an increase in compression forces in the adjacent column to the added bracing member. In addition, the vertical unbalanced force (VUF) can result from CBF brace buckling, with these VUFs having high buckling potential within stories . These sThis article investigates a VED system for seismic retrofitting of steel moment frame structures using ABAQUS for FE modeling. Static and cyclic tension tests are conducted because they are essential for input into ABAQUS to define the hyperelastic function, in addition, since the likely deformation state for the damper will be simple shear, the finite element analysis (FEA) results of the VEM under shear force are compared with experimental results to ensure the validity of the modeling of the VEM behavior. In columns, compared with chevron bracing, lesser increase in compression force is observed under pushover cyclic loading. Cyclic loading tests of the steel moment frames disclose the fundamental characteristics of the proposed damper. In order to estimate the effectiveness of RRBD under sinusoidal excitation, a small scale laboratory model underwent shaking table tests both with and without the proposed damper system.The suggested damper uses VE pads sandwiched between steel plates to provide shear resistance , ensurinThe damper is based on the pushing and pulling of chevron brace members as well as slight rotational shear. When a frame structure is displaced in the horizontal direction, the damper steel plates connected to the CBs slide along with the bracing members, allowing the bracings to pull and push the rubbers; thus, energy dissipation occurs as bracings are subjected to tension and compression. The following sections will show that the VEM has a moderate initial stiffness at strains lower that 60%. However, the stiffness is reduced at mid-range strains around 90% and strains in excess of 90% cause the rubber to have a stiffening or hyperelastic effect. Nevertheless, the specific VEM compound largely dictates the levels at which these stiffness changes occur. As such, the VEM stiffness behaviors have been incorporated into the RRBD design, which will be discussed further in the next sections.The following parameters are used to control the behavior of the RRBD system:Rubber thickness (T)Rubber diameter (D)Aspect ratio (D/T) of the deviceNumber of rubber pads that directly affect the shear areaStrength of VE material; cored holes in the VEM can reduce the stiffness (k)Different types of rubber, e.g., natural rubber, high-damping rubberDynamic constitutive behavior of VEMABAQUS ver. 6.12 is used to conduct FE modeling of the materials used in the construction of the damper . The cycThis section discusses the development of an analytical FE model for the RRBD. It is necessary to understand the behavior of rubber in order to create a device that uses rubber materials; therefore, the material properties of the rubber need to be ascertained through the use of appropriate models in order to analytically model a VEM.A suitable numerical rubber model should consist of hyperelasticity that describes the variation of the elastic modulus at large strains and the viscosity of the rubber. Hybrid elements are used for nearly incompressible materials, like rubber with high Poisson ratio. Simplistically, under loading conditions, rubber exhibits a high volume change resistance with this assumption of incompressibility being considered an important aspect of rubber’s mathematical models. Many different models such as Arrude-Boyce, Van der Waals, Mooney-Rivlin, Neo-Hookean, Ogden, polynomial, reduced polynomial, and Yeoh exist for the hyperelasticity of rubber .I1 in the from of (I1-3) and material constants C10, C20, and C30:1 is the first invariant of the right Cauchy-Green deformation tensor, and C10, C20, and C30 are material constants that are determined from experimental data when a rubber specimen is under uniaxial load. Furthermore, in contrast to other higher-order models, Yeoh’s model is only dependent upon the first strain invariant and can fit many different deformation models by using only uniaxial tension test data. This reduces the material testing requirements. For uniaxial tension, 1 is a function of λ and is expressed as I1 = λ2 + 2λ-1.For numerical simulation, FEA is performed to obtain the shear stress—strain relationship for various elongation levels of the specimen and to evaluate shear behavior of VEM, because the deformation state for the device will be shear. The FE model considers both material and geometric nonlinearities. However, owing to the incompressibility of rubber, i.e., Poisson’s ratio close to 0.5, conventional solid elements can result in large errors. There is some uncertainty regarding the actual value of rubber's Poisson's ratio . In thisTo perform a 3D simulation of the steel parts of the device, an eight-node first-order 3D linear hexahedral element with three degrees of freedom per node is used. This is the cubic element C3D8R, with one integration point in the middle of the element in addition to those at the corners. This element was chosen instead of C3D20R because beam-column corners are slightly bent and because the analysis has lower time cost despite providing a sufficiently accurate result.exp) and tensile force (Fexp) were measured.To obtain the material properties of the VEM, both monotonic and cyclic uniaxial tensile tests were conducted based on the procedure detailed in ISO37 , and theexp and Fexp, the nominal stress Pexp and stretch λexp were calculated using 0, the initial gauge length.From the measured IAll four rubber specimens collected for the uniaxial test had the same thickness with maximum difference of 0.2 mm. The specimens tested are shown in ABAQUS provides a convenient ‘Evaluate’ option that allows the users to view the behavior predicted by a hyperelastic or viscoelastic material and that allows researchers to choose a suitable material formulation. It is possible to use the Evaluate option to calculate the material’s response based on the experimental data using the strain energy potential that researchers have specified in the material definition. Any strain energy potential coefficients and any material instabilities identified during the tests should also be reported. 2. During the vulcanization process, the rubber was bonded to the steel plate and the bond was stronger than the rubber. A number of well-known earthquake events, such as the Northridge  and the Kobe , lay within a frequency range of 0.14–1.12 Hz. As such, the rate dependent behavior of the sample was evaluated at five test rates  and at various strain levels  as illustrated in the shear test set-up in A standard double sandwich specimen was used as the shear specimen. The material's nonlinear elasticity is represented by hyperelastic material model but no time dependence. The overall material behavior in terms of nonlinear elastic and strain-rate dependencies can be predicted by the hyperelastic plus VE material model. In other words, a single stress relaxation curve can present the VE properties of the rubber regardless of the strain level. The time dependent stress response is measured in a stress relaxation test under constant strain level of specimen. To do so, a mechanical strain is suddenly imposed to the middle steel plate and held constant. Stress relaxation test was conducted at 30% strain for 250 records. The results of the test are depicted in The results are discussed in four parts: verification of VEM modeling, verification of moment resisting steel bare frame (BF), cyclic analysis of frame equipped with a damper and the shaking table test. The hyperelastic function in ABAQUS is determined by only tension inputs. However, accurate modeling of the shear behavior is critical due to the probable damper state which is simple shear. In order to evaluate the occurrence of stress softening in both directions, the samples were tested to both extremes and results revealed that strain in negative direction had a softening effect in the positive direction. Any increase in displacement amplitude causes a decrease in the tilt angle and an increase in the enveloping area of the hysteresis curve as indicated by The geometrical properties of the FE model in this study are similar to those of the steel moment frame tested by Hou and Tagawa. Bolted T-stubs cut from H-300x150x6.5x9 (steel grade: SS400) connected the column and beam members of H-150x150x7x10 (steel grade: SN400B) . Fig 8 sPushover cyclic loading and a parametric study for a frame with a damper are conducted, and the results are compared. The latter includes different components of the RRBD, and it investigates the effects of the rubber thickness and rubber diameter of the RRBD on the frame behavior. The models are subjected to cyclic loading with the same protocol as in Hou and Tagawa’s experimental test , as showThis section discusses the numerical analysis results for the considered moment frames subjected to cyclic loading. A comparison of the results indicated to reveals the characteristics and advantages of the damper system. In theory, the dimension and number of VE layers is not limited, which suggests that by utilizing numerous rubber pads of varying dimensions it would be possible to design an RRBD with different stiffness and energy dissipation values. In order to prevent any buckling of the brace, it is necessary to ensure that the buckling stiffness of the brace is higher than the total stiffness of the whole damper. Therefore the frame’s stability will be increased by evaluating the proper behavior of the brace. This also was accounted for in the design of the device by identifying that the buckling point of the brace was never reached even at maximum frame displacement. In max), energy dissipation (ED), and ratios of each value with respect to the BF. The stiffness can be measured as the average slope of the displacement-force hysteresis loop, while the energy dissipated per cycle of motion is the area of displacement-force hysteresis loop that is defined as:Any subsequent variation in the VEM volume along with an increase in the thickness and diameter affects parameters such as the stiffness, maximum load, and energy dissipation of the damper. An increase in the VEM thickness, as opposed to an increase in the diameter, can result in a reduction in the maximum induced load and stiffness.2 to 1.71 m/s2. This was due to an increase in stiffness and damping of the structures caused by the RRBD. As can be seen, a disturbance occurred at the beginning of the movement of the shaking table (point A) and at points B and C. After inspection, it was determined that this was due to the sudden movement and sudden stoppage of the shaking table at the start point of the shaking table movement and at time of five seconds, as captured by the sensitive accelerometer. Whilst the increase in stiffness may cause an increase in acceleration responses, it is considered that the increased stiffness and damping of the structures will effectively mitigate displacement responses.The displacement reduction, initial stiffness level, deformation capacity ratio and other properties of RRBD obtained from the experimental test and simulations are listed in Skeleton curves of the seven specimens were obtained by connecting the peak points at each loading increment of the hysteretic curves, as depicted in Cyclic analyses were conducted for the considered three-story model frames, as depicted in The compression force of the left-side column of the first story was monitored to examine the effect of the damper. A new VE energy dissipation device was introduced to protect structures against lateral movements. This damping device uses readily accessible materials that can be installed in structures. The performance of the rubber material was evaluated through an experimental test and FE analysis. The VEM is considered to have a fine energy dissipation capacity as indicated by the smooth, plump ellipses of the hysteresis curves. Increased excitation rates caused an increased angle of inclination of the hysteresis with fixed displacement amplitude; this indicates that VEM stiffness was positively correlated with excitation rate. There was also a corresponding increase in the areas of the hysteresis curves that represented the energy dissipation capacity. Moreover, an increase in displacement amplitude resulted in an angle decrease and a larger hysteresis loop. The damper was installed at CB. It included of a number of steel plates and vertical rubber layers for providing a shear viscoelastic behavior after a dynamic excitation such as earthquake. The amount of energy dissipation of the RRBD was disclosed to be desirable through FEA and detailed parametric studies. Analyses resulted in recommendation of proper ranges of parameters for design purposes of the introduced damper. The seismic response of the frame provided with RRBD was investigated experimentally. The responses were compared with the BF in order to establish effectiveness of using RRBDs. It was observed that the displacement responses reduced significantly and the acceleration responses increased slightly owing to higher stiffness and damping. Moreover, cyclic analyses were performed for three-story steel moment frames to examine the effects of the proposed damper on columns. The axial load variations in the columns were resemble between the BF and the damper system. This resemblance indicates that the RRBD slightly influences the outer columns.The proposed damper is inexpensive, easy to build, easy to install, and highly efficient. To conduct a comprehensive performance evaluation and to monitor the efficiency level of the damper with respect to the structural behavior, other building typologies such as different building heights, number of bays, and span lengths may need to be considered.


Long-term conditions (LTCs) are important determinants of quality of life and healthcare expenditure worldwide. Whilst multimorbidity is increasingly the norm in primary care, clinical guidelines and the delivery of care remain focused on single diseases, resulting in poorer clinical outcomes. Osteoarthritis, and anxiety and/or depression frequently co-occur with other LTCs, yet are seldom prioritized by the patient or clinician, resulting in higher levels of disability, poorer prognosis, and increased healthcare costs.To examine the feasibility and acceptability of an integrated approach to LTC management, tackling the under-diagnosis and under-management of osteoarthritis-related pain and anxiety and/or depression in older adults with other LTCs in primary care.The ENHANCE study is a pilot stepped-wedge cluster randomized controlled trial to test the feasibility and acceptability of a nurse-led ENAHNCE LTC review consultation for identifying, assessing, and managing joint pain, and anxiety and/or depression in patients attending LTC reviews. Specific objectives  will be achieved through a theoretically informed mixed-methods approach using participant self-reported questionnaires, a medical record review, an ENHANCE EMIS template, qualitative interviews, and audio recordings of the ENHANCE LTC review.Success of the pilot trial will be measured against the level of the primary care team engagement, assessment of training delivery, and degree of patient recruitment and retention. Patient satisfaction and treatment fidelity will also be explored.ISRCTN registry number: 12154418. Long-term conditions (LTCs) are, with their rising prevalence, increasingly important determinants of quality of life (QoL) and healthcare costs in populations worldwide. Over a quarter of the population of England (15.4 million people) has at least one LTC , and thePatients with LTCs are predominantly managed in primary care by general practitioners (GPs) and by practice nurses, where they utilize 50% of all appointments . Other pIncreasingly, people have multimorbidity, defined as the co-occurrence of two or more LTCs in one person . The numwho should identify patients to target, which combinations of conditions to target, and at what level of severity Patients who reside in a nursing home and/or have alternative arrangements for LTC carePatients unable to read and speak English in order to give informed consent.All eligible patients booked into the study consultations will be given a study pack at the beginning of their review inviting them to participate in the research. Participants will not be individually randomized; participants recruited during the control and intervention periods of the trial will be asked to take part in a study investigating delivery of LTC reviews in primary care, consisting of the completion of three self-report questionnaires (over a period of 6 months). Participants will also be asked to provide informed consent to follow-up questionnaires, general practice medical record review for the duration of the trial follow-up and further contact from the study team about related studies.The ENHANCE EMIS template can only be activated and completed once to ensure that patients attend only one study consultation for one LTC, hence are only invited to participate in the study once, thereby avoiding duplicate entries. A list of eligible participants to whom study packs have been provided will be generated by the practice nurse at the end of each clinic and emailed to an NIHR CRN administrator, using a secure ‘nhs.net’ email account. This will allow for the processing of reminders. The GP practices involved in this study have formal agreements with the NIHR CRN West Midlands, whereby staff in the NIHR CRN West Midlands are contracted to work for the practice, to undertake data quality and training functions associated with the GP’s use of their computerized clinical systems, and to undertake administration tasks and functions associated with identifying patients to take part in the research.Eligible participants will be invited to read the Participant Information Sheet, complete the questionnaire and consent form, and post them back to the research centre using a pre-paid envelope. The Participant Information Sheet will provide a contact number for the research trial coordinator, should the patient wish to ask any questions about the study or clarify the research process before deciding whether or not to participate. The same procedure will be followed for both the intervention and control periods. Similar methods of recruitment have been used successfully in previous studies .The flow chart summarizes the participant recruitment in both the control and intervention periods see .We plan to recruit four practices, a number sufficient to test the practical organization of running a stepped-wedge trial. As this is a pilot trial, a formal sample size calculation is not required. However, the number of participants we aim to include in the pilot are detailed below.n=400) consenting to participate, of which 75% will provide 6-month follow-up data. These assumptions are based on trials with similar recruitment methodology conducted at our research centre that were previously mentioned; however, this requires testing in this pilot trial.To achieve a desired final sample size of approximately 300, we estimate that 800 patients will need to be invited between the four practices over the 6-month trial period, allowing for approximately 50% . The process evaluation objectives are to assess:Feasibility and acceptability of the ENHANCE LTC review, with a particular focus on (i) practice nurse experiences of delivering the ENHANCE LTC review and completing the ENHANCE EMIS template; and (ii) participant experiences of receiving the ENHANCE LTC review, including experiences of treatment burdenFidelity of the practice nurse training deliveredEngagement of general practices participating in the pilot trialEngagement of participants in the pilot trial and through follow-upEvidence of selection bias in the control and intervention phasesRecruitment rates in both control and intervention periodsFollow-up rates at each time point across both control and intervention periods.We will also undertake a research evaluation to explore factors that might allow the intervention to be implemented and tested appropriately in a larger RCT by exploring the use of specific outcome measures and estimating the parameters needed for a realistic sample size calculation.The research evaluation objectives are to:Examine completion rates of the self-reported outcome measures (for primary and secondary outcome measures)Examine completion rates of the ENHANCE EMIS templateEstimate the parameters needed for a realistic sample size calculation for a larger stepped-wedge cluster RCTExamine the feasibility of using a stepped-wedge design within primary careProvide an indication of the healthcare and societal costs of implementing the new intervention in comparison with the control group, thereby allowing assessment of potential cost-consequences.Self-reported questionnaires, medical record review, and completion of the ENHANCE EMIS template will form the basis of the quantitative data collection.Participants in the control and intervention periods will be asked to complete self-report questionnaires at three phases: immediately after the LTC review (phase 1), at 6-week (phase 2), and 6-month (phase 3) follow-up. Participants will return their questionnaire to the research centre in a pre-paid envelope. To maximize response rates to the self-report questionnaires, non-responders at phase 1 will be sent a reminder postcard at 1 week and a reminder study pack  at 2 weeks. Non-responders at phase 2 and 3 will be sent a reminder postcard at 2 weeks and a reminder study pack (invitation letter and questionnaire with pre-paid envelope) at 4 weeks. A minimal data collection (MDC) ‘short’ questionnaire will be sent at 6 weeks (with invitation letter and a pre-paid envelope) and an MDC telephone call will also be conducted by a research nurse for non-responders at 8 weeks (phase 2 and 3 follow-up).The phase 1 questionnaire will collect information on participant characteristics , allowing for assessment of potential selection bias by comparing those recruited during the control and intervention periods in each practice. The phase 1 questionnaire will also provide information on any discussions concerning joint pain and/or mood, which took place during the LTC review. This will allow us to investigate acceptability and feasibility on the review and ask whether they received any advice, written information or onward referrals relating to lifestyle changes, medication, and other services. Completion rates of the validated tools will inform their use in a potential larger RCT. The EuroQol 5-dimension, 5-level (EQ-5D-5L) questionnaire , 53 willThe ENHANCE team will assess the success of the pilot trial using the following criteria, and the outcome will be reported to the independent Trial Steering Committee (TSC). Our success criteria are that we can engage GP practices to participate and stay in the trial through follow-up (four practices), successfully deliver the training to at least one practice nurse per practice, and recruit (at least 50% of those invited) and retain (75% of those that consent) sufficient participants to the research evaluation.General practice medical records of consenting participants will be accessed and securely downloaded to obtain information on symptoms, diagnoses, prescriptions, investigations, and referrals. Medical record review of those who provide consent will be undertaken for the 6 months between the ENHANCE LTC review and follow-up, and will allow the study team to examine what activities took place during the reviews, whether patients were referred to other specialists  and potential treatment burden. The data will also allow the study team to examine whether appropriate signposting was being carried out and whether there were any changes to medication during the 6-month trial follow-up. In addition, data on frequency of consultations, prescription use, sickness certification, and secondary care referrals will be examined in terms of likely service cost ; these costs will be considered alongside all clinical and process outcomes to allow an indicated cost–consequence framework to inform the suitability of a main trial.Anonymized data will be collected from medical records to examine the use of the ENHANCE EMIS template. The proportion of participants that (i) were asked the case-finding questions; (ii) reported joint pain, anxiety and/or depression; and (iii) were referred or signposted will be calculated. Baseline scores of pain intensity  , anxietyA sample of ENHANCE LTC reviews will be audio recorded. These data, along with semi-structured interviews with patient participants, practice nurses, and GPs, will form the basis of the qualitative data collection.A sample of intervention period ENHANCE LTC review consultations will be digitally audio recorded, allowing fidelity of the training to be assessed. Areas of interest will include which elements of the ENHANCE LTC review the practice nurses used, whether the content of the training was evident in practice nurse behaviour, and whether gaps in the ENHANCE LTC review could be demonstrated. In addition, fidelity checking will enable us to describe how the training intervention mapped onto delivery of the ENHANCE LTC review in actual clinical practice.We anticipate asking each practice nurse to audio record four or five consultations, 2–4 weeks after completion of their intervention period training. This will generate a minimum of 20 recorded consultations, each approximately 30–45 minutes in duration. A digital audio recorder will be used and switched on by the practice nurse (after checking the patient has consented to their consultation being audio recorded) at the start of the consultation.For those consultations during which reviews may be audio recorded, an additional 10 minutes will be scheduled pre-consultation to allow a qualitative researcher from the study team to discuss the possibility of audio recording, and to obtain initial written consent, if applicable. The researcher will explain to the patient how the audio recording links with the wider research study and will also provide the patient with a study pack for the trial.Consenting participants will be given a green postcard confirming initial consent to audio recording. This card will be handed to the practice nurse as an indication that consent has been given, therefore allowing audio recording to proceed. After the consultation, the researcher will again discuss consent with the patient before they leave the practice, and once more by telephone 2 days later (at least 48 hours later) to confirm the patient still agrees to give consent for the recording to be kept and analysed by the study team.The researcher will also obtain written informed consent from the practice nurse for the recording of up to five ENHANCE LTC reviews. Consent will also be obtained after the audio-recorded consultations and by telephone 2 days later (at least 48 hours later) to confirm the practice nurse still consents to the recordings being kept and analysed by the study team.Semi-structured interviews will be conducted with a sample of patient participants, practice nurses delivering the ENHANCE review and GPs from each practice involved in the study. Tape-assisted (or ‘stimulated’) recall will be used, where possible, to investigate experiences of delivering and receiving the ENHANCE LTC review from the perspective of the practice nurses and participants, respectively. This method facilitates respondent recall and helps to anchor respondents’ reflections in specific consultations .A sample of patient participants identified during the intervention period will be invited to participate in a semi-structured interview. Approximately 20 participants (data collection will continue until category saturation achieved) will be interviewed ensuring purposive sampling of participants with asthma, COPD, hypertension or ischaemic heart disease, and diabetes, those who responded in the affirmative to the case-finding questions for OA-related joint pain, anxiety and/or depression, and those referred onto other services. Where possible, we will use extracts of the audio-recorded consultation to prompt about specific areas of the consultation relating to the aims of the ENHANCE LTC review and use of the case-finding questions for anxiety/depression or OA. These extracts will have been selected by the study team prior to the interview.Overall, the interviews will explore acceptability of the ENHANCE review, views on the case-finding questions, initial management of newly recognized conditions , integration with their index LTC, including potential treatment burden, and their thoughts on the summary card.Semi-structured telephone or face-to-face interviews with the practice nurses will explore how the training developed their knowledge and skills to enable them to deliver the ENHANCE LTC review, whether the training could be improved, and what factors helped or hindered implementation of the ENHANCE review.All practice nurses trained to deliver the ENHANCE LTC review will be invited to participate. A topic guide will allow an exploration of the acceptability and operationalization of the training and ENHANCE LTC review and EMIS template. In addition to the use of a topic guide, we will use extracts of the audio-recorded consultation to prompt discussion about specific areas of the consultation relating to the aims of the ENHANCE LTC review and use of the case-finding questions for anxiety/depression and OA. These extracts will have been selected by the study team prior to the interview.GPs from each of the four practices will be invited to participate in a semi-structured interview at the end of the recruitment period. Where possible, two GPs from each practice will be interviewed to explore the impact of the ENHANCE LTC review on the work of the practice and the GP.All interviews and audio recordings will be digitally recorded and the interviews will be professionally transcribed verbatim. These methods will allow investigation of the extent to which the ENHANCE review needs modifying to improve either acceptability to patient participants and healthcare professionals, or relevance to the primary care LTC review and integrated care context of its delivery.In line with previous research, the development of the practice nurse training and the ENHANCE EMIS template will consist of four components , 59: (i)The content of the training and the ENHANCE EMIS template will be developed by the study team, and informed by the findings from patient and stakeholder workshops and a practice nurse focus group. The behaviour change techniques to be employed within the training will be mapped against a Theoretical Domains Framework  identifiFinally, the practical implications of delivering the training and embedding the ENHANCE EMIS template within the four practices will be considered. The study team will need to take into account the large number of demands already on the practice and work with them to address and agree practicalities, such as the location, duration, and timing of the training, and when the ENHANCE EMIS template can be put in place. It is anticipated that the training will take place in-practice on a one-to-one or small-group basis over 2 half days and will include mentoring from those with expertise in OA and mental health.We plan to work with a minimum of eight practice nurses (two per practice). Training will take place during a 2-week washout period immediately following the control period, the duration of which is predetermined by randomization. Nurses from each practice will be trained to deliver the ENHANCE LTC review which will be delivered during the ensuing intervention period, and for the remainder of the trial. It is hoped that by training more than one practice nurse per general practice, recruitment can continue throughout the duration of the trial. The training will be preceded by a 1-hour briefing session, available to all practice staff, which will include an overview of the trial and an update of current NICE guidance for OA and anxiety and depression.Serious adverse events (SAEs) include death, hospitalization, significant disability or incapacity, any life-threatening circumstance, or any other medically significant occurrence. All practice staff involved in the trial will report immediately to the Principal Investigator (PI) if any identified SAE is experienced by a trial participant. The PI will assess whether the event was related to or resulted from any of the trial procedures or interventions, according to the process laid out in the Keele CTU Standard Operating Procedures. Any SAE considered to be related to the trial procedures will be reported to the main Research Ethics Committee by the PI within 15 days of their awareness of the event. In addition, all such events will be reported to the trial sponsor, TSC, and Data Monitoring Committee (DMC). This is deemed a low-risk trial, as we are investigating the feasibility of enhancing current LTC reviews by incorporating evidence-based management of OA-related joint pain, anxiety, and depression.Analysis of the quantitative data will be exploratory and provide further data on the feasibility and acceptability of the ENHANCE LTC review and EMIS template. Specifically, descriptive statistics  will be used to describe the content of the EMIS template for those in the intervention period of the trial, and the rates of prescription and referrals over 6 months for those consenting to medical record review. Participant characteristics, self-reported at phase 1, will be compared by treatment period, by GP practice, and by practice nurse to explore the balance of patient characteristics by these stratified variables. The percentage of participants consenting to take part in the study will also be reported for each treatment period, along with follow-up rates for the 6-week and 6-month follow-up questionnaires. We will compare recruitment rates and baseline characteristics of participants to assess for potential selection bias. Follow-up data will also be examined in relation to patient characteristics to allow potential attrition bias to be assessed.Findings from the pilot study will also inform changes in the trial design, recruitment processes, data collection processes, and outcome measures used, that may be required, should the team move to a larger RCT. Specifically, we will explore the suitability of the trial design by assessing the degree of correlation between the self-reported and consultation-based GAD-7  and PHQ-Data from the pilot study will also be used to inform a sample size calculation for the main trial by fitting random effects models for the primary outcome of interest  at We have designed the pilot study to include a washout period between the control and intervention phases of the study, both to ensure the nurse training could be fitted into existing workloads and to minimize any delay in the full treatment effect being realised, i.e. to allow time for the nurse to be sufficiently trained to deliver the treatment intervention consistently over time for every patient. We therefore hypothesize that the within-GP practice mean of the primary outcome measure at the 6-week and the 6-month follow-up will not differ greatly, depending on the time period when the intervention was delivered. This will be tested using descriptive statistics and by exploring the coefficients of the term representing ‘time’ in the random effects models used to gain estimates for a sample size calculation for a main trial.We will also use data from the pilot study to explore the feasibility of a subgroup analysis for a main trial, with the subgroup defined as those participants with co-existing symptoms of anxiety/depression or pain at phase 1 who could potentially benefit from the intervention. The feasibility of this subgroup analysis will be explored by reporting the percentage of participants in each treatment period with co-existing symptoms of anxiety/depression or pain to explore if it is feasible for treatment effects to be calculated only for those participants with the potential to benefit from the intervention. It is anticipated that the proportion of such participants will be similar between treatment periods; therefore, their contribution to the mean effect in each period will be similar; this will be tested in the pilot study data.One or more researchers will examine the audio recordings of the consultations and use a previously developed tick box scoresheet to assess whether key components of the ENHANCE consultation were demonstrated by the practice nurse.A tape-assisted recall  approach  will be et al. noted, ‘chronic disease management approaches that identify patients on the severity of a single condition may miss multimorbid patients who stand to benefit greatly from improved co-ordination of care’ [Improving the management of people with LTCs has been a key priority of the UK NHS for more than 2 decades , with prof care’ .Musculoskeletal conditions and mental health problems are common and frequently co-exist, both with each other and with other LTCs. People with comorbid pain and mental health problems have higher levels of disability, a poorer prognosis, and increased healthcare costs; yet the detection and management of these conditions is challenging and frequently suboptimal. Whilst it is recognized that a shift towards integrated care is essential if we are to ensure a holistic approach addressing both physical and mental health problems , there iThe ENHANCE study will examine the feasibility and acceptability of an integrated approach to LTC management, tackling the under-diagnosis and under-management of OA-related pain and anxiety and/or depression in patients with other LTCs in primary care. Satisfaction of those participants who received the ENHANCE review should be at least as acceptable as that of those who received usual care  . TreatmeThe study has been approved by the Greater Manchester East Research Ethics Committee (REC reference: 15/NW/0335).The ENHANCE trial will be monitored in line with the protocol and Keele’s Clinical Trials Unit Standard Operating Procedures. An independent TSC will monitor the progress of the trial and the DMC will monitor the safety of participants and data integrity. Monitoring will also be undertaken by the approving Research Ethics Committee in the format of annual progress reports and the NIHR Collaborations for Leadership in Applied Health Research and Care West Midlands in the format of quarterly progress reports.The trial design and processes have been informed by user involvement in line with our Centre’s strong commitment to involving the public in research, following INVOLVE’s recommendations. Thirteen members of the public attended our patient advisory group meeting held in June 2014 and two members of the public were involved in each of our three stakeholder workshops  at which the research question, aim of the trial and design of the intervention were discussed and agreed. Two individuals from the patient advisory group have agreed to be members of our TSC. The remaining members of the patient advisory group assessed our participant information  and their feedback was incorporated in the final versions. All research users are supported by our Centre’s Public and Patient Involvement Coordinator through regular meetings and an annual conference at Keele, with funding support through the Centre’s Centre of Excellence award from Arthritis Research UK.The sponsor will have no role in the design and analysis of the data.


A three-dimensional finite element numerical modeling for the scanning microwave microscopy (SMM) setup is applied to study the full-wave quantification of the local material properties of samples. The modeling takes into account the radiation and scattering losses of the nano-sized probe neglected in previous models based on low-frequency assumptions. The scanning techniques of approach curves and constant height are implemented. In addition, we conclude that the SMM has the potential for use as a broadband dielectric spectroscopy operating at higher frequencies up to THz. The results demonstrate the accuracy of previous models. We draw conclusions in light of the experimental results. In addition, the SMM has been applied to biological imaging for single bacterial16, live cells in situ17, muscle cells18. In contrast to the scanning optical microscopy (NSOM), microwaves have larger penetration depths. Thus, the SMM provides a high-resolution mapping of both surface and internal properties of material samples. The frequency range commonly used by SMM is about 1 GHz to 20 GHz. However, in the last years the work of Lucibello et al.6, Trasobares et al.15. and Imtiaz et al.10. point out the capability of SMM operating at higher frequency bands. For example, the skin cancer detection at THz frequency19, the calculation of complex permittivity of water at millimeter-wave frequency band in biological tissues.Scanning microwave microscopy (SMM) is a near field scanning probe microscopy (SPM) technique that measures the local transmission of microwaves from a sample using a sharp probe close to the surface of sample. The SMM is a potential alternative to access the electromagnetic properties of samples such as electrical impedance and the complex permittivity with high spatial resolution. The SMM applications include the super-resolution imaging and characterization of inorganic and organic samples26. SMM usually measures the S-parameter27, shifted resonant frequency12 or directly the complex impedance28 of tip-sample interaction. Then the capacitance or conductance can be calculated from the tip-sample system which reflects the dielectric property of sample. However, it is not so obvious to map these quantities in samples with local material properties such as complex permittivity or permeability. These quantities represent complex convolutions between the probe geometry and electromagnetic response including material properties and surface topography28. Due to the small interactions of the tip-sample system the SMM setup requires a high-sensitive and stable signal detection system. Thus, a good estimation of the tip-sample impedance is of great significance in the design of the impedance matching circuit, especially for future implementation of broadband SMMs. In addition, the full-wave modeling allows the study of SMM integrated with metamaterial component, such as a flat lens of negative refraction index that amplifies evanescent waves. Such lenses have been fully-studied and demonstrated at microwave frequencies30, and its integration with SMM would further improve the spatial resolution and may enhance the ability to detect buried features.The SMM setup consists of a nano-sized sharp probe connected to a microwave source through an impedance matching circuit. The SMM provides an excellent spatial resolution down to the molecular and atomic scales compared to other near field microwave microscopy techniqueslow-frequency breakdown problem. We point out that the quasi-static model provides a good accuracy in terms of calculating the tip-sample capacitance, while the calculation of dissipation loss becomes less accurate as the frequency goes higher. Also, we demonstrate that the quasi-static model and PEC approximation are accurate methods for calculating capacitance of the nano-sized probe tip operating at K-band or lower. Our simulations show that the SMMs operating at higher frequency provide better sensitivity on dielectric loss measurement while both field radiation and skin effect need to be taken into consideration. The proposed full-wave modeling of SMM will provide some physical insights for the development of broadband near field microwave scanning spectroscopy with high imaging precision by taking both propagation and evanescent wave components into consideration. This work will present a complete modal picture of SMM in line with the collection mode used in NSOM, which determine local material properties by applying the evanescent-scattering field to propagating field conversion and it may open up new frontiers of SMM research at higher frequencies up to THz.Our goal is the modeling of the SMM setup and their electrodynamic interaction with material samples at low and high microwave frequencies. We used the finite element method (FEM) for the numerical simulations. Our model takes into account the key factor of the so-called low-frequency breakdown problem. Then is presented the equation for calculating the complex impedance of the tip-sample interaction derived from the wave equation for electric field. In addition, the finite element model for the governing wave equation is written down. We present a framework of high frequency applications linked to the SMM. We start the section of results by describing the geometrical parameters used in our simulations and comparing the quasi-static model with the full-wave model via an experimental approach curve. We discussed the model and the simulations in light of a number of experiments and applications. Finally, we draw conclusions on the proposed numerical modeling and the future directions for it.In the next section, we shall write down the full-wave model derived form the Maxwell’s equations. This section starts by describing of the so-called 31, electrostatic force microscopy (EFM)33 and SMM based applications28. In addition to the quasi-static models have been developed equivalent circuit for profiling doped semiconductors and measuring material conductivity8. The accuracy of these methods have been proved with analytical approximations for particularly shaped probes at low frequencies32. However, the scattering and magnetic field play no role in these previous models.The probe size of AFM is much smaller than the operating wavelength, and it barely radiates electromagnetic waves. In the local near field region, the electric field is nearly irrational and Maxwell’s equations are reduced to the equation of Poisson for electrostatic potential. The complex impedance of the tip-sample interaction can be calculated by solving the Poisson’s equation numerically. This approach has been widely used for modeling the SPM techniques at low frequencies (30–300 kHz) such as nanoscale capacitance microscopy35, or probes at millimeter scale for microwave applications26. The SMMs use an AFM probe with tip dimensions that can be less than 10. This leads to the so-called low-frequency breakdown problem37 for the full-wave numerical modeling of SMM. The key factor of this problem is the ill-conditioned system obtained for the finite element solution of Maxwell’s equations  leads to the calculation of the electric and magnetic field. Therefore, the complex impedance can be computed byV between the probe surface and substrateL is the path of the current source  boundary condition on the probe surface To simplify the analysis and the simulation, we use a delta-gap source as the excitation port which is a common approach in antenna simulation using the Method of Moments (MOM)ution of  leads to40In addition, we truncate the simulation domain We are now at a position to consider the numerical implementation of solving the governing wave equation  togetherS is the stiffness matrix, T is the mass matrix and R is the conductivity- and boundary condition- related matrix. Expanding the unknown electrical field E using a vector basis function N, the entities of these matrices are assembled from their elemental contributions. In the SMM simulation at low frequencies, entries of 37, and this introduces singularities to A, and then find the inverse of A can be computed via the method of Schur-Complement41  of a sample in the SMM measurement are the capacitance et al.16  and the tip-probe of AFMs is made of metals asuch as titanium, aluminum, tungsten40.In previous studies of SMM and devices at low frequency such as EFM, the metallic components are assumed as perfect conductors with zero skin depth by applying a constant AC voltage to the boundaries. To validate the accuracy of this approximation, we simulated the metallic tip as a lossy medium in the full-wave model and compared the result with the perfect electric conductor (PEC) boundary model. Here, we assumed that the conducting substrate is an impedance boundary because its thickness is much larger than the skin depth, and the electromagnetic waves cannot penetrate the substrateThe Fig. 48  tip and silicon nitride (Si3N4) tip are commonly used in AFMWe presented a rigorous modeling of nanosized SMM probes and their electrodynamic interaction with material samples at microwave frequencies. We start by set out the full-wave model derived from the Maxwell’s equations for the SMM setup and taking into account the regularization of low-frequency breakdown problem in the numerical implementation. We demonstrated the accuracy of the models in a few examples by using the scanning techniques of approach curves and constant height. First, we demonstrated that the quasi-static model provides a quite good accuracy for the calculation of capacitance at low frequencies. While this model is less accurate for the dissipation loss for the higher frequencies. We also pointed out that the quasi-static model and the PEC boundary are good approximations for the theoretical calculation of capacitance. Here, our simulations show that the SMMs operating at higher frequency provide greater sensitivity on the evaluation of dielectric loss. Here, we shown that for accurate analysis the field radiation and skin effect need to be taken into consideration.The numerical modeling presented here for the full wave model to mimics the SMM setup can be extended in a number of ways. First, the model can be used for the development of broadband near field microwave scanning spectroscopy with high imaging precision by taking into consideration the propagation and evanescent wave components. Another extension, is to use the model to determine local properties of materials by applying the evanescent-scattering field to propagating field conversion. This will enable to study new frontiers of SMM research at higher frequencies up to THz. A third extension is to embed the model in realistic physiological conditions (liquid media). This extension will enable the quantification of biological samples  in a realistic media.Supplementary information for full-wave modeling of broadband near field scanning microwave microscopy


In target detection of optical remote sensing images, two main obstacles for aircraft target detection are how to extract the candidates in complex gray-scale-multi background and how to confirm the targets in case the target shapes are deformed, irregular or asymmetric, such as that caused by natural conditions  and occlusion by surrounding objects . To solve these issues, an improved active contours algorithm, namely region-scalable fitting energy based threshold (TRSF), and a corner-convex hull based segmentation algorithm (CCHS) are proposed in this paper. Firstly, the maximal variance between-cluster algorithm  and region-scalable fitting energy (RSF) algorithm are combined to solve the difficulty of targets extraction in complex and gray-scale-multi backgrounds. Secondly, based on inherent shapes and prominent corners, aircrafts are divided into five fragments by utilizing convex hulls and Harris corner points. Furthermore, a series of new structure features, which describe the proportion of targets part in the fragment to the whole fragment and the proportion of fragment to the whole hull, are identified to judge whether the targets are true or not. Experimental results show that TRSF algorithm could improve extraction accuracy in complex background, and that it is faster than some traditional active contours algorithms. The CCHS is effective to suppress the detection difficulties caused by the irregular shape. Remote sensing images contain large amount of geo-graphical environmental information and have widely used in different scientific fields. Target detection  is one of the fundamental applications in remote sensing images. It is an important basis to conduct military attack and intelligent transportation, rapidly and correctly ,2. AmongSpecifically, there are two major challenges that hinder the improvement of the detection effect:One is that how to extract targets exactly from the complex background. For this challenge, there are few systematic methods to cope with it. A suspicious target is usually extracted from the thumbnail slice containing the well-marked target. Arandjelović  proposedThe other one is identifying the targets in case of irregular target shapes target due to natural conditions  and occlusion by surrounding objects . This part could be classified into two major strands. One strand is to take advantage of the shape of an aircraft. With the aid of the obvious structural features, including principal axis, contour and rigidity, the scholars extracted and detected the aircrafts by symmetry and various rotation-invariant moments of aircrafts. Some classical algorithms are combined to be used, such as principle component analysis, Zernike invariant moments, contour tracking and so on ,5,6,7,8.In this paper, we solve the above-mentioned problems in two steps. Unlike the ocean target detection, the remote sensing image of land consists of many gray levels, which causes relative difficulty to extract the candidates from the image utilizing pure threshold segmentation, e.g., the popular Otsu’s algorithm . TherefoThe proposed detection algorithm is divided into two steps, as shown in the The binarization of the input image is a necessary operation before extracting the connected regions. In the Otsu’s algorithm, the segmentation threshold is obtained through the gray histogram calculation based on statistical information. Such algorithm is characterized by simple, stable and effective calculations and ensures the image segmentation quality in the case of simple background. It is usually regarded as one of the most fashionable threshold segmentation algorithms. However, considering that a remote sensing image consists of numerous grey levels, it seems a difficult task to extract the ROI from such a complex image directly through Otsu’s algorithm. It is found out that the aircraft luminance is usually very high through observation. So the suspected aircraft area can be obtained through further gray histogram segmentation based on Otsu’s algorithm pre-segmentation. The active contour algorithm, such as C-V model , can effThe Otsu’s algorithm characterizes the separating properties of both the targets and the background through the Interclass Variance, which is defined as:Equation (3) is composed of three terms, where The introduced non-negative kernel function C, which is defined as: When the closed boundary The introduced kernel function Downsample the original image by a factor of 4, and then implement initial Otsu’s algorithm segmentation for the low-resolution image. In this way, the complexity of computation is reduced.After the completion of Otsu’s algorithm, weed out small areas at first, and then process the segmented region through secondary segmentation and morphological processing at a high gray level (10%). At this point, the aircraft area can be located basically.Take the segmented binary image as the local region and initial condition of active contour, define the initial level set function Evolve the level set function through energy functionality, and search for the level set Repeat the steps c and d, and stop the repetition when the energy functionality doesn’t change any more. Finally, the segmentation result can be obtained.Process the segmented binary image morphologically, and weed out small areas.This paper employs in coarse-to-fine fashion to extract the ROIs. For subsequent processing, we employ the searching algorithm for 8-neighborhood connected regions to extract the connected regions from a binary image . SupposeThe area is the zero-order moment, In this section, a corner-convex-hull based segmentation (CCHS) algorithm is given. Furthermore, the new features—namely TFR and FHR—are introduced into the judgment of true targets particularly.R of Harris corner points is:After the last step, many of the connected regions, which include the connected regions of the aircraft target, have been extracted by TRSF algorithm. Then we would exclude the false targets in these connected regions. The aircraft targets should be filtered in accordance with the aircraft features that we presented below. The most fundamental features, such as area and aspect ratio of the minimum external moment, are used to eliminate a large number of regions. Since the aircraft contour takes on typical geometric features, its feature points are available for target screening. With a small calculation burden and steady results, the Harris corner operator  is adoptAfter the extraction of corners from a segmented binary image, it is found that an aircraft has five salient corners at the aircraft nose, wings and tail respectively. Convex hull  of theseWhen multiple adjacent corners overlap, the similar corners can be merged in accordance by applying the Euclidean distance to prevent one feature point from being detected as several corners. In this way, the pentagon corners for an aircraft become extremely clear. The usage of extracted corner set can greatly reduce the calculation burden in convex closure detection in a whole connected region.Algorithm 1The process of convex hull detection in this section is given as follows (Algorithm 1):Points in the result will be listed in counter-clockwise order.After drawing the convex hull of ROIs, there are still some false candidates in a pentagon shape which needs to be further wed out. Here, we propose a segmentation approach that divides a connected region into several parts so that every slice can be independently analyzed to remove the false targets.In this section, the centroid of a connected region is connected to the vertexes of convex hull to segment the region into five fragments. The shape of each fragment is a triangle which includes a part of connected region and a part of convex hull background. The new feature TFR describes the radio of the area of each target part to each triangle and the other feature FHR describes the radio of area of each triangle to the whole hull. The definitions are as follows.The result of fragment segmentation is shown in According to The fragment features are applied to different aircraft models  shown inIf the extracted aircraft is irregular, as shown in Through the SVM learning and training for a large number of remote sensing aircraft image slices, the targets can be judged accurately .Due to the lack of standard data sets of high resolution remote sensing images for object detection, we evaluate the proposed method on 52 images from Google Earth for aircraft detection with the resolution of 60 cm/pixel. . We collect 500 positive patches from the Google Earth to train the TFR and FHR features. Simulation is done with Visual Studio 2012 in a computer with a CPU of Intel 4 GHz and 32 G memory to evaluate the calculation time.As shown in In this part, we show the result of the ROI extraction using our proposed method. According to , we use Then, the segmentation algorithms of Otsu’s algorithm, watershed, and C-V level set are compared with our proposed method. After the ROI segmentation, the corners are detected and their convex hulls are drawn. Then the ROI is segmented into several fragments and the features are extracted. That we adopt the Harris points to calculate the convex hull can greatly improve the running speed compared with the method based on the whole contour. In details, the local enlarged drawing of the P and R [After the results of target detection output, we evaluate the performance metrics in terms of precision and recall, denoted as P and R . The preP and R are respectively defined as: In order to verify the proposed method has a positive impact on aircraft detection, a wide range of tests are conducted on a large number of images involving 312 aircrafts in total. In comparison, a method based on size and Hu moments multi-normal features and a method based on HOG-SVM are used as comparison. All of the methods extract the ROIs using our first stage method and then validate the results in different features. In addition, the method in  is also In summary, a novel method has been proposed in two steps to settle the problem of low aircraft detection precision in high-resolution panchromatic optical remote sensing images. First of the two steps, an improved RSF algorithm has been suggested to solve ROI extraction difficulty in complex background. Then, a corner-convex-hull based segmentation algorithm has been introduced to solve the aircraft shape irregularity problems. The new features, target-to-fragment radio (TFR) and fragment-to-hull radio (FHR), have been constructed to take into the false targets elimination. The performance has been evaluated and validated in terms of precision and recall using the images from Google Earth. As a conclusion, it can be observed that the proposed method is tractable to be built and implemented to improve the accuracy.It is of interest to extend the complex remote sensing background of the target extraction from the aircraft mutatis mutandis to other targets by introducing new feature descriptors, for instance vehicles or marine vessels.We are interested in how to combine the panchromatic with multi-spectral information to detect the aircraft target. It is promising to use the high resolution of panchromatic images and the different reflectivity of different spectral bands for different objects to accurate detect targets.The further research is underway in the following two directions.


Escherichia coli cell communities, whereby low local oxygen concentrations lead to cellular secretion of weak acid products. For this reason, a metabolic model has been developed for the facultative anaerobe E. coli covering the range of aerobic, microaerobic, and anaerobic environmental conditions. This metabolic model is expressed as a multiparametric programming problem, in which the influence of low extracellular pH values and the presence of undissociated acid cell products in the environment has been taken into account. Furthermore, the developed metabolic model is incorporated in MICRODIMS, an in-house developed individual-based modeling framework to simulate microbial colony and biofilm dynamics. Two case studies have been elaborated using the MICRODIMS simulator: (i) biofilm growth on a substratum surface and (ii) submerged colony growth in a semi-solid mixed food product. In the first case study, the acidification of the biofilm environment and the emergence of typical biofilm morphologies have been observed, such as the mushroom-shaped structure of mature biofilms and the formation of cellular chains at the exterior surface of the biofilm. The simulations show that these morphological phenomena are respectively dependent on the initial affinity of pioneer cells for the substratum surface and the cell detachment process at the outer surface of the biofilm. In the second case study, a no-growth zone emerges in the colony center due to a local decline of the environmental pH. As a result, cellular growth in the submerged colony is limited to the colony periphery, implying a linear increase of the colony radius over time. MICRODIMS has been successfully used to reproduce complex dynamics of clustered microbial communities.Clustered microbial communities are omnipresent in the food industry, e.g., as colonies of microbial pathogens in/on food media or as biofilms on food processing surfaces. These clustered communities are often characterized by metabolic differentiation among their constituting cells as a result of heterogeneous environmental conditions in the cellular surroundings. This paper focuses on the role of metabolic differentiation due to oxygen gradients in the development of  In their natural or industrial settings, many bacterial species form clustered communities, such as biofilms or colonies, rather than living in a free-swimming planktonic state. Living as a community often confers specific advantages, such as antibiotic resistance and immune evasion due to horizontal gene transfer, resistance against flow shear forces and persistence in dynamic and stressing environments due to metabolic differentiation empirically based on data of microbial dynamics in well-mixed liquids and only consider the average microbial population dynamics at a macroscopic scale. However, as a result of the heterogeneous environmental conditions in mature biofilms and colonies, and due to the concomitant metabolic differentiation among the constituting cells, the individual microbial cell is the most intuitive modeling level. In individual-based models (IbM), the individuals/agents of a population are described as discrete, unique, and autonomous entities  with genome-scale models Palsson, . To reprE. coli cells on/in food products under various combinations of heterogeneous environmental conditions. Two case studies are elaborated in detail: (i) two-dimensional biofilm growth on abiotic food equipment surfaces, and (ii) three-dimensional submerged colony growth occurring in mixed or coagulated semi-solid food products. In both case studies, oxygen limitations emerge in mature microbial structures due to diffusion limitations, leading to local pH drops as a result of the cellular secretion and accumulation of weak acid substances. The resulting metabolic differentiation among the cells influences the global population dynamics: low pH values and cell lysis at the substratum surface lead to biofilm detachment, while submerged colonies are characterized by the emergence of a central no-growth zone influencing the colony radius growth.Finally, the linear metabolic model is incorporated in MICRODIMS, an in-house developed IbM  on the environmental pH and concentrations of weak acid cell products is explained.Sexch  determines a steady-state solution of Equation (1) by optimizing a specific cellular objective function Palsson, :subject tow are defined by the intended cellular objective. The constraints on the kinetic rates of the intracellular reactions  and the physicochemical constraints on the external fluxes due to environmental conditions  are taken into account in Equations  respectively.In Equation (2), the weights E. coli under different glucose and oxygen availability conditions, a phenotype phase plane (PhPP) analysis can be carried out by executing multiple FBAs for a range of specific glucose and oxygen uptake rates , while KG [mol/L] and KO [mol/L] are the Monod half-saturation constants for respectively glucose and oxygen. The optimization problem in Equation (6) is straightforward to solve as the PhPP in Figure The upper constraints for the glucose and oxygen uptake rate are determined according to the Monod kinetic law Monod, . In thesAs the PhPP contains much information about intracellular metabolic fluxes from its constituting FBAs, it is not appropriate to incorporate it in its original form into an IbM. Multiple evaluations of the whole intracellular reaction network would result in an excessive increase of the required IbM simulation run time. For this reason, the planes in the PhPP at a specific oxygen uptake rate are described by means of the linear growth law of Pirt  are expressed similarly:with qii, Yi/G [mol/mol] the production yield of metabolite i on glucose.where In the optimization problem in Equations (6–8), it is assumed that the cell aims to maximize its growth. This assumption is only valid for a non-stressing reference environment, i.e., a neutral M9 minimal medium enriched with glucose at 37°C. However, the cellular secretion of weak acid metabolites under oxygen-limited conditions in microbial biofilms and colonies constitutes an inhibiting factor for cellular growth and survival. The inhibiting effect of weak acid cell products on cellular growth is 2 fold: (i) dissociation of acid metabolites in the food environment leads to a decrease of the extracellular pH, and (ii) reintrusion of the lipophilic undissociated cell products into the cell results in an intracellular pH drop.Under the stressing conditions of low extracellular pH values and the presence of undissociated acid cell products, the cellular objective changes to maximize survival chances. As a matter of fact, the cellular objective needs to be modified asrestating the optimization problem in Equations (6–8) as a multiparametric programming problem. However, the exact mathematical formulation of the cellular objective is unfortunately not known. For this reason, a more pragmatic approach is required.Synergistic effects of low extracellular acidity and undissociated acid cell products in the environment can be taken into account in the maintenance coefficient in Equation (9):mG, ref that can be derived from the reference PhPP in Figure +], and (iii) a supplementary effect of weak acid cell products in their undissociated form [Ui]. Microbial growth stops when the proton concentration reaches a critical value [H+]min. Analogous minimum inhibitory concentrations [Ui]min exist for the undissociated acid cell products. The mathematical constants A and B are calculated by replacing this expression for the maintenance coefficient in Equation (9).In this expression, the maintenance coefficient consists of three terms: (i) the reference maintenance coefficient The increase of the maintenance coefficient due to low extracellular pH values and the presence of undissociated acid cell products does not only affect the microbial biomass growth, but also the secretion of metabolic products in Equation (10):The developed metabolic model is incorporated in the MICRODIMS IbM  Δt2 = 0.01 min, an intermediate time interval for the metabolic processes of nutrient and oxygen uptake, biomass growth and metabolite secretion, and (iii) Δt3 = 0.1 min, the long time step for slow processes such as cell reproduction, cell lysis, and cell movement. This cell movement consists of a shoving mechanism to avoid spatial overlap between the cells, and a detachment process for loosely bound biofilm cells. After the initiation of the simulation, all the subprocesses are executed consecutively as presented in the simulation scheme in Figure MICRODIMS consists of several interlinked subprocesses, as illustrated in Figure The MICRODIMS IbM has been implemented in the MASON multiagent simulation toolkit in Java  in order to clearly demonstrate the transition from aerobic to anaerobic environmental conditions in the biofilm. Furthermore, the environment has a glucose concentration of 0.1 g/L in order to ensure that the simulation starts with a metabolic regime in region 1 of the PhPP  numerical scheme  is the concentration of substance i in the environmental unit with the coordinates , andwhere The simulation starts with one initial cell which is located in the origin of the environment. The environmental boundaries are characterized by constant chemical concentrations.t1 = 0.00002 min is required in this explicit scheme for three-dimensional diffusion. For glucose and chemical compounds of the same molecular size as glucose, the diffusion coefficients in a 5% (w/v) agarose gel environment are approximately 75% of their normal diffusivities in water  signaling molecules, or through the production of N-acyl-L-homoserine lactones (AHL) by other species  biofilm growth on a substratum surface and (ii) submerged colony growth in a semi-solid mixed food product.In the biofilm case study, accumulation of weak acid cell products and a concomitant pH drop occur at the substratum surface. This leads to cell lysis and biofilm detachment from the substratum. Apart from the metabolic cellular differentiation, biofilm dynamics are mainly determined by the cell detachment process at the biofilm outer surface, inducing the formation of protruding cell chains. The acidification of the biofilm environment and the emergence of typical mushroom-shaped morphologies of mature biofilms and the formation of cellular chains at the exterior surface of the biofilm are observed. In addition, high affinity of planktonic cells in the bulk medium for the substratum surface results in a high density of initial cells at the substratum and a more continuous and flat biofilm structure. The simulations show that these morphological phenomena are respectively dependent on the initial affinity of pioneer cells for the substratum surface and the cell detachment process at the outer surface of the biofilm.The submerged colony case study demonstrates the development of a central no-growth zone with a sharp decline of the local pH, comparable to the pH drop at the substratum surface in the biofilm simulations. Cellular growth is limited to a thin band of cells at the colony periphery, resulting in a linear increase of the colony radius over time.Authors jointly designed the study and wrote the manuscript. IT implemented the algorithms and performed the computations. JV supervised the study. All authors have read and 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.


This paper reports on the development of an autonomous instrument based on an array of eight resonant microcantilevers for vapor detection. The fabricated sensors are label-free devices, allowing chemical and biological functionalization. In this work, sensors based on an array of silicon and synthetic diamond microcantilevers are sensitized with polymeric films for the detection of analytes. The main advantage of the proposed system is that sensors can be easily changed for another application or for cleaning since the developed gas cell presents removable electrical connections. We report the successful application of our electronic nose approach to detect 12 volatile organic compounds. Moreover, the response pattern of the cantilever arrays is interpreted via principal component analysis (PCA) techniques in order to identify samples. A recent study revealed that humans can discriminate among more than a trillion different smells  and the Multi-gas detection using portable systems requires the use of sensors adapted for this specific application, especially in terms of sensitivity, response time and recovery time, selectivity, application to a wide range of gases, simplicity and convenience with respect to the use and replacement of sensors, and equally important, the sensor life-time. To meet this demand, a large number of technologies, based on optical, mechanical and electrical techniques, have been developed for chemical transduction.Regarding the choice of these sensor techniques, solutions are distinguished by the type of sensitive layer and the principle of transduction. The most used for electronic nose applications are: semiconductor metal oxides gas sensors, conducting polymer sensors , SurfaceElectronic noses technologies offer a cheaper alternative to existing analytical instruments such as gas chromatography, mass spectrometry or ion mobility spectrometry . They arIn the last two decades, advances in the micro-electromechanical systems (MEMS) field have promoted the development of miniaturized sensors that are able to transduce mechanical energy  to electrical energy. The operation principle of MEMS sensors is that chemical, physical or biological stimuli can be transduced to mechanical stimuli and affect mechanical characteristics of the sensor structure in a manner that these changes can be measured by electrical or optical means. In this context, bio-chemical detection is possible by measuring mass or surface stress changes. In particular, microcantilevers, the simplest MEMS structures, offer the possibility of label-free biochemical detection with very high sensitivity . The senIn this perspective, a microcantilever-based electronic nose can offer highly desirable characteristics, including fast responses, height sensitivity and being able to accommodate a large number of sensors in a small volume. Moreover, they are suitable for mass production, taking advantage of micro-machining techniques and circuit integration.In this work, we report the fabrication and the development of a silicon and synthetic diamond microcantilever array-based electronic nose. In the MEMS field, silicon is widely used. In fact, processing methods such as etching and photolithography have been thoroughly developed by the electronics industry, and have been easily adapted for MEMS production. As a consequence, the development of new techniques has not been favoured. Nonetheless, diamond is expected to be a very promising alternative in the micro-sensors field. In fact, diamond is a highly suitable material for the manufacture of resonant microcantilevers because of its exceptional mechanical and thermal properties, biocompatibility as well as excellent hardness and robustness. Polycrystalline diamond can be an excellent choice for the fabrication of resonant sensors due to its high elasticity modulus (in the order of 103 GPa ). Moreov103 GPa .The originality of the study reported in this paper is related to the development of a complete modular and autonomous system which is designed from sensors (silicon and diamond) to signal processing to be low noise, sensitive and easy-to-operate. In order to increase the sensitivity of our microcantilever sensors to volatile organic compounds detection, a variety of polymer coatings has been used to coat microcantilever surfaces. These sensors present mass resolution down to the ng range. Finally, we report the successful application of this electronic nose approach to discriminate some volatile organic compounds.The MEMS sensor presented in this paper consists on an array of independent microcantilevers attached to a chip (2 cm × 5 cm) in which we can find electrical pads. We have fabricated silicon and polycrystalline diamond cantilevers using same geometry (same masks) in order to use in the functionalization step, a priori, silicon cantilevers for polymer coatings and diamond cantilevers for direct proteins binding. As diamond sensors have presented higher mass sensitivity than silicon ones, they have also been used with polymer coatings. The fabrication process of silicon and diamond cantilevers takes advantage of thin film technology and surface micro-machining techniques. In both cases, three metallic contact pads allow electrical connection to the integrated pair of poly-silicon strain gauges that serve as transducer elements. The piezoresistors in the cantilevers are connected to form a Wheatstone half-bridge circuit per chip as shown in The fabrication of silicon cantilevers follows well-known techniques using a silicon-on-insulator wafer (SOI) as substrate . In ordek is its spring constant, and Our sensors have been conceived to operate in dynamic mode to detect changes of the device’s mass due to adsorption of analytes on the microcantilever surface. For a microcantilever uniformly loaded on one side, as is the case of cantilevers coated with a sensitive layer, the mass change can be calculated from the measured resonance frequency shift using the following equation (model of harmonic oscillator):Silicon microcantilevers conceived to be used as chemical sensors must be adapted so that their surface acquires high affinity to the target analyte. Many types of coating layers can be used to increase cantilevers chemical sensitivity and selectivity. Noble metal coating layers have been used because they can provide surfaces which can be modified to bind biological or synthetic receptors ,23. ThesIn terms of diamond chemical sensors, several possibilities can be envisaged to increase sensor sensitivity. Because of their carbon nature, diamond sensors are good candidates for stable grafting of a wide range of biological receptors via covalent C-–C binding ,31,32,33In this study, polymeric materials have been used as thin film coatings for silicon and diamond microcantilevers. Polymer solutions were deposited on diamond and silicon microcantilevers by a spray coating and in some cases, by spreading a droplet. A commercial airbrush  was the equipment used for spray coating. The devices were cleaned prior to the polymer solution deposition (deionized water). Moreover, distance between sample and nozzle together with the pressure have been optimized to allow reproducible layer deposition and avoid the formation of droplets. Freshly coated microcantilevers were brought to 40 °C in an oven for 30 min in order to evaporate solvents. Film thickness was controlled by varying the concentration of the polymer solution and the number of depositions steps. Film thickness was measured using a mechanical profilometer. Because microcantilevers are flexible, it is not possible to measure polymer thickness on the microcantilever surface. Therefore, film thickness can be measured over the immobile part of the device thanks to the shadow mask corners. The validity of thickness measurements was confirmed by estimations of the deposit mass of polymer via the measurements of resonance frequency shifts of bare and coated microcantilevers. The thickness of the layer can be calculated from the estimated added mass, the density of the polymer and the area of the coated surface. The impact of coating on microcantilever sensors regarding energy losses depends on the geometry and the material of the sensor. We have observed that, for polymer thin layers (low added mass), the quality factor does not present significant changes for silicon cantilevers as can be observed in Detection of vapors using MEMS sensors relies on real-time measurements of cantilever deflection or cantilever resonance properties with high accuracy. Therefore, actuation and readout systems are a very important part of the development of resonant microcantilever-based sensors. The first aspect to consider is a practical aspect: microcantilevers must be placed inside a hermetically sealed gas cell which may also allow the direct actuation and read-out of the sensors. Another important characteristic of the cell is its volume size and geometry. In order to reduce time of detection, it is necessary to work with small volumes of gas. Internal geometry may also be optimized to avoid dead corners and provide a homogeneous gas flow.In this context, a customized gas analysis cell has been conceived to accommodate up to eight sensors. The cell consists of a stainless steel chamber which presents eight cavities to accommodate sensors. A 2 mm rigid conduit is attached to the chamber serving as a gas inlet/outlet . Sensor -Small dimensions: for electronic nose applications, it is not possible to use a measuring instrument such as gain-phase analyzers;-A human–machine interface: an interface is necessary for the visualization of the data in real time and for the intervention on the measurement configurations;-An analog processing interface to detect the responses of the sensors with sufficient resolution;-A memory to store a certain quantity of measurements and calibration data of the sensors;-An autonomous architecture: calibration and diagnostics executed autonomously, without user intervention;-Communication interfaces: to communicate with other modules .In order to properly interface our microcantilevers, we need to have an autonomous and stable electronic circuit that can detect very small changes in sensor resonance frequency  over very long periods of time (minutes to hours). In recent years, the need to design superior instruments for electronic nose applications has drawn researchers attention to the development of new solutions ,35. In tWith regard to the operation principle, in dynamic mode, the electronic system can operate following two methods of frequency shift detection: oscillator configuration or frequency sweep mode. In this work, the variations caused by dispersions during sensors manufacturing and the fact that we use an array of sensors make the sweep mode the best choice since it allows modularity and is easy to implement. In this operation mode, a sine-sweep signal is used to excite sensors near their resonance frequency while measuring sensors’ response for each frequency. The resonance frequency (maximum amplitude response) is recorded while sensors are submitted to a reference gas in order to generate a baseline. As the sensor response is continuously monitored, when gas samples are sent to the sensors, shifts on the frequency response can be detected.The second part , right oA dedicated LABVIEW application was developed to ensure communication between the micro-controller and the user. Eight cantilever sensors were functionalized by coating individual microcantilevers with six different polymer layers using the techniques presented in the previous section. Two diamond cantilevers have not been coated, but their surfaces were treated in order to change their hydrophobic properties. After the functionalization steps, we verified the mass changes and thickness of each cantilever in order to estimate the minimum concentration of volatile organic compounds to be used in this experiment. The eight microcantilevers are placed on the gas analysis chamber in which gases and vapors can be introduced. The exposure to different VOCs was carried out by using a gas generator calibrated using a photon ionization detector (PID). Analytes in liquid phase are placed in a temperature controlled enclosure and headspace above the sample is carried in a stream of dry nitrogen gas to the measurement chamber via flow controllers and pumps. Detection set-up is completely independent on the system as can be seen in Before using the sensors for the detection of vapors, we first checked the possible variations of original resonance frequency that are not related to the detection of analytes. Microcantilevers (bare or coated) are sensitive to pressure, temperature and humidity. We ensure the validity of the experiment by controlling the temperature and setting a constant flow of nitrogen at 0% RH.Test conditions may also vary depending on the acquisition configurations of the electronic system. Indeed, the number of points (sampling step) and the frequency span of measurement are configured for each case so as to optimize the response time without deteriorating the accuracy of the measurement. This consists of reducing the frequency band to the minimum possible and also the sampling step in order to keep the maximum number of points focused on the resonance peak.In this experiment, the detection of vapors is achieved by the diffusion of the analyte into the polymer layer and also by surface interaction with diamond sensors (bare cantilevers). As the operation mode for this application is the dynamic mode, changes in the polymer layers lead to an increase of sensor total mass, resulting in a negative frequency shift. Shifts of resonance frequency of each microcantilever are specific to the interaction between vapor molecules and the polymer. When we change to a flow of pure nitrogen in the same temperature and flow rate conditions, the trapped analyte starts to diffuse out of the sensitive layer, back to the environment, causing a decrease of mass and a positive resonant frequency shift. For each vapor tested, we have generated different concentrations in order to verify the linearity of the microcantilever sensors. Each concentration was also repeated at least three times in order to ensure that the response is reversible as shown in This procedure was repeated for 13 substances : Toluene; Styrene; Pentanal; Octanal; Hexanal; Ethanol; 2-Methyl-1-propanol; Butanol; Benzadehyde; Acetone; 6-Methyl-5-hepten-2-one; Phenyl acetate; Isopropanol. Each vapor was generated at 500 ppm and sensor response (resonance frequency shift) was measured. Relative response patterns for 12 of 13 vapors are shown in In order to identify the tested samples and evaluate the selectivity of the system, cantilever-array responses of different concentrations have been used to generate a set of “time-shift” vectors that corresponds to the dynamic development of the detection curves for each analyte. The data set was evaluated using principal component analysis (PCA) techniques, allowing to extract the most dominant deviations in the responses for the various sample vapors. In order to reduce the complexity of the analysis, we have only kept eight analytes, the best represented on the PCA first plane. As shown in In this work, we have reported the development of a system for vapor detection. Firstly, development results address the fabrication and characterization of silicon and diamond microcantilever-based sensors for VOC detection. In this study, microcantilevers were coated with different polymer layers in order to improve the sensitivity of the sensor array. A complete three-element electronic nose system  was developed and we have demonstrated that an array of resonant micromechanical cantilevers can be used as chemical sensors for electronic noses. The system developed is completely autonomous and modular. One of the most important results of the present work is the development of a gas analysis cell (patented) able to hold up to eight sensors which are exposed to a homogeneous gas flow while providing electrical read-out of sensors. Moreover, the gas cell also provides an easy and reliable actuation method employing a piezo-electrical cell. A dedicated electronic read-out circuit has been conceived in two different boards which provides low-noise detection of sensor output signals and accurately tracks frequency shifts. Sensor frequency profiles are updated to the user interface every second, which allows detections to be followed in real-time, during field operation. The system was used to detect 13 volatile organic compounds in the range of hundreds of ppm and PCA techniques were applied to identify samples. In conclusion, we have developed a microcantilever sensor array-based system that exhibits significant potential as a tool for vapor analysis. Improvements in the sensor quality factor, sensitivity and specificity of sensitive layers may be considered in future work in order to improve the identification and separation of samples.