Diabetes is an important health burden in Indonesia. However, diabetes management and treatment remain poor, with most people with diabetes in Indonesia not achieving the recommended blood glucose levels. Peer education may have particular potential in low-income settings in complementing diabetes care without being a large additional strain on the health system.puskesmas). Altogether, 29 puskesmas were recruited in Banda Aceh and Aceh Besar, each of which was randomly assigned to either the control or the intervention group. Then, 534 people with diabetes were identified and recruited through their respective puskesmas. The intervention consists of up to two peer education groups per puskesmas, which are led by previously trained people with diabetes. Peer education sessions are held every month for 18 months, with follow-up data being collected 9 and 18 months after the first peer education session.This cluster randomized controlled trial aims to identify the effect of the implementation of peer education for patients with type 2 diabetes on diabetes-related outcomes in Aceh, Indonesia, which will complement the diabetes treatment provided at primary-care health posts  levels. Secondary outcomes are the effects of peer education on lipid levels, waist circumference, blood pressure, quality of life, treatment adherence, diabetes knowledge, physical activity, and dietary diversity. Data sources for the measurement of outcomes include patient and health facility surveys and biomarker measurements. An economic evaluation will be conducted to assess the cost-effectiveness of the intervention.This trial will contribute to the evidence on the effectiveness and cost-effectiveness of peer education in improving diabetes management in a low-income setting in Indonesia and in other comparable contexts.ISRCTN68253014. Registered on 18 February 2019.ISRCTN registry, The online version of this article (10.1186/s13063-019-3656-1) contains supplementary material, which is available to authorized users. Public health systems in low- and middle-income countries are overburdened with the demands of delivering care to those with communicable and non-communicable diseases. People with the latter in particular often require long-term monitoring and support to achieve good health . For diapuskesmas, remains poor, which is partly due to the limited knowledge of health-care professionals about diabetes [In Indonesia, diabetes has become one of the main contributors to the burden of disease, surpassing many communicable diseases, especially among adults . Howeverdiabetes , 3. Consdiabetes .A potential way to complement the diabetes care available in Indonesia is the use of peer education, in which highly motivated and trained diabetes patients educate and support other patients with diabetes to manage the disease in daily life in a culturally appropriate way. Due to the need for patients to deal with their diabetes every day, and the potential of lifestyle changes and preventative behavior to prevent major diabetes complications, empowering patients by increasing their knowledge of diabetes care could theoretically yield positive results. Peer education focuses and relies on people with diabetes, rather than medical professionals, to improve diabetes care. Therefore, it may be less resource intensive than traditional approaches and particularly attractive in environments where access to and the quality of diabetes health care are very limited .Several randomized controlled trials have been conducted in recent years to test the efficacy of peer education in improving diabetes outcomes in high- and in some low- and middle-income countries. Two systematic reviews have indicated that peer education overall can lead to statistically significant reductions in HbA1c levels , 6. It aHence, there is a lack of evidence on the causal effect of peer education in low- and middle-income countries, in particular on its adaptability to non-urban environments where diabetes care mainly happens at the primary-care level.Our study results may, therefore, play an important part in advancing the knowledge base on the treatment of diabetes in low- and middle-income countries. In particular, it may provide evidence of its effectiveness in a setting that consists of both urban and relatively remote rural areas, and where traditional beliefs around diabetes and the use of alternative medicines are still relatively common .Moreover, our study will look at the effectiveness of peer education over a relatively long time of 18 months. It further aims not only to look at HbA1c, but also at changes in lipid levels as well as blood pressure and waist circumference, given their role as risk factors for diabetes-related complications. Because peer education relies on the ability of peer educators to train their peers and the peers’ ability to use this information to change their behavior, we will also assess if the personal characteristics of study participants can mediate the success of the intervention. In particular, we want to investigate the role of time and risk preferences, which may mediate the ability of participant to prioritize behavior change today to prevent diabetes complications in the future. Finally, our study will provide estimates of the cost-effectiveness of peer education in a low-income context of a developing country. This will add further evidence about the viability of peer education in health systems of low- and middle-income countries in terms of its financial costs and effectiveness.puskesmas. These are government-mandated primary-care providers and the first point of contact for people seeking care in the public health system in Indonesia. Each puskesmas normally serves one sub-district, which has a population of 30,000 to 50,000. The main role of puskesmas is the delivery of primary outpatient care, but they are also used to promote and realize public health measures such as immunization, nutrition education and health information campaigns. About one-third of puskesmas in Indonesia provide basic inpatient care for emergency obstetric and neonatal care. Outpatient care efforts have mainly focused on communicable diseases, so that many puskesmas, especially in rural areas, provide a low quality of diabetes services [puskesmas in the districts Banda Aceh and Aceh Besar in the north of Sumatra, with Banda Aceh consisting of mostly urban areas and Aceh Besar of rural areas.In Indonesia, most people with diabetes receive their regular diabetes treatment at the primary-care level at public health posts called services . This isservices , 3. The services . This stpuskesmas from Banda Aceh and Aceh Besar Regency.puskesmas after they joined the study and baseline data collection had been terminated. This study design allows us to establish two groups of participants (treatment and control group) so that we can causally identify the effect of the peer education on the primary and secondary outcomes. Blinding was possible at baseline, which preceded the allocation of clusters into treatment and control groups. However, after the randomization and allocation, the blinding of the treatment allocation of participants, project managers, and investigators is no longer possible. For the duration of the study, the control group will not receive any intervention beyond being informed about their blood test results. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist is provided as an Additional file The study is a cluster randomized controlled trial with a parallel group design, with the clusters consisting of Peer support has been defined as “support from a person who possesses experiential knowledge of a specific behavior or stressor and similar characteristics as the target population” . It has puskesmas informed the intervention design, in particular regarding practicable ways to train peer educators and to provide them with the means to transfer their knowledge successfully to their peer groups.The intervention was designed in cooperation with the local expert team as well as experts experienced with the implementation of peer education in a low-income context in Mali . FurtherSelected peer educators will receive training before and after the start of the implementation. A 2-day intensive training session by local physicians on diabetes and nutrition was carried out at the beginning of April 2019 before the start of the peer education sessions. It provided general information about diabetes as a disease, its risks, and the ways to treat it. This initial information session will be followed up by monthly half-day training sessions for the peer educators until the end of the study. These training sessions for peer educators will be led by two specially trained nurses, who, prior to each training session, will be educated by a member of the research team on the specific topic to be discussed. The topics and structure of the peer educator training sessions will be guided by the peer leader manual published by the International Diabetes Federation . The goapuskesmas and the number of potential peer educators, one or two peer educators will be selected per puskesmas, to limit the group size to 13 participants. Peer education sessions are planned to be held once a month for 18 months. They will be conducted by the peer educator only, without the presence of a trained nurse or a member of the research staff, to avoid any potential changes in the behavior of the peer educator or the patients. To preserve some flexibility in how peer educators conduct the peer education sessions and react to the needs of the group, we will refrain from closely monitoring each session. Rather, we will use feedback from the peer educators about the sessions to determine if they are successful in discussing the planned topics.Depending on the number of patients recruited per Will HbA1c levels decrease in patients who take part in peer education groups and if so, by how much?What effect will peer education have on lipid levels, waist circumference, blood pressure, and quality of life?What effect will peer education have on health and self-care behavior of participants in the intervention group?Is the intervention cost-effectiveness?What are important mediators for the effectiveness of peer education?The specific research questions are:changes in lipids  collected using point-of-care testing devices at baseline, during the trial, and at the final assessmentblood pressurewaist circumferencediabetes knowledgemedication adherence diabetes distress healthy behaviors, such as smoking status and number of cigarettes per day, and physical activity levels dietary diversity (dietary diversity questionnaire published by the Food and Agriculture Organization of the U.N. )The primary outcome is the change in HbA1c levels from baseline to the final assessment. HbA1c will be collected at baseline, midline and the final assessment using point-of-care testing devices allowing for the immediate measurement of HbA1c levels. Secondary outcomes are:Finally, to assess the cost-effectiveness of the intervention, changes in health-care costs and changes in quality-adjusted life years (based on EQ-5D-3 L questionnaire ) will beRegarding potential mediators, we specifically focus on the behavioral characteristics of the participants. In particular, we measure risk and time preferences as well as trust in other people using unincentivised questions. We also use the Collective Self-Esteem Scale, which measures the ability of participants to function in and identify with social groups , and theA qualitative study to inform the intervention was carried out in May and June 2018. As shown in the SPIRIT figure  their willingness to take on this role, (2) a recommendation from the health facility staff, and (3) how well they were already controlling their diabetes based on the HbA1c level from the baseline data.puskesmas were randomized. Because recruitment took place before randomization, the researchers, participants, and facility managers did not know which facilities would be allocated to the treatment and control groups. We used covariate-constrained randomization to ensure the treatment and control arms were balanced in terms of baseline covariates while maintaining the randomness of the allocation [puskesmas . Randomization was carried out using the statistics program Stata.Following data collection, the location , 21. Thepuskesmas in the treatment group. Peer educators will receive continuous training in diabetes management skills and will be supported in the administrative processes  required to run their peer education group in their local sub-district.Peer education groups were formed at each To ensure that the effect of using peer education can be observed in comparison to normal patient education efforts, the control group will not receive any additional education apart from standard therapy.As detailed in Fig. We will then compare the outcomes between treatment and control groups, carry out a cost-effectiveness analysis, present the results to local health authorities, and discuss how to implement the program more widely if it proves to be effective.Costs related to the implementation of peer education will be collected from the the documented project expenditures. Data on resource use for diabetes treatment and care, including equipment, drugs, and doctor and hospital visits, will be collected retrospectively using cost information from the health insurance provider if possible, or via the expert opinion of local specialists. These data will be supplemented with information on participants’ health-care seeking behavior and utilization, drug use, and out-of-pocket payments collected through the surveys.To estimate cost-effectiveness, the incremental cost-effectiveness ratio will be calculated from the health-care system perspective and the societal perspective taking into account out-of-pocket expenditures and costs related to participating in peer education. The incremental cost-effectiveness ratio is defined by the difference in costs between receiving no intervention plus standard diabetes care and the standard care plus intervention costs, divided by the difference in their effect. Here it represents the average incremental cost for peer education associated with one additional quality-adjusted life year.Data will be collected using tablets and directly entered into the electronic data entry program Open Data Kit (ODK collect). Data will be anonymized, and the original data will be stored separately on an encrypted hard storage device. Any biomarker data will be stored separately from the participant’s name on an encrypted hard storage device. The results of the biomarker tests will be reported back to the participants.Random sampling and random assignment of intervention units to the treatment and control groups will allow us to interpret differences in mean outcomes as causal effects of the intervention. By comparing outcomes between participants in the peer education groups compared to study participants in the control group, we will be able to draw conclusions of the intent-to-treat effect and the size of the effect.puskesmas).Because covariate-constrained randomization was used to balance the baseline characteristics, it is necessary to account for this design at the analysis stage , 22. We Because this study does not involve any testing of medications or procedures that are outside the usual care provided to individuals with type 2 diabetes, monitoring patient safety will be limited to mandatory reporting of adverse events and unanticipated problems. Participants will be made aware of unexpected test findings identified during the trial. Adverse events include clinical reactions to blood draws related to the study, as well as any reported stigma or physical or mental harm as a result of participation in the study, including disclosure of diabetes status.Trial participation is voluntary, so that participants may leave the trial at any time for whatever reason. Because the provision of education should only add to the participants’ knowledge about how to manage their diabetes, we see no immediate risks for participants. This additional information may lead to an increased awareness of the risks of sustained high glucose levels and could increase anxiety in participants. Theoretically, the personal experience or beliefs of the peer educators may lead them to diverge from the educational material to promote potentially harmful or ineffective practices for treating diabetes.The possible high returns from participating in the peer education sessions and from knowing their HbA1c and other biomarkers will be emphasized to motivate patients to continue trial participation. Because the control and intervention groups will receive their blood test results, any effects on our outcome variables due to receiving this information should not affect the estimate of the intervention effect. To prevent peer educators from promoting ineffective and potentially harmful treatments of diabetes, we will carefully select peer educators and emphasize the need to follow the content of the education materials during the peer education sessions. We may also aim to address some myths surrounding diabetes and how diabetes should be treated to increase awareness of the potential dangers of ineffective treatments, which peer educators can use to address such beliefs in their peer education sessions.The goal of this cluster randomized controlled trial is to test the effectiveness of peer education to improve diabetes-related outcomes in a low-income setting with a high burden of diabetes.This trial has several advantages over previous trials carried out on peer education for diabetes in low- and middle-income countries. First, its relatively long follow-up allows us to observe the effectiveness of peer education over a longer time. Second, because we measure not only HbA1c but also blood lipids, we will be also able to investigate the effects of peer education on these risk factors for diabetes complications. Further, we collect information on risk and time preferences, which will allow us to assess whether the effectiveness of the intervention depends on such personal patient characteristics. Finally, we will provide a first estimate of the cost-effectiveness of peer education in a low-income context with the goal of informing policy makers of the costs and benefits of the intervention, and in comparison to other interventions in the health sector.If the trial shows that peer education is effective in improving diabetes outcomes in Indonesia, the next step will be to explore the potential for the intervention to be integrated into the local health-care system, considering the practicability of the intervention and its cost-effectiveness. We have been in contact with local health authorities who are supporting the study and will disseminate the results to them and other authorities once the study has concluded.The current version of this protocol is 1.5, dated 5 August 2019. Enrollment began on 18 February 2019 and concluded on 10 April 2019.Additional file 1:SPIRIT 2013 Checklist. Recommended items to address in a clinical trial protocol and related documents. (DOC 122 kb)Additional file 2:Consent Forms (patients and facilites) in Indonesian. (PDF 399 kb)Additional file 3:Consent Form (patients and facilities) in English. (PDF 313 kb)


The denial of pregnancy is the non-recognition of the state of the current pregnancy by a pregnant woman. It lasts for a few months or for the whole pregnancy, with generally few physical transformations. In this study, we will consider the denial of pregnancy as a late declaration of pregnancy (beyond 20 weeks of gestation) as well as a lack of objective perceptions of this pregnancy. The main objective of this study is to explore the relationship between pregnancy denial and the development of the infant .The design is a case-control prospective study, which will compare two groups of mother-infant dyads: a “case” group with maternal denials of pregnancy and a “control” group without denials of pregnancy. A total of 140 dyads (mother + infant) will be included in this study (70 cases and 70 controls) and followed for 18 months. The setting is a national recruitment setting with 10 centers distributed all over France. The follow-up of the “cases” and the “controls” will be identical and will occur over 5 visits. It will include measures of the infant attachment pattern, the quality of early mother-infant interaction and infant development.This study aims to examine the pathogenesis of pregnancy denial as well as its consequences on early infant development and early mother-infant interaction.NCT02867579 on the date of 16 August 2016 (retrospectively registered).Clinical Trial Number:  Described in the 1970s , pregnana large range of occurrences, which are the refusal or incapacity of a pregnant woman to admit her condition” [There is no consensus concerning the definition of pregnancy denial. First, there is no consensus on the threshold date from when the pregnancy is considered denied if unacknowledged. On the one hand, some authors consider that the threshold date is beyond the first trimester: 14 weeks of amenorrhea , beyond ndition” . These dThe denial of pregnancy calls into question maternal psychological functioning. However, to date, no link between any specific psychiatric disorder and denial of pregnancy has been established . During During pregnancy, a mother is getting prepared to meet her child and build quality interactions through a maturational process leading to a psychological reorganization. The pregnancy and the birth represent, for the woman, an essential phase of her psycho-affective development, comparable to the adolescence in its somatic, hormonal and psychological changes. In the past, many authors have studied these psychological reorganizations and proposed theories , 13. TheWe put forward the following hypothesis: an insecure attachment of the mother would participate or at least would increase the likeliness of pregnancy denial. These mothers would find it difficult (even impossible in some cases) to access the experiences of their infants, which are essential in the psychological reorganizations necessary during pregnancy to prepare the woman to accept her new functions as a mother.Moreover, the absence or reduction of the duration of the usual 9-month period for psychological elaboration during the pregnancy calls into question its potential impact on the quality of mother-child interactions. Are there consequences on the infant’s development as well as on his pattern of attachment? We hypothesize that the attachment and the development of the infant to be born, as well as the quality of mother-infant interaction, are disturbed when the woman presents a denial of pregnancy. Specifically, we expect these consequences to be stronger with a longer duration of pregnancy denial.The primary objective of this study is to examine the relationship between pregnancy denial and infant attachment patterns, early mother-infant interaction and early infant development.To explore among women with pregnancy denial the influence of the duration period between the pregnancy announcement and delivery on infant attachment pattern, early mother-infant interaction and early infant development;To study the factors associated with pregnancy denial, including the type of maternal attachment and the existence of a maternal personality disorder and/or a psychiatric condition.The secondary objectives of this research are as follows:This study has been retrospectively registered in the European registry (EudraCT 2011-A01498-33) and in clinicaltrials.gov (NCT02867579). The recruitments and the interventions started on April 2013 and will be completed in April 2019.This study entitled “Attachment and pregnancy denial” is a national multicenter prospective case-control study with 13 French investigation centers .Inclusion criteria are as follows. In the case group, dyads are composed of a woman with pregnancy denial and her infant. Pregnancy denial will be defined by a pregnancy announcement after 20 weeks of gestation and a lack of objective perceptions of the pregnancy by the woman. Women with no follow-up of the pregnancy due to geographical, social or administrative reasons  will not be included. In the control group, dyads are composed of a woman without pregnancy denial and her infant. The case group and the control group will be matched on primiparous and non-primiparous mothers and on premature (birth before 37 GW) and non-premature infants.Exclusion criteria are as follows: minor women (< 18 years old), women with intellectual disability, women with an acute or chronic psychotic condition, women who do not speak fluent French, women with illegal administrative status, newborn with a life-threatening prognosis, newborn with an organic malformation and/or genetic abnormality observed before leaving the hospital, and medically assisted reproduction (for the control group).In a pragmatic way, due to the lack of data concerning the relationship between pregnancy denial and infant attachment pattern in the literature, participation will be proposed to all women with pregnancy denial during the inclusion period. Given the average number of births per year and by center (2500 on average), the number of participating centers (N=13), the frequency of pregnancy denial (2/1000 child births), the duration of the inclusion phase (48 months) and the expected participation acceptance rate (25%), 70 women with pregnancy denial will be included in this study. Therefore, 140 dyads mother-infant women will be included in this study. Based on the hypothesis of a score for disorganization , 23 of 3Participation to the study will be proposed during hospitalization after delivery. The follow-up of the cases and the control will be similar. The total duration of participation of each dyad is 20 months. The design of the study will not change the eventual care provided to the dyad. If some care is proposed or given, a description of this care will be included in the data collection.The study’s follow-up includes 6 visits Table .Table 1VDuring the first visit (during the week after delivery), informed consent, data  will be collected. Additionally, medical information, including gestation and parity, pregnancy records, and medical, surgical and psychiatric history, will be extracted from the mother’s charts. Direct assessment of perceived social support with the Perceived Social Support Questionnaire (PSSQ)  and psycThe second visit (6 to 8 weeks after delivery) includes the following: assessments of depression with the Beck Depression Inventory (BDI)  the EdinThe third visit (6 months after delivery) includes assessments of mother-infant interaction during a meal with the Coding Interaction Behavior system (CIB) , 32, of The fourth visit (12 months after delivery) includes evaluations of maternal depression (BDI and EPDS), of maternal anxiety (STAI), of perceived social support (PSSQ), of interactions during a meal (CIB), of child development (DSST) and of the relational retreat behavior of the child (ADBB).The fifth visit (18 months after delivery) includes evaluations of the infant’s pattern of attachment with the SSP (Strange Situation Procedure)  and of tThe sixth visit (20 months after birth) is a free assessment with the objective of thanking the parents for their participation and surveying them about the organization and design of this study.For the infants: The attachment pattern of the infant is assessed with the Strange Situation Procedure , 38 A moThe quality of early mother-infant interaction is assessed with the Coding Interactive Behavior (CIB) of Feldman , 32. TheThe infant’s development is evaluated with the Denver Developmental Screening Test . The chiSocial contact is also evaluated on the Alarm Distress Baby Scale . This scFor the mothers: The representations of the adult’s attachment are studied with the Adult Attachment Narrative  through The evaluation of personality disorders described in the ICD-10 is completed with the International Personality Disorders Examination (IPDE) . This seThe main psychiatric disorders of the axis I of the ICD-10 are explored with the Mini International Neuropsychiatric Interview (MINI) . This stThe mothers’ depressive feelings are evaluated with two scales. First, the Edinburgh Postnatal Depression Scale  a quick The mothers’ anxious feelings are evaluated with Spielberger’s State-Trait Anxiety Inventory Form Y . The invThe availability of and satisfaction with the social support received are evaluated with the Perceived Social Support Questionnaire  a self-aWe expect a percentage of women to drop out of the study before its end, especially in the case group. Mothers who experience a denial of pregnancy are more likely to drop out of the study earlier than mothers in the control group. This early attrition will impact the size of our sample.The attachment pattern of the mother (AAN) and of the infant (Strange Situation) and the mother-infant interactions (CIB) will be all evaluated based on videos conducted by each center. Ratings will be performed by one single qualified team  and by two trained raters who will remain blind to group status.Data will be described using means and standard deviations for quantitative variables and numbers and percentages for qualitative variable. Normal distributions will be checked.To study factors associated with pregnancy denial, characteristics of women with pregnancy denial and characteristics of women without pregnancy denial will be compared with univariate analysis  and multivariate analysis (logistic regression).Factors associated with the attachment pattern of the child, divided into two categories (“secure” and “insecure”), will be studied by univariate  and multivariate analysis (logistic regression).P-value <0.05 will be considered statistically significant.A All analysis will be performed using SAS version 9.4 .This study aims to examine the pathogenesis of pregnancy denial as well as its consequences on the attachment pattern of the child, the quality of early mother-infant interaction and infant development. We expect this study to more clearly define what pregnancy denial is and, thus, to improve the care of mother-infant dyads.The denial of pregnancy remains a poorly understood symptom, and there are few publications and no prospective studies on this topic, especially case-control studies.This is the first study exploring the relationship between pregnancy denial and the development of the infant.This is the first study, influenced by attachment theory, to evaluate and compare the attachment patterns of the mothers and infants in case and control groups.This study did not limit mothers’ access to specific care, if indicated.Mothers who experienced a denial of pregnancy are expected to drop out of the study earlier than mothers in the control group, which will impact the size of our sample as well as the results of the study.


Sensing the wideband spectrum is an important process for next-generation wireless communication systems. Spectrum sensing primarily aims at detecting unused spectrum holes over wide frequency bands so that secondary users can use them to meet their requirements in terms of quality-of-service. However, this sensing process requires a great deal of time, which is not acceptable for timely communications. In addition, the sensing measurements are often affected by uncertainty. In this paper, we propose an approach based on Bayesian compressive sensing to speed up the process of sensing and to handle uncertainty. This approach takes only a few measurements using a Toeplitz matrix, recovers the wideband signal from a few measurements using Bayesian compressive sensing via fast Laplace prior, and detects either the presence or absence of the primary user using an autocorrelation-based detection method. The proposed approach was implemented using GNU Radio software and Universal Software Radio Peripheral units and was tested on real-world signals. The results show that the proposed approach speeds up the sensing process by minimizing the number of samples while achieving the same performance as Nyquist-based sensing techniques regarding both the probabilities of detection and false alarm. The growing number of wireless devices, the increasing demand for higher data rates, and the current static allocation of the radio spectrum are the leading causes of the radio spectrum scarcity problem. To address this issue and to enhance access to the radio spectrum, cognitive radio technology has been proposed as a viable solution. A cognitive radio system is a smart wireless communication system that can sense the radio spectrum, detect unused spectrum holes, and adjust dynamically its transmission parameters to access free frequency channels without causing any harmful interference to the licensed users or primary users ,2,3. In These techniques aim at detecting spectral opportunities over narrow frequency bands; however, cognitive radio systems aim to exploit spectral opportunities over broad frequency bands ranging from hundreds of megahertz to hundreds of gigahertz and consequently these sensing techniques cannot be applied directly to perform wideband spectrum sensing.Wideband spectrum sensing is one of the challenges facing researchers to design next-generation communication systems because this process requires a high sampling rate, which results in a high processing time and energy consumption. In conventional communication systems, this sensing is performed by an Analog-to-Digital Converter (ADC) working at the Nyquist rate leading to a high sampling rate and implementation complexity . For insSeveral sensing approaches have been proposed to perform wideband spectrum sensing ,9,10,11.Uncertainty is yet another problem that affects wideband spectrum sensing. The authors of  proposedTo speed up the process of sensing the wideband spectrum, compressive sensing has been proposed ,23,24. TTian et al.  introducMost of the proposed compressive-sensing techniques have been evaluated in either a noise-free environment or using simulations in non-realistic scenarios. For instance, the authors  evaluateA few research works have been conducted on the implementation of compressive sensing to investigate the reliability of this new sensing framework. For instance, the authors of ,37 propoIn this paper, we propose a Bayesian compressive approach for sensing the wideband radio spectrum. The proposed scheme is based on Bayesian compressive sensing via fast Laplace prior (BCS-LP) to recover the wideband signal from a few measurements combined with an autocorrelation-based detection technique to obtain an accurate sensing decision. Unlike most of the existing techniques, the proposed model uses an autocorrelation-based detection technique because it is insensitive to noise. The proposed approach was implemented using GNU Radio software and universal software radio peripheral (USRP) units and was extensively tested on real-time signals. The experimental setup uses real-time signal transmitted and recorded using the USRP and GNU radio. The level of the signal-to-noise ratio was measured using a method based on the eigenvalues of the sample covariance matrix of the received signal ,25,26,27A review of the wideband sensing techniquesThe mathematical model of the Bayesian compressive sensing-based methodAn experimental setup using software defined radio unitsAn evaluation of the proposed approach using several metricsA Comparison between the proposed approach and three Nyquist-based sensing techniquesThe contributions of this paper can be summarized as follows:The rest of this paper is structured as follows. The proposed approach for sensing the wideband spectrum is based on Bayesian compressive sensing and an autocorrelation-based detection technique. During this sensing, the receiver only captures a few samples. Then, the Bayesian-based recovery technique recovers the wideband signal from these few measurements followed by the autocorrelation-based detection technique to obtain the sensing decision. In the first part of this section, the mathematical model of the proposed approach is described, and in the second part, the implementation of this approach is described as well as the experimental setup used to test the model.N sub-bands. Then, the received signal at the secondary user can be expressed as:The wideband signal considered is divided into In the frequency domain, this signal can be expressed as:At a time The received signal is then reduced using a sensing matrix to obtain the vector of measurements. A sensing matrix, which has to satisfy the Restricted Isometry Property, is used to select the few measurements from the sparse signal. The vector of measurements is then given by:The signal is then reconstructed from the set of measurements The recovery formulation is given asThe signal is then reconstructed from the set of measurements Bayesian compressive sensing requires determining a joint probability distribution function (pdf) of the hierarchical model The hyper-parameter The signal model is equivalent to using a Laplace prior on the coefficients The Bayesian inference is given by:Since The updates of other parameters can be determined by setting the two partial derivatives of the logarithm of the joint probability density function Thus, we find expressions for these two hyper-parameters, which are given by: Once we determine the hyper-parameters, we can find an expression for the joint probability density function s(n) denotes the primary user signal, and Once the wideband signal is recovered, a detection technique has to be applied to obtain the sensing decision. In our model, we performed the detection using autocorrelation-based sensing detection because of its advantages compared to other techniques . This seE denotes the expectation and the The statistical covariance matrices of the vector I represents the identity matrix.The matrix ij-th element of the matrix If the signal thors of  proposedThe proposed approach and the Nyquist-based model were implemented using GNU Radio and USRP units. GNU Radio is open source software that contains several digital signal-processing blocks, which can be used to implement radio subsystems. To create a new customized block in GNU Radio, either C++ or Python language can be used. USRP units are Software Defined Radio devices designed for RF applications and can be interfaced with GNU Radio software, which has a USRP Hardware Driver (UHD) block allowing the computer to capture the samples coming from these units. The USRP units used in this work have This experimental setup is illustrated in The second USRP, which acts as the receiver, is tuned to a center frequency. Then, the samples corresponding to this center frequency are captured by the UHD block and saved in a Python Numpy Array using the block printer_f. For each center frequency, the measurement matrix is applied to the array that contains the samples captured from the USRP unit to obtain only a few samples. The sensing matrix used is a random Gaussian matrix. Based on these few samples and a Toeplitz measurement matrix, the signal is reconstructed via the BCS-LP recovery technique, and then the autocorrelation technique is applied to the recovered signal to determine the presence or the absence of the primary user. All collected measurements are saved in a Python Numpy array. For comparison purposes, standard sensing is also performed for each center frequency, which skips the compressive sensing part and applies the autocorrelation directly to the received signal. The same operation is done for all center frequencies listed in Several experiments were performed to evaluate the efficiency of the proposed model. In the following, we present the results of the comparison between our proposed approach, Bayesian compressed sensing model, and the Nyquist-based sensing technique. The choice of the Bayesian recovery algorithm is justified by the results of a comparison between several recovery techniques  conducteThe performance of compressive sensing techniques is affected by the measurement matrix used. In a previous work that compared the performances of measurement matrices , we showIn this work, to evaluate the wideband spectrum sensing models, several evaluation metrics are used, which are the probability of detection  cable, and we change the level of noise at the transmitter side. Another challenge was how to make sure that the SNR we are targeting is the one that we have created. To overcome this challenge, we used a noise measurement method based on the eigenvalues of covariance matrix of the received samples ,41. ThisExamples of results are shown in M = 2048, the sensing time is 54 ms and for M = 1024, the sensing time is 37 ms, which means that if we decrease the number of measurements by 50%, the sensing time is also decreased by almost 32%.In this paper, we have proposed a novel approach for speeding up the process of wideband spectrum sensing, handling uncertainty, and identifying the free radio channels. This approach uses Bayesian compressive sensing combined with the autocorrelation-based detection. The proposed technique was implemented using GNU Radio and USRP units. Numerous experiments were performed to validate the proposed model using metrics, including the probability of detection, probability of false alarm, mean square error, and sensing time. The efficiency of the proposed model was compared with that of several Nyquist-based sensing techniques. These results show that this model speeds up the sensing process while achieving approximately the same probabilities of detection and false alarm as Nyquist-based sensing techniques. For future work, we will focus on further improving the detection performance of the compressive sensing techniques by measuring SNR and automatically selecting the number of measurements to reduce the recovery error. We plan also to investigate the application of one-bit compressive sensing for wideband spectrum sensing because of its advantages such as low complexity, fast sampling, and low storage cost as well as the robustness to noise.


Incisor loss constitutes a strong aesthetic and psychologic traumatism for the patient and it remains a challenging situation for the dental practitioner because of the necessity to rapidly replace the lacking tooth. Various therapeutic procedures have been proposed to replace the incisor concerned, for example by using a removable partial denture. However, the manufacturing of such a denture with classical procedures is often subject to processing errors and inaccuracies. The computer-aided design and computer-aided manufacturing (CAD-CAM) technology could represent a good alternative, but it is currently difficult because of the lack of dental softwares able to design easily immediate removable partial dentures.A 30-year- patient complained about pain caused by a horizontally and vertically mobile maxillary right central incisor. After all options were presented, extraction of the traumatized incisor was decided due to its very poor prognosis, and the patient selected the realization of a removable denture for economic reasons. The present paper proposes an innovative procedure for immediate removable denture, based on the use of an intraoral scanner, CAD with two different softwares used sequentially, and CAM with a 5-axis machine.We show in this report that associating an intraoral scanner and CAD-CAM technology can be extended to immediate dentures manufacturing, which could be a valuable procedure for dental practitioners and laboratories, and also for patients.The online version of this article (10.1186/s12903-018-0578-3) contains supplementary material, which is available to authorized users. In the case of anterior tooth loss, for example after trauma and/or infection, the rapid replacement of the lacking tooth is a major challenge for dental practitioners. Indeed, in addition to masticatory dysfunction, the absence of an anterior tooth is psychologically highly traumatic for aesthetic reasons and greatly impairs the patient’s quality of life. In this clinical situation, immediate placement of a dental implant or a cantilever bridge can provide early aesthetic solutions . HoweverTo avoid such drawbacks, digital workflow using computer-aided design and computer-aided manufacturing (CAD-CAM) technology may represent a suitable alternative. Indeed, the use of this technology has been shown to improve the fitting and aesthetics of the prosthesis while reducing costs and manufacturing difficulties for the dental laboratory . NumerouThe purpose of the present paper is to describe the clinical and technical steps of an original and rapid procedure for manufacturing an immediate removable partial denture with an intraoral scanner, CAD with two different softwares used sequentially, and CAM with a 5-axis machine.A 30-year-old male patient presented for a consultation in the Prosthodontics department of the Lyon University Hospital (France). The patient complained of a pain caused by the mobility of his maxillary right central incisor (11) Fig. . PatientAn early treatment was proposed to the patient to manage the loose incisor. It involved the extraction of the traumatized incisor due to its very poor prognosis, and then the immediate replacement of the lacking tooth with an artificial one. Several options were proposed to the patient, including the placement of a dental implant with a provisional crown, of a cantilever bridge, or of a removable partial denture. All options were discussed, and after a one week period of reflection the patient finally selected the realization of a temporary removable denture for economic reasons. The patient was informed that final prosthetic rehabilitation will be initiated only after treatment of the periodontal disease and disappearance of tissue inflammation. Clinical and technical steps were summarized in a timeline  Fig.  and d. VA virtual central incisor was generated from the contralateral central incisor (21) by using the mirror tool Fig.  and saveAfter oral disinfection with 0,5% chlorhexidine , a local anesthesia was realized in the buccal and palatal oral mucosa next to the loose incisor. The latter was then extracted atraumatically and hemostasis was realized by compress application Fig. . After hThe objective of this article was to describe a digital workflow for manufacturing an immediate removable partial denture. After the digital impression was realized with an intraoral scanner, the removable denture was designed by using sequentially two CAD-CAM softwares, milled in the dental laboratory and immediately positioned into the mouth after tooth extraction. To our best knowledge, this report is the first one describing a strategy of immediate removable partial denture manufacturing associating an intraoral scanner and CAD-CAM technology.The realization of immediate removable partial dentures is nowadays indicated in many clinical situations that need the placement of transitional prostheses or to overcome financial limitations . HoweverCandida albicans [Laboratory steps for classical immediate denture conception are numerous and include cast pouring, articulator mounting, teeth removing from the cast, and wax conception. All of these steps are error-prone, and a diminution of their number is clearly warranted. In our study, we increased the precision of the rehabilitation by setting up an alternative protocol using milled resin. Indeed, the latter offers a higher accuracy and reproducibility than the auto- and chemo-polymerisable resins that are used for traditional manufacturing of removable prostheses . Indeed,albicans .Removable dentures have to be designed as retentive and stable as possible , 16. We Interestingly, the digital workflow allows for keeping a virtual backup of the situation that can be easily reached in the case of future repair or reproduction that would be needed if the prosthesis is fractured or lost , 8. JodaDespite being a relatively nascent approach compared to implantology, the use of digital workflow for immediate removable partial dentures’ manufacturing is promising. We show in this report that digital workflow can now be extended to immediate partial dentures’ fabrication by using a combination of two softwares, one for the virtual extraction of the damaged tooth and the second for the conception of the denture. The use of the intraoral scanner makes easier data acquisition in the presence of a loose tooth compared to classical impression taking. The present protocol is currently making progress to propose applications for manufacturing larger immediate dentures.Additional file 1:Timeline of events. Clinical and technical steps of the case report. (PPTX 39 kb)


The dynamical systems view of movement generation in motor cortical areas has emerged as an effective way to explain the firing properties of populations of neurons recorded from these regions. Recently, many studies have focused on finding low-dimensional representations of these dynamical systems during voluntary reaching and grasping behaviors carried out by the forelimbs. One such model, the Poisson linear-dynamical-system (PLDS) model, has been shown to extract dynamics which can be used to decode reaching kinematics. However, few have investigated these dynamics, especially in non-human primates, during behaviors such as locomotion, which may involve motor cortex to a lesser degree. Here, we focused on unconstrained quadrupedal locomotion, and investigated whether unsupervised latent state-space models can extract low-dimensional dynamics while preserving information about hind-limb kinematics. Spiking activity from the leg area of primary motor cortex of rhesus macaques was recorded simultaneously with hind-limb joint positions during ambulation across a corridor, ladder, and on a treadmill at various speeds. We found that PLDS models can extract stereotyped low-dimensional neural trajectories from these neurons phase-locked to the gait cycle, and that distinct trajectories emerge depending on the speed and class of behavior. Additionally, it was possible to decode both the hind-limb kinematics and the gait phase from these inferred trajectories just as well or better than from the full neural population (18-80 neurons) with only 12 dimensions. Our results demonstrate that kinematics and gait phase during various locomotion tasks are well represented in low-dimensional latent dynamics inferred from motor cortex population activity. With the advent of large scale intracortical recordings allowing for the simultaneous interrogation of dozens to hundreds of neurons, the study of the role of motor cortex in the generation of movement has been steadily moving toward investigation of cortical dynamics in the brain on the population level. Ensembles of cortical neurons are organized as recurrently connected networks, introducing shared variability among the constituent cells, in turn constraining firing activity to a lower-dimensional space  is one such technique which employs both unsupervised dimensionality reduction as well as explicit temporal dynamics. PLDS maps low-dimensional latent states to the measured high-dimensional neural spiking activity through an observation point-process model and explicitly estimates the dynamics of these latent states as it evolves through time with a linear mapping  in one hemisphere of the leg area of primary motor cortex (M1), located medially along the precentral gyrus , greater trochanter (hip), lateral condyle (knee), lateral malleolus (ankle), 5th metatarsophalangeal , and outside tip of the fifth digit (toe tip). Marker locations were identified by feeling for the bony projections of the above anatomic landmarks under the skin; see Capogrosso et al.  for a viSubjects carried out various behavioral motor tasks . MonkeysRecording was carried out over 1–2 days for each monkey. Each day consisted of recording different randomly interleaved sessions for each task. Each treadmill session consisted of approximately 1 min of walking. These sessions were divided into epochs which contained only those time periods where the monkey was performing a single clear ambulatory behavior . Corridor and Ladder sessions consisted of walking back and forth along the corridor or ladder for a total of 20–30 rounds. These rounds contained only the steps performed at the middle of the corridor or ladder, to avoid the initiation and termination phase of locomotion.Neural data was obtained using the Blackrock Cerebus system, and saved onto a local computer through the Blackrock Central Suite program. The data was transmitted through a custom wireless headstage system .Occasionally, neural data would become lost or corrupt for periods within a trial. Trials were manually inspected for data corruption, and if a trial was missing neural data, it was excluded from the analysis. All the trials shown in We used explicit state-space models to estimate the latent states of full population neural activity during locomotion. A LDS model assumes the neuronal ensemble activity as Gaussian linear observations, and uses expectation maximization (EM) learning to estimate the unknown model parameters and the latent states given only the observations  provide a low-dimensional representation of the ensemble activity, unlike PLDS, they do not explicitly account for any temporal dynamics in the latent states. PSS selects a subset of n neurons from the full population that optimize neural decoding through a greedy supervised learning algorithm, hence the name predictive. Details of this method can be found in a previous paper , and also the activity of an optimal subsample of neurons from the full population, referred to as predictive subsampling (PSS). For PCA, the trials were concatenated across time and z-scored. The covariance matrix was computed, and the PCA projection matrix was constructed by eigenvalue decomposition—stacking the eigenvectors corresponding to the To generate the example neural trajectories shown in pmtm function in Matlab), and the values were averaged across all the trials of all the sessions. This was done for each of the decoded kinematic variables.To compare the smoothness of the decoder outputs, the power spectral density (PSD) of the decoded kinematics was computed for each of the four decoders, along with the real kinematics. For each trial, we estimated the PSD using Thomson's multitaper method  and determined the performance of each through a 10-fold cross-validation paradigm . The PSS2) between the estimated and the true signal as defined by equation 1. n is the number of points of the kinematic or gait variable in the trial, yi is the actual variable value at point i, ŷi is the estimated value from the decoder at point i, and ȳ is the average value of the kinematic or gait variable for the trial.Cross validation was performed on each recording session of each monkey. All of the trials of all five tasks were combined and randomized. The trials of all the tasks were then divided into 10 cross-validation blocks. Each block consisted of 5–24 (for decoding kinematics) and 7–27 (for decoding gait) trials which were used as the testing set while the remaining nine blocks were used as the training set. Decoder coefficients were calculated from the training sets using the least-squares regression algorithm between the neural data (Full Population and PSS) or latent states (PCA and PLDS) and the measured output signal . The decoder was then used to estimate the output signals of the testing set, and the decoding accuracy was calculated as the coefficient of determination  was used to decode the kinematics and gait cycle phase from the neural data. The decoded signals included the horizontal and vertical positions of the hip, knee, ankle, metatarsal, and toe tip joint markers, the joint angles, the leg extension, and the percentage of the gait cycle phase. The decoder is described by the equation:y[t] is the output signal being decoded at time t, and X[t − n] is a vector of the decoder inputs at lagged times t − n, for n = 0, …, 9. An is the corresponding vector of regression coefficients computed from the training set.where 2 values were carried out in Matlab (signrank function).Statistical tests comparing the RUsing the PLDS model, we extracted cyclic, low-dimensional neural trajectories during locomotion. Visualizing in three dimensions, the trajectories follow similar, saddle-like rotations across different tasks, and across different walking speeds . The MahWe used several neural features  of the population firing rates) as inputs to a Wiener filter decoder and measured how well each input feature could decode various kinematic variables under cross-validation. To determine the total number of dimensions to use in our decoders, we measured the PLDS decoder performance for all the kinematic variables while varying the input dimensionality from 1 to 20. We found that the performance plateaued at approximately 12 dimensions ; we usedR2 = 0.8294 vs. R2 = 0.5461), as well as compared to the PCA and PSS decoders . We then compared the cross-validation results for the various decoders across all monkeys and recording sessions that have kinematics (n = 7) for each of the kinematic variables, including the horizontal and vertical position of the joints, the joint angles , and leg extension . The PLDS decoder performance was not significantly different from the full-population decoder for any of the tested kinematic variables despite having only 12 input features, and indeed for all variables, the average PLDS decoder R2 was higher than the full population, although none of them reached significance when corrected for multiple testing , leading us to conclude that PCA and PSS features, at the same number of dimensions, do not preserve the kinematic information as completely as those obtained with the PLDS model. From the sample trial in 2. The power spectrum of the decoder outputs verifies that the PLDS decoder and the real kinematics have less power at high frequencies compared to the full population, PCA, and PSS decoders . The decoding performance was similar to the decoding of kinematics; there was no significant difference in R2 between the PLDS decoder and full population decoder, and the PCA and PSS decoder performed worse than the full population decoder .In addition to the above kinematic variables, we also investigated how well gait information, such as the phase of the gait cycle, could be estimated using each decoder. Trials consisted of a single gait cycle, and the phase of each cycle were standardized to a range of 0–100%. The phase was then estimated by each of the decoders, and the change in RWhile the PLDS and PCA models are both dimensionality reduction techniques, a key difference of PLDS is it explicitly models the temporal dynamics using a linear dynamical system. Other techniques have been developed which also models these dynamics such as jPCA , as well as autonomous locomotion . As far as we are aware, this is the first demonstration of explicit state-space models of neural dynamics robustly decoding kinematic and gait information during primate locomotion. These results also points to the potential of using PLDS in hind-limb BMIs, although direct testing in a closed-loop system would be required before any determination of the usefulness of PLDS as a feature extraction step can be made. Recently, newer techniques have been developed to extract neural dynamics using recurrent neural networks , license number 50120102-A.DB, EB, and GC performed data collection experiments. DX and MA performed decoding analysis. WT and DB conceived of and oversaw the project. EB and GC oversaw the original data collection. DX wrote the manuscript with MA. All authors contributed to the editing and finalization of the 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.


However, the SUV approach has several well-known shortcomings which adversely affect the reliability of the SUV as a surrogate of the metabolic rate of glucose consumption. The standard uptake ratio (SUR), i.e., the uptake time-corrected ratio of tumor SUV to image-derived arterial blood SUV, has been shown in the first clinical studies to overcome most of these shortcomings, to decrease test-retest variability, and to increase the prognostic value in comparison to SUV. However, it is unclear, to what extent the SUR approach is vulnerable to observer variability of the additionally required blood SUV (BSUV) determination. The goal of the present work was the investigation of the interobserver variability of image-derived BSUV.Today, the standardized uptake value (SUV) is essentially the only means for quantitative evaluation of static %. However, interobserver variability partly differs distinctly for different patients, covering a range of % in the investigated patient group.Interobserver variability in the pooled data amounts to RMS = 2.8% and is much smaller than the intersubject variability of BSUV (SD The present investigation demonstrates that the image-based manual determination of BSUV in the aorta is sufficiently reproducible across different observers and delineation tools which is a prerequisite for accurate SUR determination. This finding is in line with the already demonstrated superior prognostic value of SUR in comparison to SUV in the first clinical studies. However, the SUV approach has several well-known shortcomings, notably, uptake time dependence of the SUV, interstudy variability of the arterial input function (AIF), and susceptibility to errors in scanner calibration %. In comparison, the overall performance of the different observers when averaged over the whole patient group is rather similar as illustrated by Fig. d range of %.As demonstrated by our data, it is, however, relevant to ensure that the evaluated portions of the reconstructed images are free of spurious changes of the lesion to blood image contrast which might be caused by attenuation and scatter correction related effects in certain regions, notably induced by organ motion near the diaphragm and liver dome. Indeed, while the overall interobserver variability in the investigated patient group is very small, closer inspection of the data on a per-patient basis revealed that some patients exhibit substantially increased interobserver variability . However, by using a prescribed safety margin of about 8 mm to the aortic wall, partial volume effects are reduced to a negligible level. Even for a rather pessimistic scenario with a combination of small luminal aorta diameter of 21 mm , 27 and The present investigation demonstrates that the image-based manual determination of BSUV in the aorta is sufficiently reproducible across different observers and delineation tools which is a prerequisite for accurate SUR determination. This finding is in line with the already demonstrated superior prognostic value of SUR in comparison to SUV in the first clinical studies. The next logical step will be to fully automatize BSUV determination for a more streamlined use of SUR in the clinical setting. The presented data might serve as a valuable resource for validation of such future algorithms.


We validate the General Evolution Criterion, stating that the change in the chemical affinities proceeds in a way as to lower the value of the entropy production.Replicators are fundamental to the origin of life and evolvability. Biology exhibits homochirality: only one of two enantiomers is used in proteins and nucleic acids. Thermodynamic studies of chemical replicators able to lead to homochirality shed valuable light on the origin of homochirality and life in conformity with the underlying mechanisms and constraints. In line with this framework, enantioselective hypercyclic replicators may lead to spontaneous mirror symmetry breaking (SMSB) without the need for additional heterochiral inhibition reactions, which can be an obstacle for the emergence of evolutionary selection properties. We analyze the entropy production of a two-replicator system subject to homochiral cross-catalysis which can undergo SMSB in an open-flow reactor. The entropy exchange with the environment is provided by the input and output matter flows, and is essential for balancing the entropy production at the non-equilibrium stationary states. The partial entropy contributions, associated with the individual elementary flux modes, as defined by stoichiometric network analysis (SNA), describe how the system’s internal currents evolve, maintaining the balance between entropy production and exchange, while  The importance of studying chemical systems subject to various architectures, and capable of spontaneous mirror symmetry breaking (SMSB), owes to the problem of the origin of biological homochirality, an outstanding problem in origin of life research ,2, as weSpontaneous mirror symmetry breaking, or absolute asymmetric synthesis (AAS), refer to the transformation of achiral or racemizing initial products to final chiral reaction products in detectable enantiomeric excesses, and in the absence of any chiral polarization or external chiral forces and influences. SMSB and AAS involve transformations yielding nonracemic  outcomes as non-equilibrium steady states (NESS) ,4,5,6. TReaction networks able to lead to SMSB require, as a necessary but not sufficient condition, nonlinear kinetic dependences of enantioselective autocatalysis. Although a rare reaction in laboratory chemistry ,12, it isimultaneous emergence of biological homochirality during the formation of replicator networks with catalytic activity . Furthermore, such an hypothesis also implies that the current chiral machinery present in extant living beings, capable of transferring chirality and which is highly resistant to racemization, is a complex SMSB network which evolved from the primordial ones.Enantioselective hypercycles enable quadratic (first order) autocatalysis to achieve the enantioselective behavior of cubic (second-order) autocatalysis, and therefore may lead to spontaneous mirror symmetry breaking  for specific reaction rate constants in systems with thermodynamic architectures that maintain them out of equilibrium with their surroundings . The sigbalance of the former and the latter at a NESS, for non-equilibrium systems in terms of the extreme flux modes, as defined by stoichiometric network analysis (SNA) [The question of biological homochirality requires an understanding of the non-equilibrium thermodynamic conditions that may lead to stable deviations from the racemic composition. The purpose of this work is to place a strong emphasis on the entropic changes and exchanges associated with SMSB. In so doing we will understand how such chemical dynamical systems can be conceived and in strict obeyance of the thermodynamic laws. This approach is developed in detail employing a model of two cross-catalyzed chiral replicators. This may be regarded as a primitive infrabiological system  built ouis (SNA) .The so-called hypercycle model  solves tA represents the achiral resources needed to form the chiral replicators which engage in homochiral mutual cross-catalysis, Equations (1) and (2). We place these micro-reversible reactions within an open flow system, The species The resultant fourteen transformations are numbered sequentially as indicated, a convenience for setting up the stoichiometric network analysis (SNA)  that folintersected with the positive orthant of a 14-dimensional Euclidean space), and corresponds to the set of all the stationary state reaction rates [The chemical pathway structure of the reaction plus flow scheme Equations (1)–(6) is provided from knowledge of the right null space of on rates . Knowlede COPASI ) yields j-th transformation  the inflow of achiral resource A, (ii) its conversion into enantiomers of the replicators, and followed by (iii) the outflow of these enantiomers from the reactor. After SMSB, these racemic flux equalities are broken, indicating that relatively more flux flows through one of the corresponding flux mode pathway than through its oppositely handed flux mode pathway. This can be appreciated clearly, in for example, the SMSB bifurcations revealed by the partial entropy productions for each EFM, see Figures 4 and 5. After SMSB, we have A SNA stability analysis of the racemic configuration can be carried out following the procedure established in , and leaA is allowed to enter and exit the reactor, but none of the replicators, then SNA proves that the racemic state is absolutely stable, and for all values of closed “unproductive” pathways, while the fifth is the unreactive flow-through of the resource A. In this case, the non-equilibrium racemic states (which define the thermodynamic branch) are the only stable outcomes: the equalities By marked contrast, if only the achiral species The reaction rate constants in Equations  and (2) There is a relatively long induction period for which both replicators remain close to their initially extremely low concentration values, followed by a relatively rapid consumption of the shared achiral species A lnv7v8+v−v10lnv9vj and in the following way:SNA reveals the specific reaction pathways that are responsible for producing entropy . Thus frunidirectional extreme flux modes only and necessarily in the presence of the open unidirectional modes—and cannot produce entropy of and by themselves. Note furthermore that the input/output unreactive flow of resource A plays no role whatsoever in the production of entropy, since Equation  belolculated  using Taith reaction (if it appears in that pathway) by the number of nonzero entries appearing in the ith row of the matrix As these are defined for each elemementary flux mode (EFM), they generally involve combinations of partial entropy productions associated to either a forward or reverse internal transformation and entropy exchange contributions coming from one or more of the input/output fluxes. Therefore, they can have have, in principle, any sign: either positive or negative. The relative weights for each partial entropy contribution are a consequence of the network stoichiometry. These weights simply count the number of times a given transformation occurs in the set of all the EFM pathways of the network. They must be included to avoid the multiple counting of any specific partial contribution. The partial entropy associated to each EFM pathway is obtained by dividing the partial entropy of the Equation . Then, squality)  involvinity) [σe :(24)σe=Rresolves the entropy balance between production and exchange in terms of the individual entropic contributions coming from each elementary pathway within the reaction network. At a NESS the entropy production is balanced by the entropy exchanged with the environment: The reference concentrations ality in  resolvesM EFMs, the sum is extended over M. We evaluate this sum to cover the time range subsequent to the large production peak in Mirror symmetry breaking lifts the degeneracy in the values of the partial entropy productions associated with the EFM pair The entropy production Equation  can be wflows Jk ,27. For on rates :(25)σ=∑kNow, the General Evolution Criterion (GEC) ,27 stateJ: both the internal reversible reactions and on the irreversible pseudoreactions, or matter fluxes, that maintain the system out of equilibrium. This explicit dependence is made manifest, see Equation (A18). We thus evaluate this expression for our model and confirm its validity and the compliance of the GEC over the full time range of our simulation.Note: the derivative of the entropy production with respect to the time-variation of the flows  account ,26,27, s account . We are We first consider the total derivative of the entropy production This complete time dependent behavior is resolved into two important contributions : (i) oneWe conclude from this analysis that the increase of the entropy production along the non-equilibrium racemic thermodynamic branch see  can leadWe have analyzed entropic pathway features underlying spontaneous mirror symmetry breaking for two chiral cross-catalyzed replicators. We have underscored the role of the open elementary flux modes (EFM), as defined by stoichiometric network analysis, for driving transitions from the unstable racemic thermodynamic branch to the branch of organized scalemic states, e.g., from racemic to homochiral, which takes place in the non-linear regime of non-equilibrium thermodynamics.In our chiral replicator network, the EFMs can be organized into three distinguishable classes. Namely (i) internal closed pathways  showThe GEC states that the generalized forces  evolve in such a way as to lower the entropy production. In open flow systems, the affinities depend on both the internal reversible reactions and on the irreversible matter fluxes. We derive this dependence Equation (A18) and calculate the GEC based on this analytic result, it agrees identically with the calculation of the GEC from the numerical simulation of the rate equations. This confirms the dependence of GEC on the matter fluxes and shows how the lowering of the entropy production predicted by GEC is achieved and consistent with the interdependence of the chemical reactions and the matter fluxes into and out from the reactor.unidirectional matter fluxes responsible for the production of entropy and the role of external controlling factors, such as the input/outflow flows and their representation as pseudo-reactions. SNA leads to the expression for the rate of change of the total entropy (density) of the system partial entropy productions over all the extreme flux modes (EFM), both the internal closed pathways and the open unidirectional ones. This yields insight into the coupling between chemical reactions and the input/output matter fluxes. At a NESS, the sum over all EFMs vanishes identically, and implies the balance between entropy production and entropy exchange. The entropy production is minimized at the final chiral NESS.The EFM approach to entropy production, entropy transport and total entropy balance described here applies to any mass-action chemical reaction network in an open system and under a variety of system architectures. The usefulness of this SNA approach is the identification of the specific The hypercycle model involving solely the mutual cross catalyses was chosen for the purposes of illustrating in detail the methods and techniques. Naturally, more chemical realism can be built into the model by adding in the direct uncatalyzed synthesis of the replicators  . This ta


The droplet response to vibrations has been well characterized on open substrates, but microfluidic applications for droplets on open systems are limited by rapid evaporation rates and prone to environmental contamination. However, the response of enclosed droplets to vibration is less understood. Here, we investigate the effects of a dual-plate enclosure on droplet transport for the anisotropic ratchet conveyor system. This system uses an asymmetric pattern of hydrophilic rungs to transport droplets with an applied vibration. Through this work, we discovered that the addition of a substrate on top of the droplet, held in place with a 3D printed fixture, extends the functional frequency range for droplet transport and normalizes the device performance for droplets of different volumes. Furthermore, we found that the edge movements are anti-phasic between top and bottom substrates, providing a velocity profile that is correlated to vibration frequency, unlike the resonance-dependent profiles observed on open systems. These results expand the capabilities of this system, providing avenues for new applications and innovation, but also new insights for droplet mechanics in response to applied vibration. The response of liquid droplets to a vibration is typically studied with unconfined droplets on a homogenous substrate. In this configuration, researchers have provided thorough characterizations of resonance ,2, contaAnisotropic ratchet conveyors (ARCs) transport droplets through a periodic pattern of curved hydrophilic rungs, defined by a hydrophobic background. The curvature of these rungs divides the footprint of these droplets into leading and trailing edges, that experience a difference in pinning forces, as only the leading edge of the droplet conforms to the curved rungs  14]..14].A sinusoidal vibration, applied vertically, causes the edges of the droplet to oscillate between wetting (edges of the droplet are advancing away from the centroid) and de-wetting (edges are contracting toward the centroid) phases. This combination of edge oscillation and a difference in pinning forces between leading and trailing edges results in a net force that drives droplet transport ,18,19. P2) rungs defined by the hydrophobic FOTS background [ARC fabrication begins by patterning a negative resist (NR9-1000PY) on an oxidized <100> p-type silicon wafer. Following development, the wafers are vapor coated with a hydrophobic silane  to create the hydrophobic background . Wafers ckground . Plate hARC devices are driven by an electromagnetic motor  controlled by a function generator. The performance of the ARC devices is characterized by the minimum acceleration amplitude of the substrate required to initiate droplet transport (defined as the ARC threshold), which is measured with a laser Doppler vibrometer . This measurement was performed by increasing the vibration by small increments until transport occurs and recording the reading on the laser doppler vibrometer. The ARC threshold is reported in acceleration rather than displacement because, with a sinusoidal motion, the acceleration of the platform scales with the product of displacement and vibration frequency squared, and acceleration is directly proportional to the energy input of the system, as previously established ,19,22,25The configurations used in this work consisted of the ARC pattern on bottom and hydrophobic coating on top (ARC-FOTS) and the ARC pattern on both top and bottom (ARC-ARC) substrates. Separations of 2.0 and 2.5 mm were used for both configurations with 8, 13, and 18 µL droplets. Measurements of 8 µL droplets were only recorded with the 2.0 mm plate separation because 8 µL droplets did not contact the top plate when separated by 2.5 mm.Qualitatively, droplets transported in this dual-plate configuration appear pillarlike, with leading and trailing edges on both plates and a liquid bulge (the center of mass of the droplet) oscillating back and forth between the two plates . ARC thrTransport on the dual-plate system also appears to be independent of droplet volume. Plotting these measurements on the same axes for each separation distance shows aligned ARC threshold profiles for droplets of each volume interrogated . These dThe velocity of droplets transported under these configurations was also determined . VelocitOn the enclosed system, local maxima and minima were observed, but these peaks occurred at higher frequencies than on the open system and, generally, the transport velocity increased with increasing frequency. The velocity was also slightly higher on the ARC-FOTS configuration, which is likely due to the reduced pinning forces acting on the top of the droplet. This result is likely due to the tethering of the droplet to both top and bottom plates. In the dual-plate configuration, the droplet edges are wetting on the top plate and de-wetting on the bottom plate as the droplet center of mass moves upward and vice-versa as the center of mass moves downward. Thus, the movement of droplet edges is anti-phasic , so the In previous work, droplet transport profiles on an open system were non-dimensionalized with respect to the radius of the droplet, as it was assumed that the displacement of the center of mass during vibration scaled with the radius of the droplet  . The aliThe similarity in ARC threshold and velocity profiles between ARC-ARC and ARC-FOTS configurations indicate that pinning forces acting on the top and bottom plates of the ARC-ARC configuration do not sum. This effect is likely a result of the anti-phasic nature of this system, as these pinning forces will be out of sync. However, if only one plate were moving , then these phases would be synchronized between the top and bottom plates. This configuration may provide for a lower ARC threshold and could potentially transport droplets vertically, but the changing plate separation would also complicate the formation of a seal to prevent evaporation.Compared to an open ARC system, a dual-plate configuration expands the functional frequency range and normalizes device performance with regard to droplet volume. The dual-plate configuration also provides a simple means of sealing this system to reduce evaporation rates and offers new opportunities to improve the capabilities of the ARC system—particularly the ability to handle fluids with lower surface tension than pure water, control droplets with smaller volumes, and perform new functions  that have yet to be achieved on ARC systems, which will be the focus of future work. Overall, these results demonstrate the increasing potential of ARC systems to meet a wider variety of applications in microfluidics.