This study used a statistical approach to measure how urban citizens in certain provinces of Indonesia handle their waste. It illustrates how the desirable habits related to environmental consciousness differ across urban citizens among different regions and economic classes. A wide disparity was found in people's understanding of a healthy and clean environment across provinces and cities. Waste management ignorance was also found to be prevalent. Inculcating personal awareness of the local environment was found to be a good start toward keeping the environment clean. The observed positive correlation between the overall living conditions and littering behavior indicates that households that exhibit littering behavior also tend to score higher on living conditions. This significant positive correlation is indicative of self-interest and ignorance. The study also suggests that a higher level of household economic prosperity correlates with a more desirable behavior toward maintaining a clean and healthy environment; such behaviors are also adopted by citizens living in clean neighborhoods. Furthermore, a clean and healthy lifestyle is also supported by environmental consciousness in conjunction with hygienic environmental conditions. Specifications Table•These inferential statistical data and analyses are useful to understand how lifestyle and littering behavior affect the self-assessed living conditions of Indonesia's urban citizens.•Indonesia's urban citizens as well as policymakers can benefit from these data. The data show that environmental conditions can be improved by enhancing the economic prosperity and focusing on the education of the urban citizens.•The study data can aid policymakers at the city- and province-level in reshaping citizen behavior regarding waste management.•The study's analysis of representative cities indicates a degree of ignorance regarding the environment in Indonesia's urban citizens; in these cities, a positive relationship is observed between desirable “environmental habits” and living conditions. Hence, to aid in solving the waste-handling problem, the issue of ignorance must be addressed.•This analysis also suggests that correlations between certain waste-handling behaviors, socioeconomic factors, and other external factors affect the self-assessed living conditions.The data used in this study were acquired from over 600 households in 6 different provinces in Indonesia. Data were gathered from 100 households in different cities within these provinces. The same family ID was used across all provinces . However, each family ID was unique within the province; only one family was coded 01 in each province, and no two families were assigned the same code within the same province. The number of observations by provinces and by cities are shown in The provinces corresponding to these data include the Special Administrative Region of Jakarta, Jambi, West Java, East Java, Maluku, and West Sumatra. Sampled cities include Jakarta, Ambon, Tasikmalaya, Jambi, Muaro Jambi, Padang, and Surabaya. These cities were chosen as they are characterized by relatively high urban populations within the provinces of interest. Meanwhile, provinces were chosen based on their population density in conjunction with the magnitude of the waste-handling problem. The cities were also chosen as representative major cities in Indonesia with urban waste management problems. Here, in the following discussion, the words “respondents” and “urban citizens” are used interchangeably, and both refer to the urban citizens who participated in this research.In the study, the questions on waste-handling activities were classified into certain categories. These categories cover self-regulated routines/habits with regard to trash disposal, waste disposal facilities, waste-handling awareness and perceptions, knowledge and contribution, and “self-assessment” of lifestyle Moreover, citizens across the economic strata were chosen for random sampling. The respondents were queried on behavioral information related to waste-handling activities. To ensure greater depth of analysis, the respondents were also asked about their income and expenditure per capita per day. From According to the summarized statistics described previously, there is a significant difference between the means of the per capita expenditure among provinces and cities. The significant differences among geographical factors show that the data are normally distributed across locations in terms of socioeconomic conditions.The scores of the overall living conditions and living environments also differ significantly across the expenditure groups. A low score for the living conditions is observed in the case of low-expenditure households and regions with residents with low daily expenditure ,4,5. TheIn the study, the first part of the analysis focused on detecting whether the self-assessment scores significantly differed among the groups of respondents. In addition, the analysis focused on detecting the existence of interactions between the tested variables ,7.The first stage involved the evaluation of the score of the overall living conditions. This score was measured on a scale of 1 to 5, with 1 denoting unsatisfactory and 5 denoting very satisfactory and comfortable. The score categorization was explained by the surveyors under certain criteria. From The next stage involved the evaluation of the environmental hygiene/cleanliness score. Environmental cleanliness was measured from scale 1 to 5, with a score of 5 denoting the highest level of hygiene. The ANOVA test results in As regards the score of the knowledge/awareness of the need for a healthy and clean environment , the obsAs regards the score of environmental cleanliness/hygiene , the resThe last stage of the analysis focuses on how the chosen variables affect each other and the significance of the correlation. The confidence level in the following analysis was set to 95%, with the alpha value (significance level) set to 5%. In The abovementioned findings are convergent with those of other studies ,14,15; tThe major factor toward creating a clean and healthy lifestyle among urban citizens is environmental consciousness, as indicated by the coefficient correlation of 0.526, meaning that the overall environmental cleanliness score will increase by 0.526 when the environmental consciousness score is increased by 1. Here, it is noted that such a correlation is not an accurate reflection of how urban citizens handle waste; however, it reveals how each of the variables correlates and the anomalies occurring in society.The experimental design also aimed at evaluating how economic conditions correlate with the littering behavior of the households surveyed. The analysis also measured the significance of the mean differences among groups based on the survey data. Here, it is noted that the survey covered 600 households from 6 different provinces, with 100 samples being acquired from different cities within these provinces. Importantly, the respondents were residents and not migrants. The dataset containing the respondent records was suitably filtered by data processing software. In particular, qualitative records were encoded, and quantitative ones were cleared from string inputs.The survey also elaborates the socioeconomic dimensions of waste-handling behavior by focusing on the economic status, which affects the quality of living and waste-handling behavior of urban citizens. These indicators were embedded in the questionnaire form, which consisted of eight sets of questions. The details and description of the survey are listed in vice versa. The self-assessment scores were not completely subjective as the surveyor explained the classification criteria for each score to the respondents. Hence, the scores can be considered as guided self-assessment scores.The following variables were scored based on self-assessment (from session 7): (i) living state/conditions, (ii) knowledge/awareness of healthy environment and lifestyle, (iii) cleanliness and hygienic living conditions, and (iv) hygiene and lifestyle relative to socioeconomic conditions (approximated by decile group of expenditure per capita), city of living, and the dummy variable of littering behavior. The self-assessment scores are designed such that higher scores correspond to better conditions and The variables were analyzed via various possible analysis of variance (ANOVA) approaches in conjunction with the non-parametric Spearman's correlation test. The tests were conducted to check whether these variables exhibit a significant mean among the categories of cities of living, decile group of incomes, and households with littering habits.In addition, the Spearman's rank correlation matrix (including significance levels and asterisk) was used to analyze the correlation tendencies between variables. The significance levels and asterisk under the coefficient correlation mark important significant tendencies between two variables, and this can enable focus on the factors of interest. The recorded significance levels can also guide researchers and policymakers on what factors or variables they should focus on to raise awareness of the need for a clean and healthy lifestyle.In inferential statistical analysis, the definitions of groups (categories) or the division of respondent groups are important. In this study, respondents (households) were classified into several types of groups: First, the domicile-based group categorized respondents at the city or province level. Second, respondents were categorized based on waste-handling behaviors or littering. Here, it must be noted that only some households were surveyed on their littering behavior. Thirdly, respondent data were classified into deciles based on their expenditure per capita. The 1st decile indicated the 10% of respondents with the lowest expenditure per capita, while the 10th decile indicated the 10% of respondents with the highest expenditure per capita. For the sake of simplicity, the summarized statistics are provided based on domicile-based groups at the province level.The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article.


The traditional cerebellum’s role has been linked to the high computational demands for sensorimotor control. However, several findings have pointed to its involvement in executive and emotional functions in the last decades. First in 2009 and then, in 2016, we raised why we should consider the cerebellum when thinking about drug addiction. A decade later, mounting evidence strongly suggests the cerebellar involvement in this disorder. Nevertheless, direct evidence is still partial and related mainly to drug-induced reward memory, but recent results about cerebellar functions may provide new insights into its role in addiction. The present review does not intend to be a compelling revision on available findings, as we did in the two previous reviews. This minireview focuses on specific findings of the cerebellum’s role in drug-related reward memories and the way ahead for future research. The results discussed here provide grounds for involving the cerebellar cortex’s apical region in regulating behavior driven by drug-cue associations. They also suggest that the cerebellar cortex dysfunction may facilitate drug-induced learning by increasing glutamatergic output from the deep cerebellar nucleus (DCN) to the ventral tegmental area (VTA) and neural activity in its projecting areas. It is remarkable that during evolution there has been a coordinated scaling in the number of cortical and cerebellar neurons across species . HoweverIt is now clear that reciprocal connectivity between the cerebellum and the rest of the brain is crucial to understanding cerebellar function . A key pBeyond the well-accepted role of the cerebellum in the high computational demands for sensorimotor control, several findings have pointed to its involvement in executive and emotional functions in the last decades . Direct Accordingly, in 2009 and then in 2016, we raised the question to why we should consider the cerebellum when thinking about drug addiction and drew attention to the cerebellum’s roles in several of the brain functions affected in drug addicts. A decade later, mounting evidence strongly suggest the cerebellar involvement in this disorder. It is worth noting that the cerebellum connects bidirectionally to functional loops involved in drug addiction. In particular, the cerebellum modulates cortical influences on striatal activity  and exerFirst evidences of drug effects on the cerebellum came from the toxicology of alcohol and cannabis. For many years, it was thought that the main role of the cerebellum was limited to tolerance to motor incoordination and some of the withdrawal symptoms induced by drug misuse . It is uA critical part of aberrant drug-induced plasticity in several brain regions is linked to Brain-Derived Neurotrophic Factor (BDNF) mechanisms . Indeed,In contrast, cocaine reinstatement after protracted abstinence (1 month) increased mature-BDNF mechanisms in the cerebellar cortex of cocaine sensitized mice. The increase was a post-transcriptional effect plausibly fueled through the enhancement of tissue plasminogen activator (tpA) levels responsible for proBDNF cleavage . In consThe central role of the cerebellum in associative motor and non-motor learning has been well established . It has In drug addiction, learned reinforcing properties make drug-associated cues strong motivational triggers for drug seeking. The consolidation and persistence of these associative memories  togetherA strong support for a cerebellar role in long-lasting drug-cue associations comes from human and animal research . NeuroimWe have been investigating the cerebellum’s contribution to cocaine-cue associative memory during the last decade , b. UsinA significant issue in the addiction field is to explain why drug-induced memories are so persistent and long-lasting. In this respect, we have been interested in the function of perineuronal nets (PNNs) in the cerebellum and their regulation by cocaine-related behavior. PNNs are extracellular matrix lattice cartilage-like structures that wrap the soma and proximal neurites of several neuronal populations, the majority fast-spiking GABAergic interneurons . These sTaken together, our findings indicate that drug-related memory may be represented in the cerebellum through two hallmarks signatures localized in the apical region of the granule cell layer: increased granule cell activity and strong fully condensed PNNs around Golgi interneurons. We have not been able to reproduce either of these effects in ventral regions of the posterior vermis though these regions expressed high granule cell activity and a large number of Golgi cells bearing a PNN , 2017. TIn a pursuit of an explanation for the relevance of this cerebellar region, we investigated the effects of a neurotoxic lesion restricted to the apical part of the posterior vermis (lobule 8) on cocaine-related memory , b. UnexReinforcement learning involves two distinct and parallel processes with dissociated neural substrates . During Recent findings provide compelling support for the role of the cerebellum in reward-based reinforcement learning and goal-directed behavior , but alsin vivo, eliciting excitatory synaptic currents in DA and non-DA neurons. Optogenetic inhibition of cerebellar terminals in the VTA did not induce aversion but prevented the establishment of social preferences. Altogether, these findings reveal that the cerebellum not only is able to encode the goal and the context but also to regulate behavior to reach the goal.One of the most relevant insights into the role of the cerebellum in goal-directed behavior has been provided by the recent study by Evidence about the contribution of the cerebellum to habits has come from animal and human research. A bilateral lesion in the interposed nucleus or hemicerebellectomy  prevent Drug addiction like other compulsive disorders might result from an excessive dominance of model-free control . With exStructural neuroimage findings also point to a role for the cerebellum in compulsive behavior. The most common finding of patients with compulsive disorders has been decreased gray matter (GM) volume in several regions of the cerebellum and increased basal ganglia-cerebellar connectivity see . AnotherOverall, our recent findings reveal that the cerebellum may modulate cocaine-induced learning, but also neural activity and synaptic stabilization mechanisms in the IL . ImpairmOverall, findings point to a modulatory function of the cerebellum on the establishment of drug-induced associative memory through the regulation of VTA activity. Nonetheless, research about the cerebellum’s role in drug-related memory is still in its infancy and there are open questions that remain unanswered. First, it is unknown through which neural pathways drug-related cue and unconditioned signals are conveyed to the cerebellum. Second, it is also ignored how cerebellar cortex encodes the conditioned cue and unconditioned properties of the drug. Third, the role of Purkinje neurons in drug-cue associative memory needs to be further explored. Finally, it is crucial to test the hypotheses including addictive drugs with distinct neuropharmacological actions. It is expected the modulatory role of the cerebellum to affect not only the expression of the conditioned response but also non-motor aspects of drug-induced reward. To address all these questions more precisely cell-specific tools such as DREADDs (designer receptor exclusively activated by designer drugs), optogenetics, electrophysiology and viral tracing will be required.Our findings also suggest that pathological conditions impairing the cerebellar cortex may increase the likelihood of acquiring drug-induced associative memory and promote drug relapse through disinhibition of VTA and its projecting regions. Moreover, they may explain why both cerebellar disfunction and prefrontal impairment enhance susceptibility to compulsive and impulsive disorders including drug addiction, eating disorders, attention deficit/hyperactivity (ADHD), and obsessive-compulsive disorder (OCD) . AccordiFindings discussed in this work were obtained by IG-M and JG-C as a part of their doctoral theses and also critically reviewed the manuscript. MM was responsible for writing and critically edited the review. All the authors approved the final version for publication.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.


Suicide in adolescence is a worldwide issue, and it continues to present a serious problem in terms of its prevention. Among the various aspects of suicide, a very interesting area of research is represented by suicidal ideation. Recently, neuroimaging-based methods have made it possible to study the cognitive processes involved in several social situations and clinical conditions. This theoretical perspective article with an interdisciplinary approach integrates evidence from developmental psychology and social neuroscience with the aim of investigating the role of the brain area responsible for regulating negative emotions during the cognitive processes of suicidal ideation: the ventromedial prefrontal cortex. By highlighting the role of brain areas in the few studies published so far, it is possible to develop perspectives of considerable impact. Studying and understanding the role of brain areas involved in suicidal thoughts in adolescents could facilitate the creation of new perspectives on prevention programs and interventions. Worldwide, suicidal ideation (SI) is one of the two leading causes of death in adolescents in the 15–19-year-old age group . The preThe ventromedial prefrontal cortex (VMPFC) plays an important role in controlling social tasks, including moral judgment, social decision-making, and social emotions, as well as in regulating emotions . Hiser aAmong the few studies in the literature, the recent research by Recent studies  have invIn this regard, another study explores how social rejection can represent a potential risk factor for depressed adolescents with non-suicidal self-injury NSSI; . The autSocial exclusion and emotion dysregulation related to anxiety and depression in adolescents are the most important predictive factors of SI or suicide attempts. Interventions that aim at preventing SI in adolescents before such thoughts develop into suicidal behavior are very important . The neeRM wrote the first draft of the manuscript. CL wrote the final version of the manuscript. All authors approved the submitted version.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.


Background:Ex situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results.Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial hemoglobin-based oxygen carrier solution for 6 h. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored.Results: Trends in hepatic artery and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalized for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes.Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions. Each lobe has their own inflow and outflow vessels as well as bile drainage, during Four donor livers were included in this study, resulting in a total of eight perfusions. All donor livers included in this study were originally retrieved with the primary intention for transplantation as per the policy of the National Health Service Blood and Transplant (NHSBT). The organs were subsequently rejected for transplantation by all UK liver transplant centers and, following that, were offered nationally for research by NHSBT. The authors had no influence in the process of declining donor livers. This was done by the transplant surgeons at each center. Informed consent for research use of donor organs was obtained by specialist nurses in organ donation from the donor's next of kin during informed consent for organ donation. Authorisation for research was mediated by each centre's specialist nurse in organ donation. All methods described were performed in accordance with NHSBT guidelines and regulations. Study ethical approval was obtained from the London-Surrey Borders National Research Ethics Service (Reference Number 13/LO/1926) and the NHSBT ethics committee (Reference Number 06/Q702/61). No organs used in this study originated from executed prisoners.Donor liver exclusion criteria for this study were: gross macroscopic appearance indicative of moderate or severe steatosis; asymmetric or poor perfusion demonstrated during organ retrieval; presence of hepatic malignancy; organ subjected to machine perfusion prior to being discarded.During transportation to our center, the organs were preserved in University of Wisconsin fluid at hypothermic temperatures in ice as per current standard clinical practice for static cold storage in the United Kingdom. Donor livers were split while in cold storage prior to commencement of perfusion in order to ensure that both lobes were subjected to similar ischaemic times and assessed simultaneously when placed in the perfusion devices. Upon receipt by our center, the liver was initially cleared of excess tissue in order to assess the quality of the organ. This also allowed for assessment of the organ's outflow, with respect to the hepatic veins and post-hepatic inferior vena cava, as well as the inflow, in terms of the hepatic arterial tree and portal vein . Since tOnce the vena cava was opened, the liver hilum was cleared further of excess tissue in order to identify the left and right branches of the portal vein and hepatic artery, respectively . ParticuIf vessel length and diameter was deemed to be inadequate for safe cannulation of either lobe, particularly with respect to the isolated branches, then a decision was made to reconstruct the vessels to enable proper positioning of the cannulas for perfusion. This was done by fashioning a conduit using native vessels for extra length in one of two ways: (1) resecting the distal portion of the main arterial or venous trunk retained by either lobe, which was then anastomosed onto the branch of the other; (2) utilizing the length of donor iliac vessels for the reconstruction  . Which tBoth perfusion devices were primed with our previously described  perfusioThe pre-perfusion weight of each lobe was recorded post-splitting. The arterial and portal venous supplies were cannulated with each lobe positioned inside the organ reservoir such that the open drainage from the hepatic veins could be visualized directly. Perfusion was commenced at 36–37°C with oxygenated pulsatile flow and non-pulsatile flow in the hepatic artery and PV, respectively. Perfusion of each lobe was commenced within five to 15 min of each other . PerfusiData analysis was carried out using Prism 7 . Continuous data at each timepoint was compared using Wilcoxon signed-rank test. Statistical significance was set at p <0.05. Data is presented as per lobar mass as well as following normalization of pre-perfusion lobar weight per gram of tissue.Four livers were included in the study. Information relating to donor characteristics and liver characteristics can be found in . Right lLactate levels were comparable at the start of perfusion, T0, and decreased significantly in all lobes up until the end of the perfusion experiment, T6 . Trends Hepatic artery and portal venous flows were relatively consistent in both left and right lobes with a trend toward an increase in flow rate as the perfusion experiment progressed . DiffereOverall histological analysis showed that both liver lobes behaved in a similar manner throughout the perfusions. Lobar architecture was well-preserved in both pre- and post-perfusion biopsies. Some variable centrilobular necrosis was observed at both time points. However, this was present to the same degree before and during NMLP. All biopsies were PAS positive with staining showing a range of intensity from mild to strong and ranging from even distribution throughout the parenchyma to patchy. Whatever the variability between liver, each of the paired lobes showed strong similarity, with no change throughout the perfusion. In addition, patterns of histology did not correlate with any parameters of functional assessment. Only one liver showed evidence of significant macrovesicular steatosis which did not change between lobes or throughout the perfusion .Several studies have demonstrated that NMLP enables the functional recovery of discarded donor livers and provides a window of opportunity for viability assessment prior to transplantation. However, results are compounded by small sample size as a consequence of the limited availability of discarded donor livers for research, further compounded by the inherent differences between donor livers. This limits comparability between groups of individual livers.ex situ end-ischaemic NMLP, therefore, has the potential to provide a platform for suitable comparative controls for the investigation and assessment of therapeutic interventions prior to being subjected to the rigor of a clinical trial. Research published previously by our group allowed for an initial four-hour window of NMLP before a full viability assessment of the perfused organ is carried out  did not require any reconstruction as the blood was freely drained and collected in the device reservoir. As such, hepatic veins anatomy and inferior vena cava accessories did not influence the surgical technique or the perfusion parameters. The situation would be different if a closed circuit was being used or if clinical use of these segmental grafts was under consideration.The incorporation of NMLP to the split liver model has the benefit of enabling liver functional assessment under near-physiological conditions. The use of an artificial acellular hemoglobin-based perfusion fluid also has its advantages. Unlike blood products (derived from various donors), it has low immunogenicity and may therefore be of greater value in the study of liver-specific immune cell populations and mechanistic studies . SecondlIt must be noted that there are limitations to the design of this perfusion model. First, splitting of the liver requires considerable surgical expertise and increases the cold ischaemia time beyond what is usual for the preparation of a whole liver for machine perfusion. Secondly, due to the liver's anatomy, the right lobe is invariably larger than the left lobe and therefore they cannot be split into entities of equal mass without compromising blood supply. Furthermore, the shorter and smaller caliber of hepatic artery and portal vein branches makes them much more difficult to cannulate. We attempted to circumvent this issue by retaining the main trunk of the vessel with one lobe while performing vascular reconstructions on the other, using donor iliac vessels or larger caliber sections from the proximal celiac trunk or splenic artery (if included in the specimen). In all experiments this provided the additional length for safe cannulation. However, this technique further increases the cold ischaemia time of the liver and would also require the appropriate surgical expertise for a robust reconstruction that would not compromise lobar perfusion. All these aforementioned factors may lead to differences in the perfusion characteristics of each lobe and must be considered. Finally, not all livers can be split. This is often a result of variations in arterial anatomy due to branching patterns which would compromise the inflow of a segment of the lobe if divided.We acknowledge that the data presented in this manuscript is from a small number of human donor livers. Nevertheless, the results of this proof-of-concept study indicate that trends in the functional recovery and metabolic parameters between lobes were very similar and may therefore prove useful in the assessment of responses to therapeutic interventions in the pre-clinical normothermic setting. Additionally, this model addresses the variability that exists between individual donor livers by enabling the same donor liver to be placed in the treatment and control groups. This also maximizes use of resources as one donor liver for pre-clinical studies.Other benefits observed during these experiments came from the use of a perfusion machine with an open circuit. These included: facilitated manipulation of the graft for direct visualization, direct visualization of and access to graft outflow and superior access to graft for direct therapeutic interventions when compared to closed circuit alternatives.Liver splitting is a feasible model for providing comparative controls for pre-clinical normothermic machine perfusion research. Further work should involve the optimisation of this protocol to minimize the need for surgical expertise when preparing the liver for machine perfusion as well as its application to other perfusion modalities, namely, hypothermic and sub-normothermic perfusion. This novel split liver model can be tested for cellular therapies to investigated cellular phenotype and lineage changes and future pharmacological interventions of donor liver before implantation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the London-Surrey Borders National Research Ethics Service (Reference Number 13/LO/1926) and the NHSBT Ethics Committee (Reference Number 06/Q702/61). Informed consent for research use of donor organs was obtained by specialist nurses in organ donation from the donor’s next of kin during informed consent for organ donation.JA, YB, LW, and SA designed the study and established the methodology. JA, LW, DO-B, and VR conducted the experiments. JA and LW collected the data. DM and HM supervised the liver splitting procedure. JA performed the data analysis and drafted the manuscript. SA and GR reviewed the histological specimens. YO, MP, HM, and DM contributed to critical revision and editing of the final manuscript. All authors approved the final version of this manuscript.JA is a clinical research fellow at the Queen Elizabeth Hospital in Birmingham and employed by University Hospitals Birmingham. The remaining 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.


Evidence shows that behavioral nudges could be used to enhance enrollment rates in randomized controlled trials (RCTs) by addressing enrollment barriers, but research on this topic is limited. We conducted an online field quasi-experiment with separate pretest (October 2017–January 2018) and posttest (February–May 2018) samples designed to examine the use of behavioral nudges to engage pregnant smokers in a couple-focused smoking cessation RCT relying on online enrollment through paid Facebook ads and a dedicated website, by reporting aggregate Facebook ads and Google Analytics data. The Facebook ads pretest conversion rate of 1.6% doubled and reached 3.41% in the posttest period. The pretest eligibility assessment rate decreased from 10.3% to 6.46%, but registered a relative increase of approximately 50% in the posttest period, as opposed to the pretest. The number of women who signed the informed consent in the posttest period has increased with 63%, from a proportion of 8.54% in the pretest to 11.73% in the posttest period. These findings might lend support to integrating behavioral nudges in the recruitment and enrollment materials of RCTs to boost enrollment. Many randomized trials (RCTs) fail to meet their recruitment targets  and partIn this exploratory study, we aimed to investigate whether behavioral nudges can improve participants’ recruitment in the Quit Together (QT) couple-focused pregnancy smoking cessation RCT . The RCTWe employed the behavioral diagnosis and design framework  as the bThis paper examined whether the use of behavioral nudges to inform the development of trial recruitment paid Facebook ads and a modified interface for its website has influenced: (1) the Facebook ads conversion rate (percentage of people who saw the ad vs. who clicked om the ad and reached the website); (2) the percentage of individuals who reached the website and who initiated the process of self-assessing their eligibility to participate in the RCT; and (3) the proportion of women who signed the informed consent among those who initiated the self-enrollment process.We conducted a field quasi-experiment with separate pretest and posttest samples. Aggregate data were collected through Facebook Ads Manager and Google Analytics, for 93 days, between 22 October 2017–22 January 2018 (pretest data) and 93 days, 20 February–24 May 2018 (posttest data). The Quit Together RCT was implemented in Romania and consisted of over-the-phone motivational interviewing counselling sessions, designed to increase motivation and facilitate problem solving related to difficulties pregnant women meet in their smoking cessation attempts. The RCT protocol has been described elsewhere  platformThis field quasi-experiment involved the natural selection of participants based on their performance of natural or everyday tasks . The participation in this experiment did not involve the subject’s authentication or identification. This type of experiment implies that subjects do not know they are participating in a research study. Hence, in nearly all cases, subjects are not asked to sing an informed consent , as thisThe intent of the Facebook ads was to target pregnant smokers in Romania who have access to the internet and own a mobile device able to connect to the internet, which was the RCT target population. The sample of the quasi-experiment consisted of 124,359 RCT enrollment Facebook ad views .The quasi-experiment was designed following the five steps of the behavioral diagnosis and design framework . More spThe identification of behavioral nudges to increase engagement with the QT RCT was conducted by the first author, following a rigorous and systematic three-step process: (1) identifying specific points/stages in the enrollment process through which a potential participant (smoker pregnant woman) should go in order to enroll in the RCT; these points map the enrollment process; (2) identifying behavioral biases or bottlenecks potentially associated with each stage of the enrollment process; these constitute potential drop-off points for participants; and (3) proposing potential behavioral nudges as solutions designed to prevent drop-offs at each step of the enrollment process. The process map for QT RCT enrollment, potential drop-off points, bottlenecks, behavioral nudges/solutions, and sample materials are available in The list of identified behavioral biases or bottlenecks that might affect the engagement of potential participants with the Facebook Ads and website of the trial included information overload , anchoriFor this quasi-experiment, aggregate Facebook Ads and Google Analytics data were available. The main outcomes of interest were: (1) the Facebook Ads conversion rate ; (2) the percentage of individuals who initiated the process of assessing their eligibility to participate in the RCT among those who reached the project’s website; and (3) the proportion of women who enrolled in the RCT (by signing the informed consent) among those who initiated the self-enrollment process.This experiment made use of aggregate Facebook ads and Google Analytics data collected in the pretest and posttest periods. No individual-level data were used. We were not able to perform statistical tests between pre-post intervention group because the available data were aggregated  and no sample variances were available. Thus, data analysis includes comparisons of absolute numbers and percentages on the variables of interest .When comparing identical pre- and post-experiment ad campaign durations (93 days) with the same weekly campaign budget, there were 50,970 ad views pre-experiment and 73,389 post-experiment, a 30% increase in ad views . The ad The main finding of this study is that the Facebook ad conversion rate has more than doubled following the use of behavioral nudges in the development of Facebook ads, while using identical parameters for population ad targeting, the same weekly budget for Facebook ads, and with identical ad campaign durations in both pre-and posttest period. At the same time, the eligibility assessment rate decreased following the behavioral nudge experiment. It is possible that adjustments of the website interface made the information about the RCT easier to understand and, consequently, women who were not eligible to participate were able to understand this from the information listed on the website and were less likely to initiate the self-assessment of their eligibility post-experiment. Importantly, the proportion of women who enrolled in the RCT increased by almost two-thirds, resulting in close to three times more women enrolled post-experiment vs. pre-experiment.Strengths of this quasi-experiment include the fact that it takes place in a natural setting for the study population, resembling the real-life situation in which pregnant female smokers, who are interested in quitting smoking, see an ad promoting a smoking cessation program on their Facebook news feed, and decide (or not) to find out more information about it. This real-life scenario increases the external validity of our results. Several of the more important study limitations merit attention. First, it is possible the results could be due to other factors . However, it is likely that the large increase in the ad conversion rate and the increased percentage of enrolled subjects are due to the behavioral nudge experiment, because the parameters of the Facebook target population , the duration, and the weekly ad campaign budgets were unchanged pre- and post-experiment. Second, due to availability of only aggregate data for our variables of interest , the study authors did not perform statistical tests to assess the significance of the pre-post experiment changes and were not able to account for individual characteristics that may have influenced the results. Nevertheless, the aggregated findings do show a large, more than double, increase in the ad conversion rate, and an increase in the proportion and number of enrolled subjects following the implementation of the behavioral nudges. Third, due to the experiment being nested into an ongoing RCT, we could not manipulate the amount of exposure to or specific combinations of behavioral nudges. Future studies may use randomized factorial designs to gain greater insights into which changes (or cluster of changes) in Facebook ads and the RCT’s website interface have had the greatest impact.Despite limitations such as these, the study findings are of interest because they provide initial evidence that might support the use of behavioral nudges to increase enrollment in RCTs and other types of research studies. There are few studies informing the topic in general, including one study providing a taxonomy of proposed behavioral economics interventions to improve clinical trial enrollment  and one Very few studies used behavioral nudges as a tool to improve clinical trial enrollment. To the best of our knowledge, there are only two other studies published on this topic. Consistent with our results, an RCT of screening of undiagnosed atrial fibrillation that used behavioral nudges under multiple forms, including personalization, managed to increase enrollment rates from 0.8% to 9.4% over 10 months . SimilarBehavioral nudges represent low-cost solutions that have been proven to advance health, prevent diseases, and reduce morbidity and mortality . They arThe current study meaningfully contributes to the literature on using behavioral nudges to improve enrollment in research studies. The findings of this study provide initial evidence that might support the use of behavioral nudges to increase enrollment in RCTs and other types of research studies. An important issue for future research on this topic is to establish which specific behavioral nudges have more success in increasing enrollment rates, while minimizing potential ethical concerns.


Candida interacts to enhance the invasive potential of Acinetobacter and Pseudomonas bacteria cannot be resolved within individual studies. There are several anti-septic, antibiotic, anti-fungal, and non-decontamination-based interventions to prevent ICU acquired infection. These effective prevention interventions would be expected to variably impact Candida colonization. The collective observations within control and intervention groups from numerous ICU infection prevention studies simulates a multi-centre natural experiment with which to evaluate Candida, Acinetobacter and Pseudomonas interaction (CAPI). Methods: Eight Candidate-generalized structural equation models (GSEM), with Candida, Pseudomonas and Acinetobacter colonization as latent variables, were confronted with blood culture and respiratory tract isolate data derived from >400 groups derived from 286 infection prevention studies. Results: Introducing an interaction term between Candida colonization and each of Pseudomonas and Acinetobacter colonization improved model fit in each case. The size of the coefficients  for these interaction terms in the optimal Pseudomonas  and Acinetobacter models  were similar to each other and similar in magnitude, but contrary in direction, to the coefficient for exposure to topical antibiotic prophylaxis (TAP) on Pseudomonas colonization . The coefficient for exposure to topical antibiotic prophylaxis on Acinetobacter colonization was not significant. Conclusions: GSEM modelling of published ICU infection prevention data supports the CAPI concept. The CAPI model could account for some paradoxically high Acinetobacter and Pseudomonas infection incidences, most apparent among the concurrent control groups of TAP studies.Background: Whether  Candida colonization at the respiratory tract and elsewhere is associated with poor outcomes among high-risk ICU patients [Candida itself is a rare cause of ventilator-associated pneumonia (VAP) and candidemia occurs infrequently in the ICU [Candida colonization and invasive infection with Gram-negative bacilli including Pseudomonas and Acinetobacter bacteria [patients . The rea the ICU ,3. Severbacteria .Candida–Acinetobacter–Pseudomonas interaction (CAPI) is unlikely to be achieved within the constraints of a single centre study as there are several obstacles. Moreover, measuring colonization and quantifying the impact of the various interventions on it is not simple [Defining the clinical relevance of the postulated t simple . HoweverPseudomonas and Acinetobacter bacteria and also Candida [Candida [Acinetobacter [Pseudomonas bacteraemia [The prevention of VAP and other ICU acquired infections is of great interest and various anti-septic, antibiotic, anti-fungal, or non-decontamination-based interventions have been studied ,24,25,26 Candida . Topical Candida . Surpris[Candida ,29 and ltobacter  and Pseuteraemia  are unusThe objective here is to develop candidate generalized structural equation models (GSEM) founded on CAPI concepts and then confront these models using group-level infection data from published studies of ICU patient groups being subject to various group-level exposures.Being an analysis of published work, ethics committee review of this study was not required.Pseudomonas or Acinetobacter infection data available, was expanded to include Candida infection data and studies of single anti-fungal prophylaxis [The literature search and study decant used here is as in phylaxis ,29. All Candida, Pseudomonas and Acinetobacter infection data serve as the measurement components, the group-level exposure parameters serve as the structural components and colonization with Candida, Pseudomonas and Acinetobacter, each represented as latent variables, link the structural and measurement components.In the GSEM modelling, the Pseudomonas and Acinetobacter VAP as well as the incidences of Pseudomonas and Acinetobacter bacteraemia were extracted. As Candida is generally not thought to be a cause of VAP, the count of Candida as a respiratory tract (RT Candida) isolate among patients with suspected VAP was recorded along with counts of candidemia. Counts for all subspecies of Candida, Pseudomonas and Acinetobacter were included. These were each expressed as a proportion using the number of patients with a prolonged (>24 h) stay in the ICU as the denominator.The incidences of The following data were extracted and used to form the structural components of the models; year of study publication, whether the majority of the group were trauma patients, whether more than 90% of patients of the group received more than 24 h of MV, and whether the mean (or median) length of ICU stay for the group was less than five, five to ten days, or more than ten days. In the extraction of MV percentages, if this was not stated for any group, a percentage less than 90% was assumed. In the extraction of ICU length of stay (ICU-LOS) data from the studies, surrogate measures including mean (or median) length of mechanical ventilation were taken if the length of ICU-LOS was not available in order to generate broad categories of ICU stay of less than 5 days, 5 to 10 days and more than 10 days.Candida infection were noted including liver transplantation or liver failure, use of parenteral nutrition, surgery for intestinal perforation, pancreatitis and being colonized with Candida, regardless of how Candida colonization was defined. An anti-septic exposure included use of agents such as chlorhexidine, povidone-iodine and iseganan. All anti-septic exposures were included regardless of whether the application was to the oropharynx, by tooth-brushing or by body-wash.Additionally, the presence of any of the following group wide risk factors for candidemia and invasive Topical antibiotic prophylaxis (TAP) is defined here as the group wide application of topical antibiotics to the oropharynx or stomach without regard to the specific antibiotic constituents. Protocolized parenteral antibiotic prophylaxis (PPAP) is the group wide use of any parenteral antibiotic used on a prophylactic basis. Group wide exposure to anti-fungal prophylaxis was identified whether this was as a single agent, or as part of a multi-agent decontamination regimen such as within selective digestive decontamination, without regard to the specific anti-fungal agent.Candida colonization and either Pseudomonas  or Acinetobacter colonization  as the latent variables intermediary between the structural and measurement components. The models were constructed with  and without  the inclusion of studies with group mean length of ICU stay less than 5 days and with  and without  an interaction term between the Candida colonization and respectively the Pseudomonas and Acinetobacter colonization latent variables.Eight candidate GSEM models were developed with As the observations are clustered by study, in each model, a study identifier was used in order to generate a robust variance covariance matrix of the parameters of each coefficient estimate. The GSEM model with the lowest Akaike’s information criterion (AIC) score was selected as having parsimony and optimal fit from among the candidate models using the “GSEM” command in Stata .Candida, Pseudomonas and Acinetobacter infection data were generated to facilitate a visual survey of the entire data as derived from the literature. To facilitate this visual survey, a benchmark for each outcome of interest was generated from the groups of the observational studies as described previously [Scatter plots of the eviously .All data generated or analysed during this study are included in this published article and its supplementary information files see .Of the 286 studies identified by the search, 135 were sourced from 23 systematic reviews . Others Of the 286 studies, there were 23 groups from 12 studies having a group mean ICU-LOS less than 5 days including the largest , which was a study of targeted versus universal decontamination versus standard care .Candida infection.There was inequality in the numbers of infection prevention exposures. The majority of studies of anti-fungal exposure occurred within an exposure to combined TAP and anti-fungals in the context of a Selective Digestive Decontamination (SDD) regimen for which the antifungal used was topical amphotericin in 50 groups. The TAP exposures included either topical polymyxin or a topical aminoglycoside or both in every case except four intervention groups. PPAP, most commonly a cephalosporin, was used within ten control groups and 44 intervention groups of TAP studies. By contrast, anti-fungal prophylaxis used as a single agent  occurred in only nine groups and for most of these groups, the patient groups were selected on the basis of risk factors for invasive Candida . As previously noted, PPAP displays a strong positive association with Pseudomonas bacteraemia [Pseudomonas and Acinetobacter. In this regard, the cumulative days of exposure to antibiotics without activity against Pseudomonas has been reported as being a risk factor for acquiring Pseudomonas and Acinetobacter in the ICU [A strength of this analysis is that it attempts to unpack the separate associations between the teraemia . This is the ICU ,48,49,50Another strength is that the results of the model is robust to the inclusion of groups with ICU-LOS < 5 days in a sensitivity test. These groups are of interest because of the increasing focus on ICU patient groups with a shorter overall length of stay. Likewise, whether patients receiving MV are the optimal patient group to target for decontamination is unclear and the analysis here is not limited to the MV patient group.Pseudomonas, Acinetobacter and Candida colonization, each as latent variables, versus group-level exposures, provide support to the CAPI concept. The magnitude of the interaction between Candida colonization with indices of infections arising from Acinetobacter and Pseudomonas colonization could be as large as the association of these indices with TAP exposure. The CAPI interactions could explain the observed infection incidences being higher among the groups of TAP studies and the TAP interventions being paradoxically without effect against Pseudomonas VAP [GSEM modelling of onas VAP . These oonas VAP ,53,54,55


Understanding the defect characterization of electronic and mechanical components is a crucial step in diagnosing component lifetime. Technologies for determining reliability, such as thermal modeling, cohesion modeling, statistical distribution, and entropy generation analysis, have been developed widely. Defect analysis based on the irreversibility entropy generation methodology is favorable for electronic and mechanical components because the second law of thermodynamics plays a unique role in the analysis of various damage assessment problems encountered in the engineering field. In recent years, numerical and theoretical studies involving entropy generation methodologies have been carried out to predict and diagnose the lifetime of electronic and mechanical components. This work aimed to review previous defect analysis studies that used entropy generation methodologies for electronic and mechanical components. The methodologies are classified into two categories, namely, damage analysis for electronic devices and defect diagnosis for mechanical components. Entropy generation formulations are also divided into two detailed derivations and are summarized and discussed by combining their applications. This work is expected to clarify the relationship among entropy generation methodologies, and benefit the research and development of reliable engineering components. Entropy generation is a physical quantity representing energy loss, and it can quantify energy transmission and judge thermal performance. The heat flux density of chips has increased with the miniaturization of power devices. The continuous high heat injection causes heat concentration and defects at critical interfaces. High power density and high operating temperature require electronic and mechanical components to have high mechanical and thermal performance . SeveralThe aging process is generally regarded as a cumulative result of irreversible thermodynamics . DissipaEntropy generation methodologies have been widely applied in the reliability field. The applications of entropy generation are summarized in Characterizing the defects of electronic and mechanical components to diagnose component lifetime systematically has gradually become a hot topic in recent years. The current work aimed to review previous defect analysis studies that used entropy generation methodologies for electronic and mechanical components and to provide a clear theoretical framework and its applications. In this work, entropy generation methodologies are classified into two categories: damage analysis for electronic devices and defect diagnosis for mechanical components. Developed entropy generation formulations are also classified into two detailed derivations and then summarized and discussed by combining their applications. S is the entropy generation, Q is the heat, and T is the temperature. The following is an introduction to the application and analysis of irreversible properties for evaluating the aging failure of electronic devices. On the basis of the research progress of entropy generation analysis for the damage characterization of electronic systems  at a certain temperature (T). Normally, the internal heat generated during the operation of electronic devices, such as resistors [The entropy generation rate can be described as the input power dSdtIn a continuous bias voltage, an electronic device undergoes heat dissipation until the final heat is balanced to environmental conditions. Formulas (6) and (7) can be combined as follows to express the relationship between irreversible damage entropy and the damage deterioration of power devices :(8)P=UI=Therefore, the slope of the linear relationship in Formulas (8) is the irreversible loss entropy generation, and the intercept is the heat dissipated into the environment.Generally, when an entire system fails due to internal failure or degradation, the relationship between the system failure’s entropy generation rate and the internal failure’s entropy generation rate can be expressed in inequality asS(t) was proposed to project an LED lifetime. The proposed method is promising for avoiding light measurement and failure rate statistics through long-term reliability testing or aging.Entropy generation analysis can determine how much heat power is wasted for the destructive process in a resistor device and is, therefore, important for the assessment of the reliability of electronic devices. Following a similar idea to that for resistors, Cuadras et al.  investigHsiao et al.  monitoreThe entropy characteristics of a Li-ion battery pack have also been considered in thermal design . An effeChanges in microstructures, such as solder joints , microinterconnection structures (through silicon via (TSV)), bonding interfaces, and thin attached layers (DA layers), represent a major concern in electronic devices. Hence, the entropy generation theory, characterizing their behaviors and effects, has been attracting increasing research attention.k is the Boltzmann’s constant, and s is the entropy per unit mass. Then, the thermal migration of a Pb37Sn63 solder joint and the thermal decay process of low carbon steel were investigated.Lai et al.  performerocesses . SharifaT(t). Entropy generation analysis indicated that the TSV structure was easily influenced on the pad corner than on the pad center under thermal cycles and that a sharp increase in entropy generation at both ends of a diagonal implied a possible crack [Wang et al.  first aple crack . The runle crack .The traditional cohesive zone model has been used to analyze the effects of delamination propagation behavior on interface heat transfer and plays a key role in interface crack prediction . Extensiwer LEDs . The heawer LEDs . The evoS=∫0xkT2 exergy of a flip-chip package at any point is expressed in Equation (16) . The basThe thermal resistance of a junction-to-printed circuit board has been ignored. Only three thermal resistances, namely junction-to-case, case-to-sink, and sink-to-ambient resistances, have been considered . ContactCase-to-sink exergy is presented asWithout the heat sink temperature, the case-to-sink exergy is expressed assaR is the sink-to-ambient resistance, aT is the ambient temperature, P is the pressure. Herein, the intermediate derivation process based on entropy generation analysis is expressed asSink-to-ambient exergy is presented asReducing the heat resistance of a radiator to air generally means increasing the efficiency of the second law of thermodynamics. The exergy loss of a chip package can be presented asA second law efficiency has been proposed to quantify energy efficiency :(24)η∐=1The power distribution uniformity on the same board has been quantified using the proposed input uniformity and unevenness coefficient Zpower :(25)ZpowA large value of n et al.  reviewedFatigue is an important indicator of the reliability of mechanical components, including microscopic TSV structures  and macrFollowing the popular stress life (S–N curve) proposed by Wöhler et al. , existinHowever, these articles did not evaluate fatigue reliability from the perspective of energy loss until the work of Italyantsev et al. . The entA method for evaluating fresh crack surfaces has been proposed on the basis of the macroscopic entropy formula and energy equation to study the damage in isothermal composite materials, such as laminates and sandstone . Apart fThe first and second laws of thermodynamics can be applied to predict mechanical reliability, and statistical entropy plays an important role in estimating the fatigue life of components. The reliability of a Gatling gun’s automatic mechanism can be analyzed by combining the entropy generation value with neural networks, and the fault recognition rate can be improved effectively . Zhang eThe significant investigations about the entropy generation analysis of mechanical failure are summarized in From its initial proposal to its subsequent evolution, the second law of thermodynamics has been proved to be effective. It has roughly evolved into two specified directions, including internal and surface entropy losses. Internal entropy is further deduced by considering the unit cycle energy and reliability-entropy.First, the internal FFE generation of a metal sample can be obtained as ,64(26)St is time. This entropy formula takes into account temperature gradients, specific heat, and density. Al-6061-T6 and SS304 have been tested on the basis of Formula (27). The result indicated that entropy is constant in value and is not affected by other loadings and frequency [Equation (26) shows the entropy generation that consists of mechanical dissipation due to plastic deformation and thermal dissipation due to heat conduction. The entropy generation owing to plastic deformation is far greater than the entropy generation owing to heat conduction under a low cycle process. Therefore, the latter is negligible, and Equation (26) can be simplified asrequency . Equatiorequency . The resTraditional unit cycle energy nt value ; that isThe unit cycle energy formulas :(30)FFE=FFE determination can be employed to study the irreversible fatigue process of metal materials, such as AI7075-T6 and 1018 carbon steel . ReliabiThe correspondence between frictional wear and entropy production is expressed asConsidering the wear-time curve and entropy generation-time curve, we haveBased on Equation (32), the reliability-entropy hypothesis, which has been proposed to establish the relationship between reliability and entropy, can be calculated as follows (34)ReS˙e=The heat flow to the environment can be expressed asained as (38)S˙e=The total entropy flow can be obtained in the integral of the entropy flow rate over time using the equation (39)Se=∫N is the cyclic number. The parameters of the critical defect of mechanical materials can be characterized and predicted using Equation (39). Meanwhile, the damage parameter (ND) has been provided as [The relationship between standardized cyclic failure entropy and normalized cycle number can be expressed as (40)SeSfvided as (41)DN=−D) can be given asThe damage variable The reliability prediction and defect diagnosis for electronic systems are focused on the influence of temperature gradient. In addition, the investigation on the relationship between power and entropy generation and the assessment of electronic system reliability is still in its early stages.(2)The prediction of fatigue in mechanical components focuses on the influence of structural deformation by ignoring the influence of temperature gradient. Mechanical materials are mostly metal materials with good thermal conductivity during the entire fatigue failure; thus, their temperature change is minimal. Further investigations into the defect characteristics of mechanical components with internal and/or surface entropy losses should be carried out in the future.(3)Unlike that of electronic and mechanical materials, the entropy generation of heat transfer systems focuses on temperature gradients and many fluid parameters, such as friction coefficient, Nusselt number, and Boit number. Moreover, the cooling system parameters and structural parameters of a heat exchange system are optimized on the basis of the second law of thermodynamics to improve system reliability.(4)Care should be taken on the boundary conditions; radiative heat transfer is neglected in the vast majority of studies on entropy generation. This oversight is an important drawback because radiation dramatically affects most high power devices and plays an important role in high-density circuit design. Thus, the consideration of thermodynamic irreversibility due to radiative phenomena is necessary for future works, especially those on high density electronic and mechanical components.(5)Further irreversible aging monitoring of electronic devices is expected to become a growing trend in the future for entropy generation methodologies. Power devices, sensors, and third-generation semiconductors should be considered in irreversible burn-in evaluation to improve their reliability.(6)The research on the fatigue testing of metal materials should be expanded to ensure variety. Metal materials, such as stainless steel and Al, have been studied in a number of investigations, but few studies have focused on the fatigue analysis of other types of metal materials  based on entropy generation. In addition, the research on fatigue testing should progress to nonmetal materials with the second law of thermodynamics. Nonmetal materials for epoxy, such as Si, are widely used in electronic components, but related irreversible thermodynamic research theories and applications are limited.In this work, an overview is given of the development of methods for the evaluation of irreversible degradation based on the entropy generation. Two categories of methods are identified: damage analysis for electronic devices and defect diagnosis for mechanical components. The detailed derivation of the developed entropy generation formulas is discussed. It is highlighted that damage analysis entropy for electronic devices focuses on the heat generated by electronic devices. Meanwhile, the entropy generation theory in defect diagnosis for mechanical components focuses on mechanical deformation work. On the basis of the entropy generation studies reviewed, the following conclusions are made:


The growing pollen tube has become one of the most fascinating model cell systems for investigations into cell polarity and polar cell growth in plants. Rapidly growing pollen tubes achieve tip-focused cell expansion by vigorous anterograde exocytosis, through which various newly synthesized macromolecules are directionally transported and deposited at the cell apex. Meanwhile, active retrograde endocytosis counter balances the exocytosis at the tip which is believed to recycle the excessive exocytic components for multiple rounds of secretion. Therefore, apical exocytosis and endocytosis are the frontline cellular processes which drive the polar growth of pollen tubes, although they represent opposite vesicular trafficking events with distinct underpinning mechanisms. Nevertheless, the molecular basis governing the spatiotemporal crosstalk and counterbalance of exocytosis and endocytosis during pollen tube polarization and growth remains elusive. Here we discuss recent insight into exocytosis and endocytosis in sculpturing high rates of polarized pollen tube growth. In addition, we especially introduce the novel integration of mathematical modeling in uncovering the mysteries of cell polarity and polar cell growth. NeverthIn this mini review, due to space constrains we predominantly focus on the recent insights into exocytosis and endocytosis in regulating cell polarization and polar cell growth. In addition, we discuss the novel integration of mathematical modeling in underlying the roles of exocytosis and endocytosis in cell polarization and growth, and highlight a few outstanding questions that needed to be addressed to understand the mechanisms by which pollen tube polarity and growth are regulated.trans-Golgi network (TGN) is regarded as an independent organelle serving as a hub for connecting multiple endomembrane sorting and trafficking pathways in plant cells. It is responsible for receiving, sorting, packaging and secretion of different types of cargoes to their target destinations for the proper functions (Nicotiana tabacum pollen specific pectin methylesterase 1 (NtPPME1), a key pectin modification enzyme regulating the rigidity of cell wall  of different types of exocytic proteins has demonstrated that exocytosis takes place in the apex region, the same region as for endocytosis . For exadistally . It seemdistally . Actualldistally . DespiteThe generation of theoretical models by mathematical analysis has been employed as a useful tool in biological studies to better understand the molecular basis of cells. More importantly, it helps to develop a testable hypothesis, apply the modeling on broader similar biological systems and stimulate new experiments .via ROP1. The model is firstly generated basing on the experimental estimation of the rate of GFP-ROP1 diffusion on the PM of Arabidopsis pollen tubes determined by FRAP and the strength of positive and negative feedback loops (kpf and knf) regulating active ROP1. Thereafter, the mathematical model is validated by comparing the parameters between the stimulated model prediction and actual experiments which examined the apical cell wall formation, pectin distributions and tip morphological shapes of the pollen tubes of the wild type and genetic mutants altered in ROP1 activation. After the proof of the model, they sought to explore model-inspired new insights into the roles of exocytosis in pollen tube growth guidance. The model then is employed to reproduce the connection between pollen tube polarity switch during growth guidance and exocytic parameters of the tip growth. The stimulating results from the modeling reveal a central role of exocytosis in coordinating pollen tube tip growth and guidance  like Buddha’s Paper Seal 1/2 (BUPS1/2) and ANXUR1/2  family proteins and ANXUR1/2 . HoweverAs our understanding comes into focus, tip-focused exocytosis and endocytosis appears as two sides of the same coin. Meanwhile, they coexist and reach a dynamic yin-yang balance which is not a fifty-to-fifty static state, but rather turning out as an anterograde growing equilibrium as shown in LZ, MR, and HW designed the concept and organized the manuscript. MR and HW wrote the first draft of the manuscript. LZ and HW revised and finalized the manuscript. All authors contributed to the article and approved the submitted version.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.


Simulating transcranial electric stimulation is actively researched as knowledge about the distribution of the electrical field is decisive for understanding the variability in the elicited stimulation effect. Several software pipelines comprehensively solve this task in an automated manner for standard use-cases. However, simulations for non-standard applications such as uncommon electrode shapes or the creation of head models from non-optimized T1-weighted imaging data and the inclusion of irregular structures are more difficult to accomplish. We address these limitations and suggest a comprehensive workflow to simulate transcranial electric stimulation based on open-source tools. The workflow covers the head model creation from MRI data, the electrode modeling, the modeling of anisotropic conductivity behavior of the white matter, the numerical simulation and visualization. Skin, skull, air cavities, cerebrospinal fluid, white matter, and gray matter are segmented semi-automatically from T1-weighted MR images. Electrodes of arbitrary number and shape can be modeled. The meshing of the head model is implemented in a way to preserve the feature edges of the electrodes and is free of topological restrictions of the considered structures of the head model. White matter anisotropy can be computed from diffusion-tensor imaging data. Our solver application was verified analytically and by contrasting the tDCS simulation results with that of other simulation pipelines . An agreement in both cases underlines the validity of our workflow. Our suggested solutions facilitate investigations of irregular structures in patients  or new electrode types. For a coupled use of the described workflow, we provide documentation and disclose the full source code of the developed tools. The simulation of transcranial electric stimulation (tES) is increasingly employed when designing tES intervention studies  and obseAll these pipelines implement a common, general workflow covering standard use cases, i.e. the tES simulation of healthy subjects based on their individual magnetic resonance imaging (MRI) data using rectangular, circular or ring electrodes. The starting point of this workflow is the segmentation of the MRI data of the subjects into the electrically most important tissue classes. The obtained segmentation image is then used to create the head volume mesh, which is complemented by electrodes that need to be modeled and positioned. The simulation problem is solved using this individual head model, and results are visualized. The implementation of the outlined workflow by current tES simulation pipelines does not entirely cover use cases with suboptimal imaging data, the presence of pathological tissue in patients or alternative electrode shapes.For instance, MRI data from large-scale imaging studies usually were not primarily acquired for the purpose of computational head modeling. Performing simulation studies based on such data can become difficult due to challenges in the segmentation of low-contrast tissue such as the skull using standard segmentation approaches. Following the image segmentation, a surface-based meshing approach is commonly used to create the head volume mesh. The advantage of this approach is a maximum of control over the approximation of the boundaries of the sub-compartments of the head model, which, on the other hand, must not intersect, restricting the topology of the included structures and complicating the inclusion of irregular tissue such as lesioned tissue. ROAST circumvents this restriction by applying an image-based meshing approach, which is free of any topological constraints , with thhttps://github.com/benjamin-kalloch/tes-simulation-workflow) allowing a coupled use of the entire tool set as well as usage of single tools only.In this work, we present approaches to address the above-mentioned non-standard use-cases when simulating tES on an individual basis. Segmentation routines were selected based on the robustness of the structure segmentation of T1-weighted MRI data using JIST  a pluginThe process of simulating tES involves the head and the electrode modeling, solving the underlying electrostatic problem, and the visualization.Computational Geometry Algorithms Library (CGAL) API, version 4.13.1 61] are rOur solver application was verified using an analytical three-layered sphere model and by comparison of the simulation results with the established simulation pipelines SimNIBS and ROAST. However, a verification of the obtained simulation results with in-vivo recordings of the electrical field remains an open task. Promising approaches are electrical current density measurements obtained by the means of magnetic resonance electrical impedance tomography  or in-viSince our workflow mainly focuses on addressing individual problems that we faced during the simulation of tDCS, it only provides a loose framework for the coupling of the suggested tools. While we documented the information flow between the individual steps of the workflow, we did not couple the involved tools in an overarching script yet as our main focus was the easy interchangeability of the involved tools and the extendibility of the workflow. As a result, familiarization with the individual tools and knowledge about the information flow between the tools  is necesFirst simulation studies suggest that damaged brain tissue due to a stroke influences the field distribution . ConsideThe advantageous properties of our suggested approaches for head and electrode modeling, as well as segmentation, facilitate simulation studies investigating alternative electrode shapes or irregular structures of the head model such as lesions and tumors in patients, impla nts, holes in the skull or vascular tissue.


Research supports that an agreement about the consequences of the illness within related parties is critical for optimal patient outcomes. This study aimed to explore the association between patient QOL and the degree of agreement in the perceptions of patient disability within the stroke patient-rehabilitation therapist dyad. A cross-sectional study was conducted in Japan from March 2019 to February 2020. A total of 81 dyads consisting of a male stroke patient living at home and the therapist in charge of the eligible patient participated. Patient QOL was measured using the WHOQOL BREF. Perceptions of patient disability were measured using the 12-item WHO Disability Assessment Schedule 2.0 (DAS). DAS scores of patients and therapists were classified into two  and three  categories, respectively, and six patterns of agreement on patient ability were created to use in the analysis. Generalized estimating equations were used to examine multivariable associations between the degree of agreement within dyad and WHOQOL scores in patients. Results suggested that when the patient appraised himself as having a low disability, the degree of patient-therapist disagreement was negatively associated with patient QOL. When the patient appraised himself as having a high disability, his QOL was lower, regardless of the degree of agreement. Disagreements in the perception of disability between patients and therapists can worsen patient QOL, especially when the patient perceives himself as having a low disability.


Chest wall motion can provide information on critical vital signs, including respiration and heartbeat. Mathematical modelling of chest wall motion can reduce an extensive requirement of human testing in the development of many biomedical applications. In this paper, we propose a mathematical model that simulates a chest wall motion due to cardiorespiratory activity. Chest wall motion due to respiration is simulated based on the optimal chemical–mechanical respiratory control-based mechanics. The theory of relaxation oscillation system is applied to model the motion due to cardiac activity. The proposed mathematical chest wall model can be utilized in designing and optimizing different design parameters for radar-based non-contact vital sign (NCVS) systems. Continuous monitoring of vital signs, namely respiration and heartbeat, can provide information in predicting the undesired events like cardiac arrest, critical dizziness, arrhythmias, cardiac rhythm, temperature regulation, synchronization with respiration rate . The conThe radar-based system for vital sign detection is developed based on movements of a target, i.e., chest wall motion due to respiration and cardiac activity. Chest wall displacement with respect to time is reflected in the phase variation in the received signals. Subsequently, the modelling accuracy of non-contact vital sign (NCVS) systems depends on the modelling of chest wall motion with respect to time, i.e., the shape of the chest wall motion. The performance and testing of a robust design depend on the analysis and strength of the experimental dataset available. Though a larger and exhaustive dataset produces an opportunity for the design to be tested and analyzed in all possible scenarios, it would require a considerable number of real-time experiments. It not only consumes time, costs, and power but is also impractical for participating subjects. This can efficiently be managed through simulation and mathematical modelling. In earlier works related to radar-based systems, many researchers conducted exhaustive experiments for analyzing radar-received signals . HoweverIn literature, most of the simulation for radar-based NCVS systems to date are based on a simplistic approach of assuming chest wall motion as sinusoidal ,5. The rThe heartbeat signal is complicated and nearly periodic. Almost all simulations to date are based on assuming the chest wall motion due to cardiac activity as sinusoidal ,16,17,18Our proposed model is the first step toward modelling chest wall motion due to cardiorespiratory activity. This would help in customizing it for the various respiratory pattern that arises due to different health conditions/diseases. For example, Kaneko et al., in their study, assess the effect of posture, age, and gender on the breathing movements in healthy subjects . The outThe rest of the paper is organized as follows. The proposed mathematical model for the chest wall motion is described in Respiration or breathing is a natural periodic activity which involves airflow into and out of lungs, also called pulmonary ventilation. The contraction and relaxation of the diaphragm cause pleural pressure variations and governs the airflow, as shown in P(t): Isometric respiratory pressure measured at FRC, V(t): instantaneous lung volume, rsR: total respiratory system resistance, and P(t1) is the isometric pressure at time t1. In this work, the respiration cycle is simulated based on the optimal chemical–mechanical respiratory control model, which has been utilized earlier to develop respiratory control simulator . The neuThe heart is placed in the space called a thoracic cavity. The thoracic cavity is protected by the thoracic wall or commonly called chest wall which consists of a rib cage and associated skin, muscle, and fascia. Inside the thoracic cavity, the heart is located atop the diaphragm having its apex closer to the anterior surface of the thoracic cavity. For every beat, the heart contracts and expands with the apex taping against the chest wall .The heart consists of muscle tissue, commonly called fibers containing contractile elements and coordinate cardiac contraction. The coordination of mechanical activity of the chambers is requisite for the efficient working of the heart. During the systole and diastole, the contraction and expansion of the muscle tissue or contractile elements govern the thoracic wall or chest wall movement  and is dThe cardiac impulse generated at the SA node is conducted by the contractile cells or the muscle tissues  of the heart. Excitation–contraction coupling ties electrical depolarization to the mechanical expansion and shortening of myocardial cells . The difThe sinoatrial (SA) node (cardiac pacemaker) rhythmic behavior is represented by a relaxed oscillatory system . It is aThe rhythm of the SA node cardiac pulse governs the contraction and expansion of contractile cells or muscle tissues. This muscle tissues directly controls the rhythm of thoracic or chest wall activity. The excitation and depolarization cycle of SA node is synchronized with the systole and diastole cycle of cardiac activity. The thoracic wall or chest wall observes expansion and contraction cycle in coordination with the systole and diastole cycle where its rhythmic behavior is synchronously represented by the SA node behavior. Therefore, the heartbeat model used in this study is represented by a relaxed oscillatory system.For a NCVS system the heart rate is extracted from the phase variations in the reflected signal caused by chest wall motion. These chest wall motion has been modelled as linear sinusoidal motion in the earlier literatures assuming the heart rhythm as simple oscillatory behavior. However, the phase variation of radar reflected signal depends on the minute movement of chest wall and small variation in movement can result in large variation in the phase or resultant heart rate. Since, heart is treated as a network of elements and these elements show the oscillatory behavior that can be modelled as nonlinear van der pol oscillator, therefore, the chest wall motion has been modelled in rhythm to the rhythm of heart network element as novel approach for chest wall movement modelling.We simulate chest wall motion pulse using Simulink, MATLAB 2019b. A sampling rate of 1 kHz is chosen to generate the simulation signals. The simulated waveforms are technically vetted through a separate experimental dataset available for the chest wall motion . The datDesign parameters including pulse duration  node and atrial ventricular (AV) node during biological rhythms for different human activities such as sleeping, wake cycle etc. Similarly, the pulse duration and maximum chest wall displacement of the wave can be simulated through variation of Design parameter for simulation of chest wall motion due to cardiac activity is given in The shape of the simulated chest wall displacement during heart activity was found to be more bulged out in the middle through higher values of the parameter (α) as illustrated in During a normal breath, chest wall motion comprises of two components, the displacement from respiration activity and second, the displacement due to cardiac activity. However, if a chest wall displacement is captured during a breath-hold condition, the displacement is caused by heart activity only. The motion due to heart activity is too small (0.2–0.5 mm) as compared to the motion due to respiration (3–12 mm). Therefore, a dataset of chest wall motion due to heart activity only is extracted from the breath-hold duration and used to perform the similarity analysis.A, respectively, and B, with each variable has N scalar observations. In time series analysis, the normalized time-dependent Pearson correlation coefficient is an indicator of similarity index as the cross-correlation coefficient value must lie in the range from −1 to 1, with one indicating perfect correlation [The time profile of the chest wall movement due to cardiorespiratory activity obtained from the simulation is compared with the human chest wall experimental data . The datrelation ,40.Additionally, in time series analysis, another technique dynamic time warping (DTW) is used for measuring the similarity between two temporal sequences . DTW worThe respiration waves are nonlinear time series in nature, and hence, revalidation of the simulated model is performed through dynamic time warping, a nonlinear similarity matching technique for two time series. The distance between two waves acquired through DTW analysis is shown in The DTW distance between simulated and experimental dataset waves for cardiac activity acquired through DTW analysis is shown in This work contributes to the development of a mathematical model for ubiquitous and nonobtrusive cardio-respiratory vital sign monitoring through radar-based NCVS system. The comparative analysis through cross-correlation demonstrates that the simulated chest wall motion is in close agreement with the real motion and hence validate the applicability of simulated chest motion in cardiac-respiratory applications. The cross-correlation coefficient between the simulated waveform and the experimental dataset approaches to the range of 0.95–0.97, indicating a high degree of similarity of both time sequences.Our proposed model is not only useful for validating the design parameters through a target modelling for radar-based NCVS system applications but can also be utilized for the development of techniques to evaluate the cardio-respiratory parameters of chest surface motion beneficial in validating the design of artificial cardio-respiratory systems. The proposed model demonstrated the ability to simulate the varying chest wall motion in different scenarios such as free-breathing and post-exercise breathing etc.The limitation of our study is that it relies on the single experimental dataset available for the chest wall motion. However, in future work, exhaustive experiments with a varying subject profile in terms of age, gender, weight, medical history can be employed for the measurement of chest displacements. This chest wall measurement may be compared with more simulation waveforms to arrive at a conclusion for a shape defining condition of diseases such as lung tumor, sleep apnea or different disease triggering scenarios. In addition, these simulation parameters may be employed for designing a care system to address the diseases or scenarios without exhausting experimentation of the design over real subjects.