The management ranges from simple follow-up of uncomplicated cases, to systemic administration of granulocyte colony stimulating factor (G-CSF), antibiotics and immunomodulatory agents, to more drastic therapies with the potential to cure, that is, hemopoietic stem cell (HSC) transplantation or even to experimental gene-based interventions using CRISPR-Cas9 technology.The diagnosis of congenital and acquired CNP remains a challenge with the underlying mechanisms still obscure in 30% to 50% of patients. Moreover, the variability in genotypic/phenotypic characteristics and natural history of these patients has thus far precluded defining common treatment patterns and guidance whereas the rarity of the underlying diseases has resulted in difficulties in recruiting patients for clinical trials. The collaboration between clinicians and scientists with special interest in these diseases as well as the establishment and interconnection of CNP patient Registries and Biobanks are essential prerequisites for the generation of a rich source of real-world data that will both facilitate the accurate diagnosis and contribute to a consensus on patient management; foster research on the pathogenetic/pathophysiologic mechanisms; and, give more opportunities for the development of novel and personalized treatment approaches as well as initiation of clinical trials.https://www.eunet-innochron.eu/) funded by the European Cooperation of Science and Technology (COST) was launched in November 2019  and the European Hematology Association (EHA). EuNet-INNOCHRON is open to any clinician, researcher, scientific or patient society with a special focus in CNP. The network aims to: (a) harmonize the laboratory investigation of different types of CNP by facilitating the exchange of knowledge, tools, reagents, protocols and experience through inter-institutional collaborations; (b) formulate common diagnostic algorithms and treatment guidelines for patients with different types of CNPs aligned with the concepts of precision medicine; (c) organize new and expand existing CNP patient Registries and Biobanks using common protocols for sample collection, storage and management as well as template forms for patients’ informed consent according to the ethical standards of the European Legal Framework and the national and local regulations; (d) collect real-world data on the epidemiology, clinical presentation and natural course of CNPs and identify markers for improved decision-making and risk-adapted treatment strategies; (e) promote training and education of young investigators on advanced techniques; (f) foster entrepreneurial innovation and explore novel approaches for targeted drug development and innovative clinical trial design in collaboration with industrial partners. EuNet-INNOCHRON has adopted an excellence and inclusiveness policy and gives particular interest in the involvement of young researchers by offering a number of networking tools such as scientific meetings, short term scientific mission exchanges, training schools and conference grants.A wide European network for the diagnosis and treatment of CNP  have been carefully designed within EuNet-INNOCHRON to address the challenges in CNP and promote breakthrough scientific developments and new concepts in the diagnosis, management and treatment of these patients Table .17 RNA-sequencing analysis of HSCs generated from isogenic iPS cell lines will help to identify deregulated intracellular signaling pathways and candidate factors underlying the cellular phenotypes of neutropenias. CRISPR-Cas9 will be used to generate Zebrafish either deficient for the candidate genes or carrying patient-specific gene mutations. This WG will also study the CNP associated with Shwachman-Diamond Syndrome (SDS) to better understand the role of the causative genes SBDS, EFL1, and DNAJC21 in ribosome assembly and also provide templates for the development of novel therapeutics.18 Robust, viable animal models will be generated and exploited to better understand SDS pathogenesis and promote the development of new therapeutics. A key objective of this WG is to establish new collaborations to achieve our goals.This WG will perform whole exome sequencing (WES) studies in patients with unknown mutations and healthy family members and promote collaborations in this field; candidate genes will be functionally interrogated for their role in granulocyte differentiation by generating induced pluripotent stem (iPS) cell lines from patients. Abnormal genes will be corrected in patient-derived iPS cells using CRISPR-Cas9 technology and the potential improvement of in vitro granulocytic differentiation of the gene corrected iPS cell lines will be evaluated. Candidate gene mutations will be also introduced into iPS cells derived from healthy individuals and their effects on granulocyte differentiation will be evaluated in vitro.19 Regarding the non-antibody-mediated CNPs, particular networking will be directed to the idiopathic cases. Specifically, the WG will help to probe the T cell receptor gene repertoires from different patients with idiopathic CNP using NGS and results will be compared with public databases or databases from other diseases with overlapping features  to identify disease-specific but also shared clonotypes.11 The role of myeloid cell populations, namely myeloid derived suppressor cells (MDSC), will also be explored in idiopathic CNP as well as the significance of clonal hemopoiesis in correlation with patient outcome.20This WG will invest in collaborative work for the investigation of antibody- and non-antibody mediated CNP. An important goal is to raise awareness of the diversity of acquire CNP and the available diagnostic platforms. Emphasis will be given on the transfer of knowledge and methodological hands-on training on the high-quality detection of anti-neutrophil autoantibodies (sensitivity and specificity). Many traditional techniques are present in special laboratories whereas new diagnostic platforms are available with a potential for more wide-spread use. Novel diagnostic tools, such as next generation sequencing (NGS) including WES to understand better rare diseases that can by themselves cause antibody-mediated CNP, such as autoimmune lymphoproliferative syndrome (ALPS) and primary immune deficiencies (PID), will be performed.21 Congenital CNP is an interesting model to study leukemogenesis considering that the very first mutation of the process is acting in both hemopoietic cells and the BM microenvironment since embryogenesis. Large-scale application of NGS in these cases as well as in acquired CNP with a propensity to develop MDS/AML will significantly improve diagnosis and risk stratification. Longitudinal NGS studies will be performed to provide new insights into driver mutations and stepwise transformation. This WG will also investigate the role of cellular stress mechanisms in leukemic evolution. Novel tools, based on iPS cells and genome editing technologies will be developed to elucidate these stress mechanisms and interrogate the sequential events leading to MDS/AML. Key findings will be exploited to develop strategies to redirect premalignant progenitors back to normal. The WG will also establish ultra-deep sequencing of the critical region of the CSF3R and RUNX1 genes and will also explore the importance of these acquired mutations in leukemic evolution through longitudinal retrospective analysis of multiple BM samples of large number of patients with Congenital Neutropenias. Animal models (Mice and Zebrafish) will be also used to study molecular mechanisms of leukemogenesis triggered by CSF3R and RUNX1 mutations. The landscape and clonal dynamics of genome-wide somatic mutations associated with MDS/AML transformation in SDS will be investigated in single-cell derived HSC and progenitor cell colonies from these patients.MDS/AML evolution in specific types of CNPs is a multistep process of sequential hits and predictive biomarkers are not available.+/SIRTs-mediated signaling as compensatory mechanisms of the G-CSF-mediated granulopoiesis results in induction of granulopoiesis in healthy individuals and CNP patients.22 This WG will promote studies on the evaluation of the effects of different NAMPT and SIRT1 activators as well as the NAMPT substrate, nicotinamide, on the G-CSF-induced granulopoiesis in vitro using iPS cell-based hemopoietic differentiation, primary BM HSCs, and in Zebrafish and xenograft mouse models. The WG will also facilitate the establishment of iPS cell lines from Congenital Neutropenia patients with different gene mutations and will study the effects of small molecules on the granulocytic differentiation. Small molecules capable of inducing differentiation will next be tested in primary HSCs and in animal models, including Zebrafish and Mice. We will also promote research on the potential of novel molecules to interfere with neutrophil elastase whose malfunction is a frequent cause of Congenital Neutropenia. Inhibitors of neutrophil elastase proteolytic activity are expected to broaden the therapeutic opportunities for these patients.23It has been shown that activation of the NAMPT/NAD24 The WG will contribute to the standardization of the modus operandi of the national CNP Registries across participant countries to ensure reliable statistics and standard indicators on incidence, prevalence, morbidity, mortality, infection rates, quality of life, proportion of patients receiving G-CSF and dose, number of patients undergoing HSC transplantation, comorbidities and rate of MDS/AML. Given that the availability of Biobanks is a prerequisite for progress in understanding CNPs and improving patient care, the WG will promote the systemic and standardized collection of patient samples and will propose guidelines for biological data collection, management, sharing and transfer according to the European Legal Framework taking also into account national and regional ethical and regulatory aspects. Issues specific to the type of samples  and the time points of collection to allow pertinent study in close linkage with clinical data will be defined. Finally, the WG will propose a single classification of all different diseases associated with CNP.Partners from national CNP patient registries, biobanking consortia and SCNIR will contribute to the organization and interconnection of CNP patient Registries and Biobanks at the European level.The EuNet-INNOCHRON is an open network focused on the investigation, characterization, harmonization of diagnosis and treatment of CNPs, promotion of research, technology and entrepreneurial innovation, consisting so far of more than 30 countries. The Action was built on a network of experts in the field of CNP with long-standing collaborations and further enriched with scientists of diverse expertise to achieve an interdisciplinary and multidisciplinary approach to study the pathogenesis of CNP and is open to researchers, particularly at early career stages, related scientific societies, patient organizations, biotechnology and pharmaceutical companies. A key intention of EuNet-INNOCHRON is to foster broad collaborations and open the way for cutting-edge research and transfer of knowledge to the clinic. The consortium is anticipated to strengthen the interactions among experts in the field of CNP at the European level and beyond, to facilitate and extend the collaboration between existing outstanding networks such as EHA-Scientific Working Groups, SCNIR and national Registries for the introduction of common policies in CNP Registries and Biobanks, and, most importantly, to contribute to the generation of the future leading physicians and researchers in the field of CNPs with appropriate knowledge and skills to promote further research, innovation and personalized patient treatment.HAP conceptualized the manuscript. All authors contributed to the writing and editing of the manuscript. All authors approved the final version.HAP has participated in Advisory Boards for Novartis and Abbvie Companies; JP is chair of the Neutropenia Advisory Board at ApoPharma Ltd, Toronto, Canada, (Chieti Canada Ltd); CD has participated in Advisory Board for Novartis. The rest of the authors declare no conflicts of interest.https://www.eunet-innochron.eu/) supported by COST (European Cooperation in Science and Technology).This article is based upon work from COST Action CA18233 “European Network for Innovative Diagnosis and treatment of Chronic Neutropenias, EuNet-INNOCHRON” (


The present study characterizes the flow of three-dimensional viscoelastic magnetohydrodynamic (MHD) nanofluids flow with entropy generation analysis past an exponentially permeable stretched surface with simultaneous impacts of chemical reaction and heat generation/absorption. The analysis was conducted with additional effects nonlinear thermal radiation and convective heat and mass boundary conditions. Apposite transformations were considered to transform the presented mathematical model to a system of differential equations. Analytical solutions of the proposed model were developed via a well-known homotopy analysis scheme. The numerically calculated values of the dimensionless drag coefficient, local Nusselt number, and mass transfer Nusselt number are presented, with physical insights. The graphs depicting the consequences of numerous parameters on involved distributions with requisite deliberations were also a part of this model. It is seen that the Bejan number is an increasing function of the thermal radiation parameter. Rapid growth in the usage of nanofluids in varied engineering arenas such as cancer therapy, finer coolants in nuclear reactors and computers, numerous electronic devices in military sectors , oil andThe inevitable and dynamic applications of MHD nanofluids , asthma treatment, and removal of tumors with hyperthermia) have attracted the attention of scientists and researchers in studying the related field of nanofluids. Sheikholeslami  deliberaThe study of heat and mass transfer of nanofluid flows with chemical reactions past stretched surfaces has numerous significant applications in core industries such as chemical and metallurgical engineering. Examples include polymer production and food processing. Furthermore, heat and mass transfer models with chemical reaction effects are vital in several processes and have gained attention in recent years. Fascinating applications pertaining to chemical reactions embrace the distribution of temperature and moisture over agricultural fields and groves of fruit trees, the energy transfer of drying and evaporation at the surface of a water body, and the energy transfer of a wet cooling tower.Entropy is pronounced the nonavailability of the system’s thermal energy for translation into mechanical work. The second law of thermodynamics asserts that throughout the process of conversion of energy into some beneficial work, there is forfeiture of energy that lowers the performance of energy conservation gadgets. Basically, entropy generation is directly proportionate to a loss of energy. Subsequently, entropy generation in a system results in the reduction of the quantity of energy present (exergy). Thus, the efficiency of the thermal system may be enhanced by slashing the entropy generation. In this regard, it is necessary to have the idea of energy generation’s distribution throughout a thermodynamic process with the intention of reduction in entropy generation. The idea of entropy generation was first floated by Bejan , who exaThe significance of non-Newtonian fluids cannot be denied due to their involvement in varied engineering and industrial applications such as petroleum production, the thinning of copper wires, and plastic manufacturing . To exhiThe literature review above indicates that few studies have been made on three-dimensional viscoelastic nanofluid flows associated with entropy generation and nonlinear thermal radiation past an exponential stretched surface. Therefore, we present our study on such an investigation by solving the proposed model analytically with three dimensionless distributions  and examz axis. The Hall and electric field effects were overlooked. The induced magnetic field was also ignored due to our assumption of a small Reynolds number. The permeable surface was stretched in both the x and y directions with respective velocities We considered the flow of MHD viscoelastic nanofluid past a permeable exponentially stretched surface with entropy generation. The analysis was performed in the attendance of nonlinear thermal radiation, chemical reaction, and heat generation and absorption with convective heat and mass boundary conditions. The magnetic field was applied parallel to the The mathematical model, under assumptions, is represented by the following equations :(1)∂u∂x+The surface stretching velocities, temperature, and concentration of the wall were given byThe transformations are presented as given below:Equation (1) was satisfied automatically, whereas Equations (2)–(5) took the formThe parameters given in Equations (9)–(12) are defined as follows:x and y directions were given byThe equations of the skin friction coefficients along the The equations of the skin friction coefficients in dimensionless form were given byThe convergence of the series solutions was adjusted and regulated with the aid of auxiliary parameters The homotopy analysis method necessitated the initial guesstimates (the form (21)f0Be=TIn dimensionless form, it becameThe value of the irreversibility parameter must lie between The averaged entropy generation number could be evaluated using the following integral formula:Rd meant more emission of heat that ultimately raised the temperature of the fluid. Also, the higher estimates of M for the entropy generation Re, thermal radiation parameter Rd, and Brinkman number Br on the variation of local entropy generation number Ns, respectively. From Ns was an increasing function of these three: Re, Rd, and Br. M, K, Pr, and Rd on average entropy (avg)Ns. From these figures, it was gathered that (avg)Ns was an escalating function of all four parameters. This meant irreversibility mounted as the group parameters grew.This section is dedicated to having a deep insight into changes of sundry parameters on involved profiles. The ranges of all parameters were selected via Turkyilmazoglu . Figure The velocity components were declining functions of the viscoelastic parameter.The temperature field improved with an increase in radiation parameter.Thermophoresis and Brownian motion parameters had an opposite effect on concentration distribution.With growing values of the magnetic parameter, both velocity components declined.The Bejan number is an increasing function of the thermal radiation parameter.Entropy generation decreased for escalating values of the temperature difference parameter.Entropy generation of 3D viscoelastic nanofluid fluid flow past an exponential stretched surface with nonlinear thermal radiation, chemical reaction, and magnetohydrodynamics was discussed analytically with the homotopy analysis method. The whole analysis was completed with the effect of heat generation and absorption supported by convective heat and mass boundary conditions. The main findings of the analysis are:


The aim of the ACE-Obesity Policy study was to assess the economic credentials of a suite of obesity prevention policies across multiple sectors and areas of governance for the Australian setting. The study aimed to place the cost-effectiveness results within a broad decision-making context by providing an assessment of the key considerations for policy implementation. The Assessing Cost-Effectiveness (ACE) approach to priority-setting was used. Systematic literature reviews were undertaken to assess the evidence of intervention effectiveness on body mass index and/or physical activity for selected interventions. A standardised evaluation framework was used to assess the cost-effectiveness of each intervention compared to a ‘no intervention’ comparator, from a limited societal perspective. A multi-state life table Markov cohort model was used to estimate the long-term health impacts ) and health care cost-savings resulting from each intervention. In addition to the technical cost-effectiveness results, qualitative assessments of implementation considerations were undertaken. All 16 interventions evaluated were found to be cost-effective . Eleven interventions were dominant . The incremental cost-effectiveness ratio for the non-dominant interventions ranged from AUD1,728 to 28,703 per HALY gained. Regulatory interventions tended to rank higher on their cost-effectiveness results, driven by lower implementation costs. However, the program-based policy interventions were generally based on higher quality evidence of intervention effectiveness. This comparative analysis of the economic credentials of obesity prevention policies for Australia indicates that there are a broad range of policies that are likely to be cost-effective, although policy options vary in strength of evidence for effectiveness, affordability, feasibility, acceptability to stakeholders, equity impact and sustainability. Implementation of these policies will require sustained co-ordination across jurisdictions and multiple government sectors in order to generate the predicted health benefits for the Australian population. Globally, the obesity epidemic is firmly established with the prevalence of overweight and obesity nearly tripling over the last four decades , 2. AustThere is global consensus that efforts to address obesity require a comprehensive societal response , 9. ThisOver the last 15 years, the availability of economic evidence to guide decision-making on obesity-related policy has increased . HoweverThe Assessing Cost-Effectiveness (ACE) methodology was developed as a priority-setting tool to facilitate evidence-based decision-making. It combines technical rigour in the cost-effectiveness analyses with other considerations that influence policy decision-making , 14. TheThe aim of this priority-setting study was to focus on the current evidence gaps in the economic evidence by evaluating a range of ‘upstream’ obesity prevention policies (including both regulatory and program-based interventions) across multiple sectors and areas of governance . In addition to the economic evidence, the study aimed to also provide a qualitative assessment of implementation considerations likely to be important to decision-makers .The ACE-Obesity Policy study was undertaken over the years 2012–2018. The research question was “What are the most effective, cost-effective, affordable and implementable policy options to prevent obesity across a range of settings?” This study used the ACE approach to priority setting, details of which have been previously published , 16; a bThe ACE approach acknowledges that decision-making requires not only technically rigorous cost-effectiveness analyses based on the best available evidence, but also consideration of the broader concerns of decision-makers and the range of issues that need to be deliberated when making policy decisions . The appGiven the large number of heterogeneous policy options that could be considered for obesity prevention, we used the following intervention selection process. The overarching principles for selection were that the intervention should: i) be aimed at primary prevention rather than treatment, and ii) impact large population groups. Program-based interventions targeted at specific populations were required to be scalable for implementation across Australia. The interventions were identified in an iterative process. This involved an initial scan of relevant international and national authoritative reports related to obesity prevention, experience of the investigator team, and advice from the project steering committee made up of obesity researchers, epidemiologists, obesity advocates and policymakers. The list of potential interventions was reviewed annually to ensure all relevant interventions based on emerging evidence and global policy activity were considered for inclusion. Intervention selection was based on the potential impact of the intervention on overweight and obesity in Australia; the relevance of the intervention to current policy decision-making across Australian government jurisdictions and the private sector; and the availability of adequate evidence of intervention effectiveness to support the analyses. The selected interventions were mapped to a policy framework  to help For interventions selected for inclusion, systematic searches of the grey and academic literature were undertaken to assess the strength of evidence for intervention effectiveness. Strength of evidence was assessed based on the quantity of evidence, study design and quality of the outcome measures used. The methods used for assessing strength of evidence are detailed elsewhere .Once interventions were selected and prioritised for evaluation, modelling the cost-effectiveness consisted of three steps . The firThis study used a limited societal perspective and therefore costs accruing to various government sectors, private companies and individuals were included in the analyses. Cost components varied by intervention, however the main elements included recruitment costs for targeted interventions, cost of passing legislation for mandatory policy interventions and the key elements of intervention implementation, administration, compliance assessment and maintenance over the duration of the intervention. The cost to industry of implementing the intervention was included in the analyses, with impacts on company revenue included in sensitivity analyses when adequate data were available. Deadweight losses associated with taxation policies were included in sensitivity analyses, however potential overall welfare losses to individuals were not included. Time and travel costs accrued by individuals were included, however time costs of children were excluded. Other excluded costs were productivity costs, and intervention research, development and evaluation costs .Unit costs were collected in Australian dollars (AUD) for the 2010 reference year largely from administrative databases. Wages included salary on-costs (13% for public sector and 14% for private sector) and 17.5% leave loading. Time costs were valued at gender free wage rates  was undeInterventions that impacted food consumption were modelled using food composition data from the Food Standards Australia New Zealand NUTTAB 2010 database  and The Interventions impacting physical activity were assumed to have an impact not only on physical activity levels, but also BMI based on the assumption that the increased energy expenditure was not compensated by increased energy intake. Changes in physical activity levels were measured in metabolic equivalent task (MET) minutes per week , 29 and To allow comparability across interventions included in this priority-setting study, we assumed that the impact of regulatory interventions on risk factors were maintained over the lifetime of the modelled population. However, individual intervention evaluations tested the impact of this assumption with variations in maintenance of effect tested in scenario analyses. The duration of intervention effect varied for program-based interventions according to the characteristics of each intervention.A proportional, multi-state life table Markov cohort model was developed to quantify the relationship between characteristics of the population, risk factor prevalence and obesity related diseases to estimate the longer-term outcomes of obesity prevention initiatives. The Markov modelling approach is widely used in economic evaluations and can adequately capture the epidemiology and associated costs of chronic diseases associated with obesity . DetailsThe model simulates the 2010 Australian population (aged 2–100 years) and estimates the effect of intervention-related changes in one or more risk factors on the incidence of diseases related to the relevant risk factors over the lifetime of the population. Over time, reduced incidence of disease results in reductions in prevalence and mortality compared to no intervention, thereby producing long-term health benefits and healthcare cost-savings.Potential impact fractions (PIFs) were calculated using relative risks (RR) from the Global Burden of Disease study  and wereThe model included nine diseases . All diseases were causally related to BMI and five were related to physical activity . The joint effects of BMI and physical inactivity on common diseases were accounted for by adjusting the relevant RRs using a multiplicative function . DiseaseThe primary health outcome was the incremental HALYs gained from the intervention. HALYs were calculated to incorporate the population level changes in the morbidity and mortality associated with the nine diseases included in the model (which only impact adults in the model) and the health related quality of life impact of elevated BMI in childhood . Unit coThe modelling was undertaken using Microsoft Excel 2013 software. Monte Carlo simulation using the Excel add-in software Ersatz  was usedThe key reporting items based on the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist  are repoThe cost-effectiveness results were placed within a broader decision-making framework by assessing various factors that were considered by the project steering committee to be of importance when funding and policy implementation decisions are made. The six factors considered were strength of evidence for intervention effect, equity impacts, acceptability of the intervention to various stakeholders, feasibility of intervention implementation and sustainability of the intervention once implemented see . The assThe results of the cost-effectiveness analysis are presented in a technical results league table with the interventions ranked by their base case ICER. Dominant interventions  do not have interpretable ICERs and therefore were ranked by total HALYs gained. To provide an indication of the short-term budget impact, the intervention costs over the first three years of implementation are also reported. Although the effect size and the variability around it were incorporated into the technical cost-effectiveness results and uncertainty intervals, we also provide a comparative assessment of the strength of evidence of the intervention on BMI outcomes, given the importance of the evidence base in policy-making .A comparative assessment of the evaluated interventions on the implementation considerations is presented in a league table, ordered by the strength of evidence for BMI outcomes, then by strength of evidence on nutrition or physical activity outcomes, followed by equity considerations. The final sorting was based on the number of ‘positive’ or ‘high’ ratings. To place these results within the context of the cost-effectiveness results, the base case ICER and where the intervention ranks in the cost-effectiveness league table is also presented.Economic evaluations were completed for 16 obesity prevention interventions. All 16 interventions evaluated in this priority-setting study were assessed as being cost-effective approaches to addressing obesity in the Australian population. The modelling predicted substantial health gains over the lifetime of the modelled population. Intervention costs were largely accrued during the initial years of the intervention, with healthcare cost savings accruing over varying time horizons.The majority of the interventions evaluated (11/16) were predicted to result in long-term cost-savings and health gains. Dominance was largely driven by the relatively low cost of the dominant interventions . The dominant interventions also tended to be universal, non-targeted interventions impacting large populations.The three most cost-effective interventions  and cost-effective (‘Community- based interventions’) options. Alternatively, if high certainty of intervention effect on BMI outcomes is most important, there are two interventions that can be prioritised . This study highlights that effective government action will require co-ordinated action across state and federal governments and a whole-of-government approach with inter-departmental co-operation and co-ordination for successful implementation of the interventions.The main strength of this study was that it used consistent methods to produce comparable evidence on the economic credentials of various obesity prevention strategies. The range of interventions evaluated included those that have been previously recommended by the WHO  and otheThere are several limitations to this study. Firstly, despite efforts to maximise the comparability of interventions, the diversity of interventions meant that the evidence base for the modelling assumptions varied. We found that interventions with higher quality evidence were modelled using more conservative assumptions. To account for the uncertainty in the evidence base, the modelling of each intervention included extensive uncertainty and scenario analyses undertaken to provide more context when interpreting the results. These results have been reported in the publications of individual studies, however given that a single paper is unable to fully explain all the intervention scenarios evaluated , we have only presented the base case ICERs in this paper. Secondly, this study was undertaken over six years, and at the outset, the 2010 base year represented the most current year available for all key data sources , 58, 59.This study demonstrates the economic credentials of a suite of obesity prevention interventions relevant to the Australian setting. It provides the comparative evidence that can be used by governments to prioritise actions for obesity prevention. All 16 interventions evaluated were cost-effective and demonstrated great potential for long-term health benefits. Individual ranking of interventions will be improved with further research that explores the longer-term impacts of obesity prevention interventions and the joint impacts of several interventions implemented concurrently.S1 Table(DOCX)Click here for additional data file.


Quarantine refers to the restriction of the movement of asymptomatic healthy people who have had contact with cases of a communicable disease. We highlight a Cochrane rapid review, published in April 2020, on the effectiveness of quarantine in limiting the spread of COVID-19.the authors of the Cochrane rapid review searched multiple electronic databases for studies of any design, which assessed the effects of quarantine compared to no intervention. Eligible participants for the review included contacts of confirmed or suspected cases and people returning from countries with a declared outbreak of COVID-19, severe acute respiratory syndrome (SARS), or Middle East respiratory syndrome (MERS). The authors used the evidence from SARS and MERS studies to provide indirect evidence on COVID-19.the authors included 29 observational and mathematical modelling studies and found that quarantine may lead to substantial reductions in new COVID-19 cases and deaths. The review also shows that combining school closures, travel bans and social distancing to quarantine may lead to larger reductions in cases and deaths.the review suggests that quarantine should be part of the COVID-19 combination prevention tool kit for Africa. Therefore, in addition to other public health measures, African countries should roll out COVID-19 testing to identify, isolate and treat infected people and quarantine their contacts. Africa is facing a large-scale public health crisis, with coronavirus disease 2019 (COVID-19), the like of which we have never seen before. By 1st of May 2020, African countries had reported nearly 40,000 cases of COVID-19 . This coThe authors included observational and mathematical modelling studies that assessed any type of quarantine alone or in combination with other interventions. Participants for this review included contacts of confirmed or suspected cases and people returning from countries with a declared outbreak of COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). The authors used the evidence from SARS and MERS studies to provide indirect evidence on COVID-19. They searched for studies in PubMed, Ovid MEDLINE, WHO Global Index Medicus, Embase, CINAHL and various Chinese databases up to 16 March 2020. The search strategy combined search terms for coronaviruses  and terms related to quarantine . The full search strategy is available in Appendix 1 and Appendix 2 of the Cochrane review (pages 39 to 41) .The comprehensive search identified 2620 records, from which the authors included 29 eligible studies (23 published in English and 6 translated from Chinese). These included 25 modelling studies and four observational studies. The findings of this review suggest that quarantine, alone or in combination with the other public health interventions, has a vital role to play in containing COVID-19. The GRADE certainty of the evidence was downgraded to low for most outcomes because of study limitations and indirectness of the evidence (as some of the studies focused on SARS and not COVID-19). The low certainty of the evidence implies that the likelihood of further research finding the magnitude of the effectiveness of quarantine to be substantially different from the results of this review is high. In implementing a strict control measure such as quarantine, one needs to be cognisant of the context in which it is being implemented. There were no studies from Africa included in the review. Therefore, an impact evaluation is warranted when quarantine is implemented in African countries for the control of COVID-19.Rigorous evaluations of quarantine for containment of COVID-19 in Africa should assess other important outcomes such as impacts on equity, cost implications and adverse effects. A recent rapid review found that quarantine may lead to post-traumatic stress symptoms, confusion and anger . The infSeven out of ten Africans work in the informal sector and if COVID-19 control measures cause them further risks such as joblessness and food insecurity, there is a high likelihood of citizens defying containment measures . If, howThe Cochrane rapid review shows that quarantine may lead to large reductions in COVID-19 related morbidity and mortality. Therefore, African countries should roll out COVID-19 testing to identify, isolate and treat infected people and quarantine their contacts. However, quarantine needs to be considered in conjunction with the contextual needs of the implementing country. Its implementation needs to be accompanied by sensitive measures which can alleviate the brunt of poverty and other challenges currently experienced by citizens.Quarantine has been used by various countries as a tactic for limiting the spread of COVID-19;No systematic review on the effects of quarantine had been published before the Cochrane rapid review.Quarantine may lead to substantial decreases in infections and deaths from the COVID-19;The benefits of quarantine may be more pronounced if the intervention is started early.The authors declare no competing interests.


Giant coronary aneurysms are late sequelae of Kawasaki disease (KD). We describe a 53-year-old patient who presented with acute myocardial infarction and proximal aneurysms of all three coronary arteries. Coronary angiography demonstrated the aneurysms, but CT angiography allowed accurate assessment of the real dimensions of the aneurysms and making the decision on the preferred method of revascularization. The patient underwent coronary bypass surgery and is asymptomatic at follow-up. Kawasaki disease (KD) is an acute multisystem vasculitis of unknown etiology, which predominantly affects infants and young children. Fifteen to twenty-five percent of untreated patients with acute KD have coronary aneurysms or ectasia , 2. SympWe present a 53-year-old man who presented with myocardial infarction and was found to have giant coronary aneurysms, probably due to KD. We discuss clinical management and review the relevant imaging modalities and potential therapies.A 53-year-old man presented to the emergency department with chest pain that started on the day of admission. He was a smoker, with dyslipidemia treated by atorvastatin 20 mg, with no family history of cardiac disease or significant pediatric history. He was in good general condition and had no signs of heart failure. His ECG showed sinus rhythm and ST segment elevation in the inferior leads .The patient underwent emergency coronary angiography. The right coronary artery (RCA) was totally occluded with an aneurysm involving the ostium . FillingAn attempt to pass a guide wire to the proximal RCA through the ostial aneurysm failed, and the patient was transferred to the coronary care unit and treated with aspirin, clopidogrel, fractionated heparin, and morphine.th day of hospitalization . The angiographic findings were attributed to KD based on the proximal location and size of the aneurysms and the lack of another explanation for these findings.Echocardiography showed good left ventricular contraction with an estimated ejection fraction of 55% and wall motion abnormalities in the inferior and posterior walls. Peak troponin T was 1027 ng/l on the second day of hospitalization and decreased to 226 ng/l on the 7A cardiac computed tomography was performed, which revealed a giant thrombotic nonocclusive aneurysm in the proximal LAD with calcifications of the margins of the aneurysm ; the maxOne week after admission, the patient underwent coronary bypass surgery. The giant aneurysm of the proximal LAD  was idenRecovery from surgery was unremarkable, and a graded exercise test performed 3 months after surgery showed good aerobic capacity with no complaints or ST segment deviations.We describe a patient with an unusual cause of acute myocardial infarction at the fifth decade of life. The most probable etiology is thrombosis of coronary aneurysms, which are a late sequel of KD. Only a few reports have documented patients with giant aneurysms presenting for the first time in the fifth decade of life , 8. AlthOur case report highlights several important issues. (a) KD can present late in life with no relevant childhood history. Although this is a rare presentation, it should be kept in mind in both young and older patients presenting with coronary aneurysms. (b) Combining different imaging modalities was important for better understanding of the anatomy and pathophysiology. We used coronary angiography and cardiac computed tomography and showed the exact size of the aneurysms and the healthier parts of the coronary tree that were suitable for bypass grafting. The use of multiple modalities shed light on the pathology of aneurysms in Kawasaki disease . As showPercutaneous interventions, bypass surgery, and medical therapy have been prescribed for KD presenting with acute coronary syndrome , 12–14. The relevance of our case report is highlighted by the potential increase of patients with Kawasaki disease-like syndrome during the COVID-19 pandemic –17.


With high certainty, extreme weather events will intensify in their impact within the next 10 years due to climate change-induced increases in hazard probability of occurrence and simultaneous increases in socio-economic vulnerability. Data from previous mega-disasters show that losses from disruptions of critical services surpass the value of direct damages in the exposed areas because critical infrastructures [CI] are increasingly (inter-) dependent. Local events may have global impacts. Systemic criticality, which describes the relevance of a critical infrastructure due to its positioning within the system, needs to be addressed to reduce the likelihood of cascading effects. This paper presents novel approaches to operationalise and assess systemic criticality. Firstly, the paper introduces systemic cascade potential as a measurement of systemic criticality. It takes the relevance of a sector and the relevance of its interdependencies into account to generate a relative value of systemic importance for a CI sector. Secondly, an exemplary sectoral assessment of the road network allows reflecting the spatial manifestation of the first level of cascading effects. It analyses the impact of traffic interruptions on the accessibility of critical facilities to point out the systemically most critical segments of the municipal road network. To further operationalise the spatial dimension of criticality, a normative assertion determining the worthiness of protection of system components is required. A nationwide spatial flood protection plan incorporates this aspect in Germany for the first time. Its formal approval process was initiated in February 2020. Convective storms are an intensifying hydro-meteorological hazard, which usually occurs in the second half of warm and hot days and result in thunderstorms and heavy precipitation dependencies. There are external dependencies of society on CI services, but more importantly, also internal (inter-)dependencies of CI systems relying on the services of other systems. For example, the water supply systems rely on electricity for the operation of pumps. The (inter-)dependencies and cross-sector services result in a tightly woven network of CI systems  structures dependencies  in spatial planning. The “systemic cascade potential” approach expresses the possibility and strength of a cascading effect potentially propagating through the CI sos over time. It encompasses the possibility and strength of cascading effects from a solely systemic, i.e. functional, system-internal, and non-spatial, perspective. It aims at uncovering the sos and its potential cascading effects under certain aspirations. First, the operationalisation approach shall be able to encompass the whole CI sos, its subsystems, and their connectivity as comprehensively as possible. Second, the sos shall be reduced in complexity so that it may be (resource-efficiently) transferred to different spatial levels and contexts. Thus, the approach needs to be generic.Based on these aspirations, conventional interdependency analyses .Experts to be interviewed were selected following specific targeting criteria. First, the experts’ organisation had to represent an objective federal perspective and ideally possess competences related to CI. Consequently, most experts represented federal authorities or nationwide associations. Second, the targeted experts have expertise and experience in CI management. Based on these targeting criteria, experts were (deliberately) contacted via email with a personalised link to the survey of “their” subsector in the online tool SoSci-Survey. Due to reasons of anonymity and representativeness, there had to be at least three responses from each of the 29 subsectors  incoming dependencies for the five disruption periods through a visual analogue scale in order to gather the information for factor 2. Additionally, qualitative information was surveyed to interpret the results.The survey took place within 8 days in spring 2019 with more than 100 experts participating. The obtained data allows for several analyses, e.g. for issuing subsector profiles contributing to a deeper understanding of single subsectors, but also the sos as a whole (e.g. through network and cascade diagrams). As this article focuses on the operationalisation of systemic criticality, Table A calculation of the systemic cascade potential becomes possible due to aggregation and averaging the survey data  and calculating closeness centrality through network analysis (parameter 2). Table The results show a great range between subsectors with the highest and the lowest systemic cascade potential, leaving electricity with about 80 times the systemic cascade potential compared to domestic shipping. These results may further be categorised, similar to the Swiss CI strategy s. BABS , prioritWhile criticality is not place-based, system-internal cascades still manifest themselves spatially. The question remains as to how the functional character of systemic criticality can be operationalised to be represented and translated into spatial models. The following section attempts to do just that by assessing the cascades following traffic interruptions following breaking branches and trees during extreme storms.This method was developed during the BaumAdapt project, which is funded by the German Ministry for the Environment, Nature Conservation, and Nuclear Safety within the framework of the German Strategy for Adaptation to Climate Change. The project was conceptualised in the wake of storm Ela in June 2014, which ranks among the five most severe convective extreme events in Germany since 1980  of each critical facility, which represents a CI subsector, should be considered in the criticality assessment to address additional system-internal cascading effects.The sectoral criticality assessment of the road network allows making assertions towards the systemic importance of a segment that is relevant for the accessibility of critical facilities. These are the network segments with an especially large increase in traffic load and that are part of multiple origin-destination-relationships. The validity of these assertions can be increased, the higher the number of simulated scenarios and the higher the number of origin-destination-relationships confirming them.The primary connection between the south-eastern boroughs and the city centre is blocked, leading to an increased traffic load on the diversion route. At up to 15,000 more vehicles per hour, this is the highest increase on any relevant network segment.The connection between the south-western boroughs and the city centre only shows a traffic load increase of up to 7000 vehicles per hour, which ranks among the medium values on the scale. However, it is a relevant network segment for twelve origin-destination-relationships, which is more than can be observed with any other segment.The third segment is only relevant to connect to one critical facility and shows a medium-high traffic load increase of up to 6000 vehicles per hour. The reason for its high systemic criticality is the importance of the facility, which is accessed from the road, i.e. the municipal waste management company. Most heavy machinery to respond to the storm impact on the urban environment is stored there; thus, inaccessibility could start cascading effects affecting other sectors.The analysis results show three network segments that have a comparatively higher systemic criticality than the rest of the network for three different reasons:Which of the three indicators - traffic load increase, number of relevant origin-destination relationships, or the systemic cascade potential - ranks higher cannot be determined on the factual level and requires a normative decision.Still, the sectoral analysis is limited and cannot operationalise the real complexity of the CI sos and its systemic criticality. It only considers the road network; thus, assertions towards systemic relevance can only be made regarding one subsector. The limitation is further determined by the boundaries of the spatial scope, as only the road network within the municipal boundaries is considered. However, the spatial scope can be scaled by applying a traffic model on a different scale. Albeit its limitations, this assessment indeed allows operationalising systemic criticality in its spatial context. Previous assessments of the transport network neglect the systemic component or only address facilities, such as tunnels or bridges, without considering the systemic criticality of the network itself  or national levels .Figure The legal implications of the criticality concept presented by this paper show that this concept is not just of theoretical nature, but it is a real-world discussion of European relevance. A new planning instrument is worth mentioning as it follows this new understanding of criticality for the first time. With the amendment of § 17 (2) clause 1 of the Federal Regional Planning Act (Raumordnungsgesetz) [ROG] in 2017, the federal legislator has enabled the BMI to establish cross-federal state regional plans for flood protection in the form of a statutory ordinance. Flood protection addresses coastal, fluvial, and pluvial flooding in this context.On this legal basis, a test plan and the conceptual design of a federal spatial plan for a nationwide spatial flood protection plan (Bundesraumordnungsplan Hochwasserschutz [BRPH]) have been developed. Opposed to the legislator’s original intention of catchment-specific plans, the upcoming plan covers all of Germany to address CI networks comprehensively, which are not limited by the borders of federal states and river basins.The plan establishes a risk-based approach providing a framework for the further subject matter of the plan. Currently, flood protection in Germany is based on hazard zones demarking the areas potentially inundated during a 1:100-year flood event. This approach does not include the hazard intensity (in terms of flood depth or velocity) and the vulnerability of exposed land uses. These aspects must be considered when demarking flood risk zones in the future.Critical infrastructures and establishments that pose a particular risk: This chapter comprises the regulated matters based on the worthiness of protection, which has been lacking in spatial planning so far. Spatial planning must weigh the protection of an infrastructure higher against other concerns and interests  require specific protection. Among these objectives are the smooth functioning of the internal market and the strengthening of economic, social, and territorial cohesion  defines European critical infrastructure [ECI] as follows: “‘ECI’ means critical infrastructure located in Member States the disruption or destruction of which would have a significant impact on at least two Member States. The significance of the impact shall be assessed in terms of cross-cutting criteria. This includes effects resulting from cross-sector dependencies on other types of infrastructure.” However, the directive just covers transport and energy infrastructures because of the given legal basis for these sectors as laid down by Art. 170 Treaty of Lisbon.However, spatial and factual definiteness or at least determinability are a condition for setting-up legally binding spatial objectives in the context of the BRPH. The regulations (EU) No. 1315/Regulation (EU) No. 1315/Due to the given spatial and factual determinability, the test plan came up with two legally binding spatial objectives that point at the worthiness of protection of the core elements of the TEN-T (transport) and TEN-E (energy) networks:Moreover, the test plan contains spatial principles targeting already existing components of the transport and energy system. These principles are not legally binding but put specific weight on particular concerns like flood protection. Specific attention must be paid to flood protection when extending, renewing, or upgrading existing network elements.A gaming simulation to test the application of the BRPH took place in September 2019 in two regions  in cooperation with representatives of regional and local planning authorities. Gaming simulations have been widely used in urban planning and since been introduced to other topics, such as risk management. The objective of a gaming simulation is to gain insight into real-life problems and relations between actors, especially related to new challenges, new analysis methods, new management approaches, or even new laws  reduces the complexity and intangibility of the CI sos. It contributes to understanding system-internal dependencies and may be used to anticipate scenarios on potential effects from internal and external hazards. This way, the approach also raises awareness of outgoing dependencies, contributes to stakeholder cooperation, and may support policymaking by classifying the systemic cascade potential into classes of the worthiness of protection.However, the approach comes at the price of abstractness and without a spatial dimension, i.e. not readily applicable for spatial planning or civil protection. Therefore, the sectoral criticality analysis of the road network (s. 3.2) attempts to operationalise systemic criticality in a way that allows investigating how it manifests itself in a spatial context. It contributes to the understanding of how hydro-meteorological hazards put the CI system at risk and, thus, may put the entire society at risk through cascading effects. The results inform about the most critical segments of the road network to uphold other services within the CI sos. This evidence can feed into decision-making processes and support the prioritisation of measures preventing infrastructure service disruptions and making society more resilient to hydro-meteorological hazards.The CI system is complex. Apart from its purpose of supplying society with critical services, it is characterised by dependencies and interdependencies within and between different sectors. A component failure can have far-reaching consequences for the sos and have an impact outside the area initially exposed to the hazard. However, the assessment simplifies the CI system to the degree that only considers the first level of cascading effects by analysing the accessibility of critical facilities during traffic disruptions. To make assertions on systemic effects following the disruption of the services of these facilities is not possible.To answer the second research question, a normative judgement is required to further operationalise the spatial dimension of systemic criticality by determining the worthiness of protection of specific network elements. This judgement should ideally consider the result of a sectoral criticality assessment, which could, in principle, be performed on various spatial levels depending on the extent of the respective infrastructure system. Without an existing legal basis, a discourse-based approach among relevant stakeholders could evaluate the risks which were identified by a factual critically assessment. The authors have initiated such community-based approaches in Tanzania and Peru as further application tests of the presented methodological concept.Current management approaches broadly neglect the criticality perspective. So does the Floods Directive (Council Directive The introduction of a criticality-based approach in spatial planning represents the departure point for a process of rethinking spatial development at all levels and in all affected coastal and inland areas. The added value results from the new duty to consider both, the vulnerability and systemic criticality of protected objects, in future planning. Thus, there is a conceptual and semantic convergence between spatial planning and flood risk management planning under the Floods Directive.Understanding systemic criticality adds to the comprehension of impacts and response options of extreme events and climate change. Mega-disasters indicate that the larger share of economic losses from disastrous events is caused outside exposed areas, which are the focus of disaster risk management and climate change adaptation. Increasingly complex interdependences within the CI sos are the reason for this. Knowledge about systemic criticality of a subsector informs the understanding of the far-reaching consequences the impairment of a system component may have. Being able to make assertions towards the potential cascading effects from a disruption of critical services supports evaluating the risks associated with weather extremes better. With CI being highly vulnerable towards these extremes and them becoming more frequent and intense as the climate changes, understanding, assessing, and evaluating the systemic criticality of CI are a prerequisite for society to adequately cope with disastrous events by implementing effective risk management and adaptation policies.The CI sos is not static but is continually evolving. The question as to how cascading effects change in the future remains. Some uncertainties might even be related to climate mitigation. For example, as society is moving away from combustion engines towards electric mobility, the electricity subsector gains even more centrality within the weave of systemic dependencies, while the petroleum subsector loses relevance. Since society is abandoning fossil fuels for renewable energy at the same time, this simultaneously increases the dependence of the entire transport sector on a functioning renewable energy sector, which in turn must expand significantly (International Energy Agency While there are uncertainties regarding the future development of the CI sos, including systemic criticality in risk evaluation can also reduce uncertainties in times of evolving hazards due to climate change. It can support anticipating probable worst-case scenarios of CI failure because it improves the understanding of the system-of-systems’ behaviour towards shocks. This evidence may support implementing measures to better cope with service disruptions, which society ultimately cares more about than the facility itself. Among these measures should be an increase in system redundancies providing the most critical services, e.g. electricity supply and ICT. Additionally, understanding the interdependencies between subsectors is crucial to engage all relevant stakeholders to improve communication and eventually break down silos in addressing disaster response and prevention.The current Covid-19 pandemic and its expected losses from lost economic output show that international supply chains and dependencies of services spanning countries and continents may exacerbate financial damages when a hazard is not locally confined but ubiquitous. The more globalised supply chains become, the higher is the complexity of dependencies. A response to better prepare for future pandemics is to reduce global dependencies. Increasing redundancies, unravelling supply chains, and focusing on regional production and distribution processes can reduce global dependencies. In addition to working with local suppliers, such a development may be able to reduce the economic impact of ubiquitous hazards and would be—as a side effect—a valuable contribution to CO2 mitigation.The key risks included in the most recent IPCC synthesis report include “[s]ystemic risks due to extreme weather events leading to breakdown of infrastructure networks and critical services” IPCC , dealing


Optical mapping is recognized as a promising tool for the registration of electrical activity in the heart. Most cardiac optical mapping experiments are performed in ex vivo isolated heart models. However, the electrophysiological properties of the heart are highly influenced by the autonomic nervous system as well as humoral regulation; therefore, in vivo investigations of heart activity in large animals are definitely preferred. Furthermore, such investigations can be considered the last step before clinical application. Recently, two comprehensive studies have examined optical mapping approaches for pig hearts in situ (in vivo), likely advancing the methodological capacity to perform complex electrophysiological investigations of the heart. Both studies had the same aim, i.e., to develop high-spatiotemporal-resolution optical mapping suitable for registration of electrical activity of pig heart in situ, but the methods chosen were different. In this brief review, we analyse and compare the results of recent studies and discuss their translational potential for in situ cardiac optical mapping applications in large animals. We focus on the modes of blood circulation that are employed, the use of different voltage-sensitive dyes and their loading procedures, and ways of eliminating contraction artefacts. Finally, we evaluate the possible scenarios for optical mapping (OM) application in large animals in situ and infer which scenario is optimal. The heart is one of the organs of which its electrophysiological properties are closely related to the autonomic nervous system as well as humoral regulation. In the last few decades, there has been constant interest in optical mapping (OM) as a prospective tool for the registration of electrical activity of the heart. Most cardiac OM experiments are performed ex vivo in isolated heart models. However, cardiac experimentation in live organisms creates conditions that are close to native ones and allows one to perform complex electrophysiological investigations of the heart. It should be noted that different authors use different terms, in situ or in vivo, to define experimentation conditions in live organisms. The first work on registration of cardiac electrical signals by optical fibres in vivo was performed in a canine model . A much In general, it is accepted that the swine model is valuable in pre-clinical research because of its similarities to humans, for example, in terms of its cardiovascular system and body weight ,6. In siElectrophysiological studies in an open-chest heart model can be performed in two ways, i.e., under physiological or artificial blood circulation. The main limiting factor of high-spatiotemporal-resolution OM is the distortion of optically recorded electrical signals by motion artefacts. The choice of blood circulation type determines which options are available for contraction artefact elimination, which is crucial for OM quality. Lee and co-authors present two ways of overcoming the impact of cardiac contraction on optically registered electrical activity in a freely contracting pig heart in vivo under physiological blood circulation: excitation ratiometry and optical-fibre recordings . In theiThe study by our group presents data obtained by using a custom-made frame  that enabled us to record optical signals from a 40 × 40 mm area of the pig heart in situ under physiological blood circulation with applied stimulation (500 ms cycle length) or ventricular fibrillation. However, our data revealed that mechanical motion arrest using a frame partially restricts the field of view and does not fully eliminate motion artefacts [2+ channel antagonists, such as diltiazem or verapamil, could be exploited. These agents are commonly used in clinical practice as class IV antiarrhythmic drugs; they are rapidly metabolized and therefore could serve as safe temporary contraction suppressors.Artificial blood perfusion, a routine procedure applied in clinical open-heart surgery, ensures controlled conditions and allows an electromechanical uncoupler to be applied. As our study suggests, it is a promising mode of circulation for the registration of cardiac electrical activity using OM . HoweverDifferent voltage-sensitive dyes were used in our study and that of Lee et al.: di-4-ANBDQBS ,4, di-4-In addition, the two studies reported different strategies for fluorescent dye loading of pig hearts in situ. Lee et al.  performeIn principle, the two studies demonstrate OM of the pig heart in situ using different methodologies: one used excitation ratiometry in the freely contracting heart and optical-fibre recordings from 16 points , whereasApplication of ratiometric analysis in freely contracting hearts has limited potential. Excitation ratiometry can reduce the influence of heart contraction movements, but it cannot eliminate the effects of the twisting movement that a freely contracting heart makes when not immobilized. It has been demonstrated that heart immobilization or mathematical data processing should be used to eliminate the effects of twisting ,18. RecoThe use of an optical-fibre array (4 × 4) allows the electrical activity of the heart to be recorded in vivo under physiological blood circulation . HoweverMechanical immobilization of the heart using a custom-made frame or Octopus tissue stabilizer is another option for OM of the freely contracting heart . The useIn our study, chemical arrest of heart contractions under artificial blood circulation was induced by injecting blebbistatin together with fluorescent dye directly into the aorta through an inserted cannula . The effThe development of in situ high-spatiotemporal-resolution OM in swine models is a significant step towards comprehensive cardiac electrophysiological investigations in the whole organism and, consequently, towards its application in clinics. In general, OM in humans could be applied in the detailed characterization of propagation of cardiac electrical impulses along with detection of stable ectopic foci or zones with altered excitability, which is crucial for the determination of arrhythmogenesis. As it was demonstrated in the studies, OM enables registration of the pathways of electrical impulse propagation during ventricular fibrillation ,4 or iscCurrent research data on OM of the pig heart in situ present different methods of contraction artefact elimination that depend on the mode of blood circulation. In addition, the use of different voltage-sensitive dyes and loading methods is examined. From our point of view, based on the results of the two reviewed studies, it can be assumed that the best  scenario in which to apply OM in large animals in situ could be chemical arrest of heart contraction under artificial blood circulation. However, it should be considered that the use of chemical uncouplers to eliminate heart motion artefacts places the heart under non-physiological conditions where cardiac metabolism is reduced due to the absence of contraction. The other option is OM in situ using mechanical heart immobilization, such as frame, which likely allows ratiometry to be applied more effectively than in chemical arrest. This option for in situ OM maintains conditions closer to a physiological state but significantly limits the spatial mapping of the heart.


The pupil response is more than a simple light evoked reflex . At any Kelbsch et al.). This living standard considers the procedures relating to data collection, processing and a minimum set of variables for reporting in publications. The guidelines cover specific applications, including the afferent pupil light response and conditions for differentiating the pupil light reflex initiated by rhodopsin-driven rod responses, opsin-driven cone responses, and/or melanopsin-driven ipRGC responses, the efferent pupillary pathway, pharmacological effects on the pupil, pupillography in psychology and psychiatry, and methods for evaluating sleepiness-related pupillary oscillations. The standard is applicable to measurements of the pupil in humans and animals and designed to facilitate its correct application and improve the comparability between studies.The widespread application of pupillometry in basic and clinical measurements of humans and animals in ophthalmology, neurology, neuroscience, psychology, and chronobiology has necessitated the demand to introduce a set of recommendations and general standards. With this in mind, experts convened at the 32nd International Pupil Colloquium (IPC) in Morges Switzerland to discuss and prepare the first iteration of an international standard for pupillography  that contain melanopsin and project to the pretectum, specifically the olivary pretectal nucleus , 4. FurtCrippa et al. report original findings in an evaluation of chromatic pupil light responses under dark- and light-adapted conditions in healthy children aged 3–18 years; in their pediatric sample, the amplitude of the melanopsin-mediated pupil response was independent of age; together with previous evidence, melanopsin function is stable between the first and eight decades of life after which dysfunction becomes apparent. This contrasts with the earlier onset of age-related declines in rod and cone photoreceptor density, and highlights the value of measures of melanopsin-mediated pupil function as a clinical biomarker. The authors stratified their sample at 10 years of age and revealed the younger age group had smaller dark-adapted baseline pupil diameters and higher stimulus thresholds for evoking a criterion pupil response compared to the older pediatric group, with the older group being more similar to adults. Crippa et al. infer that the age-related threshold pupil response might reflect decreased retinal input to the olivary pretectal nucleus due to continuing post-natal retinal development in the younger cohort.Bonmati-Carrion et al. evaluated the effects of extended (5 min) exposure to high irradiance monochromatic and bi-chromatic (polychromatic) stimuli on the pupil light reflex. Their novel evaluation of the pupil response to polychromatic lights was designed to differentially potentiate a change in the conformational state of the melanopsin photopigment; the pupil amplitudes were not however significantly different, indicating that any effect of the putative bistability of the melanopsin photopigment is not manifest in the pupil response under such conditions. On the other hand, the sustained post-illumination pupil response (PIPR) constriction amplitude increased when the monochromatic and polychromatic stimulus lights had higher levels of melanopsin excitation, consistent with literature reports.Spitschan and Woelders provide a tutorial on the silent substitution technique for generating metameric stimulus lights that preferentially activate one, or a combination of photoreceptor classes.Formalized by Estévez and Spekreijse  as a metBarrionuevo et al. quantified the summation characteristics of outer retinal photoreceptor inputs to the pupil control pathway. An electroretinogram (ERG) provided a direct measure of outer-retinal signaling and was recorded under the same conditions as the pupillary response. The authors observed that ERG and pupil measurements to photoreceptor-directed stimulus pairs of different temporal frequencies contained a response component at a frequency corresponding to the difference of the stimulus frequencies; this so-called beat response signifies the presence of non-linear rod and cone inputs to the pupil control pathway that originate in the outer retina.Using a multi-primary silent-substitution method to generate rod- and cone-pathway directed stimulus activations, Zele et al. separated the component photoreceptor inputs using silent substitution and 5-primary photostimulation methods. The authors revealed the melanopsin-mediated pupil response signature as having a long latency and slow constriction velocity that remained sustained during and after stimulus exposure; cone mediated pupil responses had shorter latencies and faster constriction velocities to stimulus onset and rapidly redilated to baseline. Together, the inner and outer retina pupil signals combine additively to set a unified pupil diameter. Cone inputs control the tonic constrictions to variations in stimulus contrast and melanopsin inputs set the light adapted pupil diameter during prolonged light exposures.To isolate interactions between melanopsin and the L-, M-, and S-cone-photoreceptor inputs to the afferent pupil light response in trichromatic humans, Carle et al. using their multifocal pupillographic objective perimetry (mfPOP) technique. The authors examined the pupil constriction to stimuli with different spatio-temporal densities originating from localized hemifields under monocular or binocular viewing. Pupil constriction amplitudes differed only when the signal density differed at the level of Edinger-Westphal nuclei (or later) but not in the retina and pretectal olivary nuclei, and for nasal and temporal hemifield stimulation this trend was present. They infer that pupillary gain controls are present in the Edinger-Westphal nucleus.The loci of gain-control processes within the pupil pathway that modulate constriction amplitude were identified by Ebitz and Moore evaluated the pupil as a peripheral measure of cortical processing. They contend that top-down modulation of pupil diameter, whether it be due to shifts in visual attention or cognition, can cause an active filtering of the incoming light signal that gives rise to functional benefits. Following this, the Research Topic includes two original articles investigating top-down modulation on the pupil.While many readers will be familiar with the constriction of the pupil that occurs with light, the pupil is also modulated by other factors including cognition, sleep, and arousal . For exaWang et al. In their study, activity of the sympathetic and parasympathetic branches of the autonomic nervous system were recorded concurrently with pupil size, using the galvanic skin response and heart rate. The authors reported a trial-by-trial fluctuation in pupil size prior to the presentation of the face that correlated with their sympathetic and parasympathetic measures. They infer that arousal levels involuntarily regulated by the autonomic nervous system can be indexed by pupil size.The effect of autonomic arousal on pupil size during presentation of human faces expressing different emotive content was investigated by Sperandio et al. modulated a person's awareness of images evoking the construct of perceived brightness, such as a picture of the sun. In their paradigm, visual awareness was altered using an interocular flash suppression paradigm. It was found that pupillary constrictions occurred in response to scenes containing images of the sun, but only when participants were visually aware of the image content. The authors suggest that extra-retinal pathways are driving these pupil responses.In a study of the role of visual awareness on pupil constriction to scene images under conditions designed to influence top-down processing. Daguet et al. in a demanding 56 h protocol that included a 36 h period of constant routine in dim light with enforced wakefulness. The baseline pupil diameters decreased linearly with time awake and had a superimposed sinusoidal rhythm wherein diameters were smallest in the morning and largest in the evening. Sleepiness also increased linearly with time awake due to an accumulation of sleep pressure, whereas the circadian drive for sleep followed a sinusoidal process that was phase shifted relative to the circadian variation in pupil diameter. Together these outcomes demonstrate that baseline pupil diameter is applicable as an index of sleepiness only at certain times of the day because of the interactions between the dual regulation of sleepiness by homeostatic and circadian processes.The relationship between baseline pupil diameter and sleepiness was investigated by Balaban et al. characterized the pupil responses and convergent or divergent movements required to resolve diplopia. The resultant eye movements and pupillary responses involved successive epochs of uncorrelated activity, coordinated near response activity and a coordinated opposite response pattern. The authors propose a system in which the disparity-driven ocular and pupillary responses are coordinated by the real-time interactive selection of different modes of a modified disparity controller with separate drives responsive to blur, binocular disparity and global luminance, and an additional three-state gain selection switch.Using virtual reality displays to generate rapid or gradual shifts in binocular disparity, Szabadi reviews the functional organization of the sympathetic pathways controlling the pupil with an emphasis on the anatomy and physiology of light-inhibited and light-stimulated pathways, sleep and arousal in nocturnal and diurnal species.The final efferent pathways controlling pupil diameter are comprised of both the parasympathetic and the sympathetic components of the autonomic nervous system. Parasympathetic postganglionic neurons project to the sphincter pupillae muscle of the iris to produce pupil constriction, while sympathetic postganglionic neurons project to the dilator pupillae muscle of the iris to produce pupil dilation . The devOstrin et al. developed a melanopsin-directed immunotoxin that was delivered intravitreally. With increasing immunotoxin concentration, the pupil constriction to narrowband pulsed lights showed a progressive amplitude decrease and the PIPR was eliminated; at the highest concentration, flicker pupil responses were confined to irregular, transient constrictions. Taken together, the ipRGCs form the primary afferent pathway for mediating pulsed and flicker pupil response in non-human primates. The melanopsin-directed immunotoxin provides a new technique to the study the role of ipRGCs in circadian rhythms, and melanopsin contributions to image-forming visual functions in non-human primates.To investigate intrinsically photosensitive Retinal Ganglion Cell (ipRGC) mediation of the pupillary light reflex in Rhesus monkey, Kircher et al. Retinal structure was quantified using immunohistochemistry analysis and the functional PLR measures were combined with electroretinography. Age-related differences in transient and steady-stated pupil diameters were observed during early adulthood . Developmental changes in the PLR in C57BL/6 mice were associated with differences in retinal sensitivity related to the rod and cone photoreceptors; in Sv129S6 mice, age-related changes in the PLR may involve variations within the central and/or peripheral pathways controlling the pupil. The authors infer that the circuitry associated with, rods, cones and ipRGCs reach functional maturity in the pupil pathways in adulthood (>2 months of age).The maturation of the pupillary response in two mouse models (C57BL/6 and Sv129S6) was evaluated by Rukmini et al. have reviewed chromatic pupillometry methods currently used for measuring inner and outer retinal photoreceptor function in ophthalmic disease. Further optimizations in these pupillometric technologies will lead to highly sensitive and accurate markers for use in disease detection and for monitoring progression, especially for they provide a direct measure of melanopsin-mediated ipRGC function. La Morgia et al. reviews the clinical studies of melanopsin retinal ganglion cell function in neurological and neuro-ophthalmic conditions, and emphasized its relevance as a biomarker in neurodegenerative disorders in which patients experience sleep and circadian dysfunction. Following this, Chougule et al. consider in their review a specialist application of the pupillary light response as a diagnostic indicator of Alzheimer's disease related effects on sympathetic and parasympathetic nervous system function, and in Parkinson's disease.Pupillometry outcomes provide clinical biomarkers of many ophthalmic and systemic diseases . ChromatOmary et al. consider in their original clinical study the difficulty in diagnosing Horner's syndrome when topical pharmacological test results are inconclusive. A framework is introduced that uses surface electrical stimulation of the median nerve to accentuate the inter-ocular asymmetry of sympathetic innervation to the iris dilator and distinguish healthy from Horner's syndrome patients. In people with an ocular sympathetic deficit, anisocoria during the evoked pupil dilation is enhanced when electrical stimulation is combined with the pupillometry measurement at 2 s after light offset. Compared to a non-electric stimulation pupillometry paradigm, all patients with Horner's syndrome and those with pharmacologically induced Horner's syndrome demonstrate increased anisocoria, whereas in the in healthy participants there was no significant change in anisocoria.Bremner determined the sensitivity of each drug test for detecting Horner's syndrome. Accounting for the pupil diameter in the dark and light, iris color and age, the sensitivity of apraclonidine for the detection of Horner's syndrome was 93% , compared to 40% for cocaine .In a retrospective analysis of the results from 660 pharmacological tests using topical administration of cocaine (2–10%) and apraclonidine (0.5–1.0%) in suspected cases of Horner's syndrome, Feigl et al. quantified melanopsin function and light exposure in people with non-seasonal major depressive disorder who live in a sub-tropical environment. Compared to age-matched controls, people with major depression had similar melanopsin function and light exposure during a 2-weeks measurement period. The implication is that in seasonal and non-seasonal depressive disorders, the effect of light on mood is likely to be modulated by different pathomechanisms and/or involve different ipRGC subtypes.Dysfunctional ipRGCs can cause aberrant signaling of the ambient illumination to alter photoentrainment and mood in patients with seasonal affective disorder (SAD). Here, Peinkhofer et al. measured ipsilateral pupil light responses in a human clinical model with patients having localized ischemic infarcts in these brain areas. In both the patient and control groups, pupil diameter and constriction velocity were positively correlated, and within normal physiological limits. The absence of cortical input to the pupils due to localized damage in the insular cortex or prefrontal eye field therefore does not appear to affect pupil diameter or constriction velocity.To investigate cortical innervation of the pupil pathway via the insular cortex and prefrontal eye field, Naber et al. introduced a gaze-contingent flicker pupil perimetry method to objectively record pupil oscillations across the central visual field. In a clinical sample of patients with glaucoma or cerebral visual impairment, the pupil oscillation amplitudes were lower in visual areas having reduced sensitivity on standard automated perimetry. The outcomes provide the initial evidence of the potential diagnostic effectiveness of gaze-contingent flicker pupillometry in quantifying visual defects routinely evaluated in clinical settings using subjective visual perimetry.Cortez et al. measured the afferent-efferent pupillary light circuit using the edge-light pupil cycle time. This pupil cycle time was sufficiently sensitive so as to distinguish each migraine severity group from the non-headache controls. These findings reveal a potential opportunity for application of the edge-light test recorded under slit lamp examination as a simple test for detecting the earliest stages of peripheral trigeminal sensitization.As an indicator of autonomic function and trigeminal-vascular system activation in people with migraine, This special issue displays the diversity of the basic and clinical research currently undertaken to understand the behavior, anatomy and physiology of the pupil control pathway. The introduction of an international standard, and the development of new pupillometry methods will facilitate its widespread translation to clinical practices for the detection and monitoring of neurological disorders, for use as a biomarker in clinical trials for objective assessment of autonomic nervous system activity and as a direct measure of inner retinal (melanopsin) and outer retinal (rhodopsin and cone-opsin) mediated function. Studies show that melanopsin expressing ipRGCs form the primary afferent pathway for the pupil light response in mice  and primAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it 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.


Intrahepatic cholestasis of pregnancy (ICP) is the most common hepatic disorder related to pregnancy in women. It usually develops within the third trimester of pregnancy and presents with pruritus as well as elevated levels of bile acid and/or alanine aminotransferase. Clinical signs quickly resolve after delivery; however, there is a high risk of the disorder recurring in subsequent pregnancies. ICP is associated with an increased risk of perinatal complications . Elevated levels of gestational hormones and genetic predispositions are important factors for the development of ICP; among the latter, mutations in hepatobiliary transport proteins  play a major role. Clinical and biochemical symptoms of ICP include pruritus and increased levels of total bile acids (TBA). Serum levels of TBA should be monitored in ICP patients throughout the pregnancy as concentrations above 40 μmol/L, which define that severe ICP isassociated with an increased risk of fetal complications. Therapeutic management is aimed at reducing the clinical symptoms, normalizing maternal biochemistry and preventing complications to the fetus. Pharmacological treatment of intrahepatic cholestasis of pregnancy consists of the administration of ursodeoxycholic acid to lower the levels of TBA and possibly reduce pruritus. If the treatment fails, premature delivery should be considered. During pregnancy, numerous physiological and anatomical changes occur in the female body so as to ensure the best possible conditions for fetal growth. All systems and organs adapt their functions to support the healthy course of pregnancy. Pregnant mothers present with an increased demand for a number of substances such as folic acid, vitamin B12, or iron .Intrahepatic cholestasis of pregnancies is one of the most common liver diseases closely related to pregnancy. The disease resolves spontaneously after delivery; however, it tends to recur in a more severe form in 45–90% of subsequent pregnancies. ICP rates are different in different ethnic groups depending on the geographical region [MDR3) involved in the biliary secretion of phospholipids, are assigned a major role in the pathogenesis of ICP [MDR3 mutations are observed in approximately 16% of all ICP cases; their presence is also related to the severity of the disease and TBA levels of above 40 µmol/L [MDR3 protein-coding disorders may occur not only in ICP but also in hereditary low phospholipid-associated cholelithiasis (LPA), as well as in drug-induced cholestasis [BSEP gene [MDR3 and BSEP genes, rare mutations within the FIC1 gene (ATP8B1) present within the bile duct membrane and the FXR gene (NR1H4) were also detected in Caucasian patients diagnosed with intrahepatic cholestasis of pregnancy [D-estradiol and sulfated metabolites of progesterone [The etiology of ICP is not fully explained, with attention being drawn to the contribution from genetic, hormonal, and environmental factors. Among the genetic factors, mutations of the hepatobiliary transport protein-multidrug resistance protein 3 . Most frequently, the disorder affects volar surfaces of hands and feet. However, all body parts may be affected. Pruritus tends to exacerbate during the night, possibly entailing insomnia, irritability, and even depression . In the At present, the most sensitive biochemical marker used in the diagnostics of intrahepatic cholestasis of pregnancy is the level of total bile acids, which may be the first or the only laboratory-detected symptom. In healthy pregnant women, TBA levels are slightly and insignificantly higher than in non-pregnant women. The cut-off point is defined as the total concentration of bile acids exceeding 10 micromoles/L . NumerouAs shown by a retrospective study by Kondrackiene et al., TBA levels alone are not a sufficiently sensitive and specific marker for this disease . AccordiAll maternal serum parameters assayed in the liver function tests return to normal shortly after delivery.Fetal biochemical parameters and wellbeing are monitored in the course of the disease. Patients should follow a light and low-fat diet. Biochemical parameters such as transaminases, total bile acids, andblood coagulation profile should be analyzed once a week. An abdominal ultrasound scan should be performed to examine the liver. The assessment of fetal wellbeing should consist in the monitoring of fetal movements, cardiotocography (CTG), and fetal ultrasound scans .Administration of ursodeoxycholic acid (UDCA) is the treatment of choice. The drug’s mechanism of action involves the displacement of hydrophobic bile acids to ensure the protection of hepatocytic membranes; UDCA was shown to stimulate transplacental elimination of bile acids from the fetus. Ursodeoxycholic acid is administered orally at 300 mg 2–3 times per day (or 10–16 mg/kg/day). The drug is well tolerated by patients . No toxiHowever, in a trial, Chappell et al. found that for women with intrahepatic cholestasis of pregnancy, ursodeoxycholic acid was not effective in reducing a composite of adverse perinatal outcomes. Although ursodeoxycholic acid appeared to be safe, it had no clinically meaningful effect on maternal itch symptoms. It did not reduce maternal bile acid concentrations, and the reduction in alanine transaminase was of uncertain clinical significance, given that alanine transaminase is not known to be associated with the risk of stillbirth or preterm labor in intrahepatic cholestasis of pregnancy. Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. Ursodeoxycholic acid is recommended in six national guidelines for the management of intrahepatic cholestasis of pregnancy, principally for the improvement of maternal symptoms and biochemical test results. Surveys of practice have found that 97% of obstetricians in the UK use ursodeoxycholic acid for treating intrahepatic cholestasis of pregnancy. However, Chappell et al. suggested that the lack of in-vivo evidence of benefit should preclude further routine clinical use of ursodeoxycholic acid, even in the absence of harm, to avoid women being offered an unproven treatment .Premature delivery is contemplated in cases involving no improvement in clinical parameters and simultaneous exacerbation of clinical symptoms. The risk of fetal death should be compared with the potential risk of premature delivery. A course of corticosteroids should be administered before the 34th week of gestation to reduce fetal mortality and incidence of respiratory insufficiency and intraventricular bleeding. After the 38th week, the risk of intrauterine fetal hypoxia is increased even in cases of moderate cholestasis .The guidelines of the Royal College of Obstetricians and Gynaecologists include a recommendation to induce premature delivery in ICP-complicated pregnancies in patients with severe biochemical disorders at 37+0 weeks .Due to the lack of recommendations based on randomized studies, the optimum management consists ofinducing the delivery at gestation week 36–37, particularly in cases of total bile acidlevels exceeding 40 mmol/L. Vaginal vs. cesarean section delivery should be considered depending on obstetric indications. The likelihood of intrahepatic cholestasis of pregnancy recurring during a subsequent pregnancy is about 60% [Intrahepatic cholestasis of pregnancy is a common hepatic disorder associated with pregnancy. Genetic, hormonal, and environmental factors are taken into account in the pathogenesis of the disorder, but the mechanism responsible for the disease has not been fully elucidated. Pruritus, developing in the third trimester of pregnancy, is the most predominant clinical symptom. The resolution of symptoms after the delivery is also characteristic. ICP presents a risk to fetal development. Laboratory diagnosis is mainly based on the determination of elevated total bile acid levels in the maternal blood. The mainstay of therapeutic management consists in the reduction of maternal symptoms and possible complications to the fetus.