Over the last two decades, while contraceptive use has improved in Ethiopia, the contraceptive prevalence rate remains low. In addition to socio-demographic and cultural factors, the quality of care in Family Planning (FP) services is an important determining factor of FP utilization. However, little research exists on the determinants of quality of care in FP services in Ethiopia. This study aims to identify the client and facility level determinants of quality of care in FP services in Ethiopia.This study was based on the first Ethiopian Services Provision Assessment Plus (ESPA+) survey conducted in 2014. A total of 1247 clients nested in 374 health facilities were included in the analysis. Multilevel mixed-effects logistic regression modelling was conducted. The outcome variable, client satisfaction, was created using polychoric principal component analysis using eleven facets that reflect client satisfaction.The results showed that both client-level and facility-level factors were associated with quality of care in FP services in Ethiopia. At the client-level; provision of information on potential side effects of contraceptive method , and number of history and physical assessments  were positively associated with client satisfaction, whereas waiting times of 30 minutes to two hours  was negatively associated with client satisfaction. At the facility-level; urban location , and availability of FP guidelines/protocols for providers  had positive significant effect on client satisfaction.Quality improvement programs in FP services in Ethiopia should focus on shortening waiting times and provision of information about the potential side effects of contraceptive methods. It is also important to improve health providers’ skills in thorough client history taking and physical assessment. Further distribution and implementation of best practice guidelines for providers working in the FP services must be a priority. In 2015, the World Health Organization (WHO) estimated that 303,000 women were dying globally from pregnancy-related causes and complications, of which 66% occurred in sub-Saharan Africa. Ethiopia is ranking fourth in the top ten countries that accounted for 59% of the maternal deaths globally . The ICC was used to assess the influence of unobserved facility-level variables on client satisfaction. Univariate mixed-effects logistic regression analysis was performed to estimate the crude odds ratios at 95% confidence interval. Those variables that had p-value of less than 0.2 in this model were included in the multivariate mixed-effects logistic regression analysis.The distribution of μj was normal with mean 0 and variance σThe model fitness was assessed using Akaike Information Criterion (AIC) and Likelihood Ratio (LR) test. Variance Inflator Factor (VIF) was employed for checking multicollinearity among the independent variables. The fixed effect sizes (measure of associations) of the client and facility-level factors on client satisfaction were expressed using the Odds Ratio (OR) and 95% Confidence Interval (CI) whereas variance (measure of variations) was used to express the random effects. To account for the complex sampling strategy, weighting was employed during the analysis as well as when performing the ICC and AIC calculations. A p-value of less than 0.05 was applied used to declare level of significance. All statistical analyses were carried out with STATA 14 .Ethical approvals were obtained from the Scientific and Ethical Review Committee (SERC) at the Ethiopian Public Health Institute (EPHI) and the University of Adelaide Human Research Ethics Committee (HREC).The clients’ characteristics are shown in The fixed effects (measure of association) and random effects (measure of variation) for client satisfaction are presented in The odds of being more satisfied were lower by 89% for clients who waited 30 minutes to two hours compared to clients who waited less than 30 minutes before being seen by the provider for consultation in FP services . Clients who were informed about the potential side effects of the contraceptive methods had about five times higher odds of being more satisfied than those who were not provided with information about potential side effects . The odds of being more satisfied were increased by 19% for each unit increase in number of history and physical assessments . There was borderline significance association between age of the client and client satisfaction .Similarly, those clients who received FP services in urban facilities had about five times higher odds of being more satisfied than those rural facilities. The availability of FP guidelines/protocols was also a significant factor in determining client satisfaction. In this regard, the odds of clients being more satisfied were nearly five times higher in facilities with FP guidelines/protocols as compared to those facilities without FP guidelines/protocols .Using data from the Ethiopian Services Assessment Plus (ESPA+) survey 2014 data, this study assessed the client-level and facility-level determinants of quality of care in FP services in Ethiopia. After controlling the effects of confounders, the findings demonstrate that both client-level and facility-level factors were associated with quality of care in FP services in Ethiopia. At the client-level; age, client’s waiting time, information provision about the potential side effects of the contraceptive methods, and number of history and physical assessments were significantly associated with client satisfaction in FP services. These client-level factors are mostly related to the process of FP services provision. At the facility-level; the availability of FP guidelines/protocols and facility location were significant factors. Excluding client’s age and facility location, the factors identified in the present study reaffirmed four out of the six aspects of the quality of care identified in Bruce/Jain framework . HoweverA recent systematic review of studies undertaken in African countries to identify factors determining quality of care in FP services suggests that client waiting time is an important factor associated with quality of care in FP services . SimilarThe other key client-level factor was the provision of information about the potential side effects of the contraceptive methods. There was higher odds of being more satisfied in FP services when the clients provided information about the potential side effects contraceptive methods. This is in agreement with a previous study conducted in Finland that underscored provision of information about potential side effects of certain contraceptive methods improved user satisfaction . AdditioBesides the client-level factors, the availability of FP guidelines/protocols was an important facility-level structural factor associated with quality of care in FP services. The odds of being more satisfied with FP services was higher for facilities that possessed FP guidelines/protocols as compared to facilities that did not. The availability of guidelines/protocols in the facility suggests that health providers in those facilities have the opportunity to gain up-to-date knowledge about the FP methods which include the potential side effects of different contraceptive methods and the counselling approach. This would in turn help provider to offer client-tailored counselling during FP services. Previous study conducted in Jordan showed similar findings in that provision of protocols to guide client’s counselling have improved clients satisfaction with the FP services .Another important determinant of client satisfaction in FP services was the location of the health facility. This study found that those clients who received FP services in urban facilities had higher odds of being more satisfied than rural facilities. This difference may be explained by the following reasons. Firstly, FP clients of rural facilities are likely rural residents who may have less information about the contraceptive methods due to less access for media. Secondly, rural facilities may have a shortage of experienced FP providers due to the possibility that experienced providers would transfer to urban facilities while newly graduated health providers assigned in rural facilities. Thirdly, some contraceptive methods such as female sterilization and Intrauterine Device (IUD) might be available only in urban facilities. As a result, client choice of contraceptive methods may not be fulfilled and eventually they could remain less satisfied with the services.A strength of this study is that it is the first ever study that provides an assessment of the quality of care in FP services in Ethiopia and to identify the determinants of quality of care in FP services based on a nationally representative sample. Secondly, this study provides findings that can be used as a baseline for future study including future rounds of ESPA+ surveys and also for assessing the impact of policy and strategies to improve FP services in Ethiopia.However, there are some limitations. Given that characteristics of health providers can influence the quality of care in FP services, the ESPA+ 2014 data involved a random sample of health providers rather than interviewing providers involved in FP services provision. A first limitation of the study is that it was not possible to control provider related confounders. A second limitation is that some factors that may be important in determining quality of FP services, including marital status, religion, and residence were not included in the analysis as this information was not collected in the ESPA+ 2014 survey. Thirdly, collecting the observation data during client-provider interaction, might have produced social desirability bias in that health providers may have altered their behaviour, and performed better, due to them being aware that their interactions were being evaluated. This may also apply to client responses.Our results have a number of policy implications. The provision of information for clients including the contraceptive method’s potential side effects is necessary and so future policies should target in the dissemination and improving uptake of best practice guidelines for providers working in the FP services. In addition, there is a need to improve health providers’ skills in terms of conducting thorough history taking and physical assessment for clients attending FP services and this could be done through targeted training. Appropriate strategies including making proper arrangement for long service hours and deploying trained providers from other reproductive health or maternity services are important to minimize clients waiting time in health facilities. The difference between rural and urban FP services need to be addressed and may a number of policies that focus on improving services in rural areas such as recruitment of health providers, provision of resources and education programs for health providers and clients.Quality of care in FP services in Ethiopia is influenced by client-level and facility-level factors. Shorter waiting times, the provision of information about the contraceptive method’s potential side effects, improved history and physical assessments, the availability of FP guidelines/protocols, and being urban facilities were important determinants of quality of care in FP services in Ethiopia.


As diabetic foot (DF) care benefits from integration, monitoring geographic variations in lower limb Major Amputation rate enables to highlight potential lack of Integrated Care. In Tuscany , these DF outcomes were good on average but they varied within the region. In order to stimulate an improvement process towards integration, the project aimed to shift health professionals’ focus on the geographic variation issue, promote the Population Medicine approach, and engage professionals in a community of practice. Three strategies were thus carried out: the use of a transparent performance evaluation system based on benchmarking; the use of patient stories and benchmarking analyses on outcomes, service utilization and costs that cross-checked delivery- and population-based perspectives; the establishment of a stable community of professionals to discuss data and practices. The project enabled professionals to shift their focus on geographic variation and to a joint accountability on outcomes and costs for the entire patient pathways. Organizational best practices and gaps in integration were identified and improvement actions towards Integrated Care were implemented. For the specific category of care pathways whose geographic variation is related to a lack of Integrated Care, a comprehensive strategy to improve outcomes and reduce equity gaps by diffusing integration should be carried out. Although many countries aim for more Integrated Care within and across institutional boundaries as a means of developing more cost-effective health services 234, this23As good outcomes for the Diabetic Foot (DF) pathway depend on the involvement of several clinicians across different care settings and institutions, this pathway is an exemplar of the benefits of integration. Despite international recommendations to diffuse multi-disciplinary teams and integrated paths in order to improve DF outcomes 5679101112139101112This study contributes to the debate on how to implement Integrated Care 1516 and 15171819202122232526272829The paper describes the successful implementation of a combination of strategies aimed at spreading Integrated Care within the DF pathway in Tuscany . The objectives linked to specific strategies are to:– encourage clinicians to focus on the geographic variation issue;– spread the Population Medicine perspective;– engage clinicians in a stable community of practice in order to identify gaps in integration and practical models of Integrated Care 32.Tuscany is a region in central Italy with approximately 3.7 million inhabitants. Its regional healthcare system follows the Beveridge model and provides universal coverage with an annual public budget of €6.6 billion.Twelve local health authorities (LHAs) are responsible for organizing and providing comprehensive healthcare services for an average of approximately 300,000 inhabitants. Hospital care is provided by general hospitals led by LHAs and three teaching hospitals (THs), which are independent health authorities (HAs) without a specific geographic catchment area and regional referral centres for complex care.http://performance.sssup.it.Since 2004, the regional government in Tuscany has entrusted the “Management and Health Laboratory” (MeS-Lab) of the Scuola Superiore Sant’Anna University with the design and management of a multi-dimensional healthcare performance evaluation system (PES) 3435. Usi34In 2012, the Tuscany Regional Government entrusted the MeS-Lab to design and coordinate an action plan to reduce the variation in DF outcomes by disseminating Integrated Care. The Italian National Outcomes Evaluation Programme  showed iDespite Tuscany performed well compared to the other regions, there were considerable internal variations among its Provinces. This variability across and within regions suggested potential differences in implementing international guidelines, leading to unwarranted geographic variations, i.e. variations not dictated by the needs of populations and patient preferences 17181921222324.2122232123The Regional Government also chose the DF pathway because of the increasing:– Incidence of DF complications, i.e. the first cause of lower-limb amputations in industrialized countries 37;– social and financial costs of DF patients who have had major amputations. DF care is associated with high additional costs of diabetes care for patients and healthcare systems 39.– the importance of assessing the overall quality of care in terms of the rate of diabetes-related lower limb major amputation, which is an indicator of poor quality and poor coordination within the overall service chain, which should trigger further investigations 41.Integrated Care covers a rich conceptual framework with many theoretical definitions [1234424344454647484950Kodner  proposed– functional integration as the coordination between back-office and support functions across all units;– organizational integration as the relationships between healthcare organizations;– professional integration as the provider relationships within and between organizations;– service or clinical integration as the coordination of services and the integration of care in a single process across time, place and discipline;– normative integration as the shared mission, work values and organizational/professional culture;– systemic integration as the alignment of policies and incentives at the organizational level.Valentijn and colleagues described also three different levels of integration : macro-lIn terms of breadth, integration between different organizations is known as vertical integration and the coordination of similar units or settings of care as horizontal integration 52.‘identifies points of friction, confusion, or discontinuity between systems and establishes structures and processes to solve these problems’ [Leutz described three configurations based on the intensity (i.e. degree) of the connections between organizations and units : linkageroblems’  , often belonging to different organizations and institutions.Based on the organization of the Tuscany Healthcare System and the conceptual framework of integration, in this study we identify the need for integration between different:– units within the same organization ;– care settings – institutions .to the population they serve, to the patients they never see, as well as to the patients who have consulted or been referred’ [With particular regard to normative integration, we considered the Population Medicine approach as the set of values that should inform professional behaviors so as to connect all the units, care settings, and organizations involved into DF care. Gray proposes the Population Medicine approach  as a meaeferred’  as “publIn order to diffuse Integrated Care into DF care, three main strategies were adopted:– Using the MeS-Lab PES to encourage clinicians to focus on geographic variation;– Using quantitative and qualitative information at both the HA and patient levels to inform clinicians’ debate and to spread the Population Medicine perspective;– Creating a stable community of professional practice in order to discuss data, identify best practices of Integrated Care and share improvement actions 32.The project started in 2012 and was carried out over a period of about two years.Firstly, the diabetes-related lower limb major amputation rate (DRMAR) was included in the MeS-Lab PES (see Supplementary File 1 for a definition of DRMAR).The most important elements of the MeS-Lab PES were then applied to the DRMAR. In fact, MeS-Lab PES proved to be effective in facilitating the comprehensiveness of the performance information and in supporting improvement 343554. T3435– The use of five coloured assessment bands based on the benchmark results: red - poorest performers; orange - poor; yellow - average; green - good; and dark green - best. Benchmarking enables performance to be evaluated by assigning the five bands considering the overall average and the distribution of HA results;– The inclusion of the DRMAR in the dartboard diagram representing the overall performance of each HA. The dartboard has five bands: when performance is excellent, the results are positioned from the central dark green zone for best performers towards the outer strips, with red representing the poorest performance (Supplementary File 2 includes an example of the dartboard).http://www.performance.sssup.it/toscana which not only provides stakeholders with all the information available but also through benchmarking creates a “competition” between clinicians based on reputation.– The public disclosure of results on a website, – The setting of quantitative targets: the Regional Government sets a quantitative target for each HA for each indicator included in the MeS-Lab PES.– A link between the target achievement and the 20% variable share of HA CEOs’ annual salaries.In order to spread the Population Medicine approach, we provided clinicians with specific analyses that mixed different issues , different levels of analysis , and different methods and sources .In addition, population-based data was cross-checked based on Small Area Variation Analyses (SAVAs) and data were calculated at the delivering facility level.By benchmarking the utilization rates of healthcare services , the SAVA compared the costs and the outcomes, between geographic areas and comparable populations . The delCross-checking these analyses provided a preliminary mapping of the real patient pathways, which usually involved several clinicians, wards and facilities in different HAs. This process challenged the inward-looking perspective and the silo-working approach of clinicians who focused only on patients seen in their own facilities or on the specific phase they managed. Regular benchmarking was essential in guiding data interpretation and discussions between clinicians regarding the potential lack of Integrated Care.All the analyses on service utilization, outcomes and costs were provided not only for each HA but also at a patient level.The first level provided data on volumes and estimated expenditure for the services delivered by each HA for the various LHA populations. These analyses checked which services were globally delivered and the overall impact on LHA budgets.Patient pathways were tracked across different services and facilities in order to help clinicians understand whether appropriate care was being delivered to each patient. These analyses focused on a cohort of 190 diabetic residents in Tuscany who had been amputated in 2011. The database was created with a record linkage of administrative flows between 2009 and 2012 regarding hospitalizations, outpatient visits, diagnostic tests, and drug consumption. Each patient’s clinical history considered the one year prior to and after hospitalization for major amputation.Finally, the analyses discussed by clinicians was based mainly on administrative data, but also on a patient survey of specific phases of DF care.From the very beginning, the program involved the DF clinicians in discussing the analyses, identifying barriers to integration and best practices and proposing improvements. The process of engaging clinicians was based on the principles of action research 32565758 325657Firstly, the two MeS-Lab researchers involved in the action research project and a representative of the Regional Commission for Diabetes designed a questionnaire to uniformly map the DF pathways . The questionnaires analyzed eight areas where integration was considered essential: screening, admissions and visits, revascularization procedures, surgery, urgent pathways, follow-up and continuity of care, education for patients and caregivers, training clinicians, and information systems.Researchers then visited the Diabetic Foot Outpatient Clinics in the 12 LHAs and in the three THs and mapped the organization of the DF pathways through the questionnaires in collaboration with the team leaders of the units. These clinicians were involved because of their role in coordinating the services and professionals involved in DF care. In addition, visits were planned so as to create a trusting relationship between the researchers and clinicians, in order to openly discuss their practices.Researchers then arranged the first plenary meeting with clinicians and their DF-teams , the managers of the Health Departments of each HA, the representatives of the Regional Government, GPs and the Tuscany Diabetic Patient Association, with a total of 47 people.The plenary meetings between researchers, managers and clinicians were then conducted around every three months to discuss the analyses and the results of the mapping, to identify good performance and Integrated Care best practices as well as to propose improvement strategies. Clinicians often suggested the calculation criteria of the quantitative analyses 32.The combined implementation of these strategies enabled those working on the project to foster Integrated Care in their local context. The project:Shifted the focus to the reduction of geographic variations by using the MeS-Lab PES;Made clinicians more accountable for the outcomes of their local populations and enabled them to foster collaboration with other professionals in their local communities as required by the Population Medicine approach;Enabled clinicians to identify the gaps in integration and the organizational best practices and improve Integrated Care by tackling weaknesses.In this section, the results are presented considering the main output of the three strategies. In addition, the specific case study of the Teaching Hospital in Pisa is described i.e. the Health Authority that faced major problems in terms of Integrated Care.The first step was to shift the clinicians’ focus on the variation in the DF care, by combining all the PES elements considering the most DF outcome: the DRMAR. The indicator was highlighted in a geographical map with coloured bands based on benchmarking Figure . Data weIn addition, the Regional Government set a specific quantitative target for each LHA and requested that the poorer performers should strive to reach the same levels as the best performers Figure .Age and gender risk-adjustments were added to the DRMAR, showing the persistence of variations even after controlling for the main population needs Figure  and highCrosschecking the population and delivery levels showed the clinicians of the Teaching Hospital of Pisa how the amputations delivered in their facilities were contributing to the poor performance of the LHA in their geographical area (Pisa-LHA). In fact, in 2012, the risk of being amputated in the area of Pisa-LHA was fivefold higher than the risk in the Arezzo-LHA. Thus, the THs and the LHAs of Pisa, Firenze and Siena were assigned a common quantitative target to reduce the DRMAR in their contexts in order to share the joint responsibility of their populations.For the 190 amputated patients included in the DF cohort, the researchers and clinicians examined whether or not each patient had received expected and appropriate care: two patients amputated in 2011 did not receive any outpatient visits and were not hospitalized within a year prior to their amputation. These cases showed that there were problems with Primary Care and Diabetic Foot Outpatient Clinics in fostering prevention, early diagnoses and early treatments. The audit process for these 190 patients showed how enhancing Integrated Care among providers was necessary, notwithstanding the overall good results of Tuscany compared to other regions in Italy.To highlight the lack of coordination with Primary Care, the MeS-Lab provided clinicians with a survey to assess the perceived quality of the Tuscan Program in the Chronic Care Model 60. PatieThe population-based perspective used for the cost-analyses enabled clinicians to discuss how the services provided in the DF pathways impacted on LHA resources. The audits on resources for DF pathways were carried out by dividing the overall healthcare expenditure for the 190 patients in the cohort (approximately € 6 million) into several components .The researchers calculated the estimated LHA expenditure (based on DRG-tariffs) of hospitalizations for diabetes-related revascularization of lower limbs by considering the average expenditure between 2009 and 2012. The expenditure estimate for DRMAs was collected with the same criteria. In order to compare the impact of these two items on LHA budgets, the estimated expenditure was then re-proportioned per 100,000 residents Figure  . Figure The population-based approach helped the clinicians to shift their focus from the costs of the productive factors they directly managed in their wards  to the impact of the overall expenditure for DF patients on their own LHA overall budgets. The new accountability also included THs because of their role in delivering DF care for the residents in their LHA.During the mapping phase and the periodic meetings, the community of practice outlined the barriers to Integrated Care in each local context and identified the best organizational practices.Table The LHA of Arezzo, which was the national and regional best performer in terms of outcomes, was identified as the organization combining the best organizational practices.The Arezzo DF-team identified clear steps for DF services in collaboration with the clinicians in other wards and settings. For instance, daily contacts between diabetologists and other clinicians led to the scheduling of weekly slots for diagnostic tests and revascularizations based on the analysis of demand. They also ensured fast-track pathways for urgent cases. In addition, communication was enhanced between wards: all the clinicians were fully aware of the DF issue and promptly informed the DF-team in case of inpatient DF complications, thus reducing both bottlenecks and late diagnoses/treatments. The cardiology department provided equipment for the DF-team in their ward so that the DF-team could directly care for hospitalized DF patients, regardless of organizational boundaries. In addition, the DFOC information system was completely integrated with the other systems implemented in other wards. Finally, the DFOC clinical staff performed minor surgical procedures thus avoiding the need for surgeons for basic treatments, and therefore reducing bottlenecks. Integration with healthcare services outside Arezzo’s hospital was also established: GPs had clear pathways for both DFOC activities and diagnostic exams through simple slot scheduling schemes. In addition, the DF-team participated in all the training initiatives organized at the Primary Care level in order to enhance awareness of DF complications.After summarizing the issues that arose from the mapping phase and taking into account the case of Arezzo, the clinicians and researchers identified three main sources of barriers to Integrated Care, linked to the categories identified in the background section in terms of integration between:units within the same organization, the main barrier was a lack of coordination among clinicians within an organization . General surgeons, orthopedics, cardiologists, vascular surgeons, interventional radiologists did not always coordinate with the DF-team . Instead, the DF-team should be quickly identifiable and involved in the decisions concerning the pathway regardless of organizational boundaries.different care settings, the main barrier was the lack of coordination between hospital, community and primary care. Clinicians experienced a lack of information flow between care settings, such as between outpatient clinics and general practitioners. This also included a lack of mutual training between clinicians on essential topics for DF care and prevention.different institutions, the main barrier was the lack of coordination between HAs. HAs in the same geographical area or in neighboring areas experienced stronger barriers to Integrated Care because of their “artificial” organizational boundaries. This occurred especially when a TH was the hospital care provider for another authority, the LHA, the other healthcare services (e.g. primary and community care).The engagement approach used to support the mapping and the discussions was needed to compare practices and data. In fact, HA representatives participated in every meeting and frequently asked for additional in-depth analyses of their local contexts. The results of this engagement process enabled them to share organizational best practices and clinicians were encouraged to propose solutions for the issues identified. This occurred both at the regional level, through the shared proposal for redesigning DF care organization, and at the local level, where each DF-team proposed initiatives to tackle the issues in their own context. In particular, the case of Pisa TH is an example of how the project changed the attitude of clinicians towards Integrated Care.Finally, the engagement process succeeded in convincing clinicians to apply the same approach on other diabetes-related pathways .A proposal to re-design the DF pathway in Tuscany towards greater Integrated Care was sent to the Regional Commission for Diabetes. The document was based on the results of the project and provided organizational recommendations for tackling the three barriers. The document was approved by the Regional Health Council in July 2013, aimed at updating the future the Regional Administration Act 1304 dated 9/12/2003 on the organization of the DF care.The document focused on the following items, and was particularly inspired by the results achieved in Arezzo:role of the diabetologist as the coordinator of the entire care with a pathway-oriented approach, regardless of organizational boundaries;implementation of flexible and shared fast-track pathways for urgent treatments and diagnostic tests;interdisciplinary collaboration of clinicians involved in the pathway at the hospital level ;training for diabetologists in basic surgical skills;clear and periodic communication, coordination and training initiatives between hospitals and primary care professionals in order to improve both preventive and follow-up care;reinforcement of the network of professionals in the different HAs, not just between the diabetologists but also between GPs, nurses and podiatrists.Pisa-LHA is one of 12 Tuscan Local Health Authorities serving a population of about 340,000 residents. Hospital care in the city of Pisa is delivered by the Pisa Teaching Hospital (Pisa-TH) and not directly by the LHA, thus leading to complex coordination between hospital, community and primary care services.The results of the Pisa-LHA DRMAR were expected to be good, considering that Pisa-TH was the regional referral center for diabetes and it was the only hospital in the Region of Tuscany with a specific department managed by diabetologists. Conversely, during the three-year period 2010-2012, Pisa-LHA had one of the highest regional values.The analyses carried out during the project identified the Pisa area as experiencing all three barriers to Integrated Care:– integration between units within the organization: there were problems in internal coordination due to the high number of clinicians and wards involved in caring for DF patients;– integration between care settings and institutions: there was a lack of coordination between care settings and Health Authorities. These Pisa-TH coordination issues were amplified because of the organizational boundaries with the Local Health Authority. Indeed, the division between the independent Pisa-TH in charge of hospital care, the Pisa-LHA in charge of community and home services, and the self-employed General Practitioners rewarded on a capitation-basis sharply increased lack of coordination. All the analyses carried out during the project confirmed these problems.– For instance, the Pisa area:– accounted for the lowest adherence to the screening for foot complications in Primary Care, as previously shown in Figure – had the greatest need for reallocating resources from amputations towards preventative care, as shown in Figure – accounted for the highest DRMAR in Tuscany due to the high number of amputations affecting the residents in Pisa-LHA and delivered by the Pisa-TH.Initially, the role of the Pisa-TH as DF regional referral center was seen as a reason for not questioning the Pisa-TH about the persistently and increasingly high DRMAR of the Pisa-LHA. However, the project was effective in shifting the focus from a delivery- to a population-based perspective. Indeed, the DFOC of the Pisa-TH started to re-consider its role as the most important delivering facility for the inhabitants of Pisa and therefore accountable for the results of the Pisa-LHA, regardless of the organizational boundaries between the authorities.Thus, the DFOC-team began a constructive improvement process to deal with the three areas lacking integration.Firstly, concerning integration between units within the organization, various improvements were carried out in order to foster structured relations with the other clinicians involved in the DF care in the Pisa-TH. MeS-Lab researchers provided more detailed information on the pathways of Pisa-LHA residents amputated in the Pisa-TH . The DF-team then carried out a comprehensive analysis of the DF care provided in the Pisa-TH. Before the project, the focus of the DFOC clinicians was only on the amputations they had performed or on those performed by other Pisa-TH clinicians for patients previously cared for in the DFOC. Hence, the patient pathways for amputations in the Pisa-TH without DFOC involvement (48%) were not analysed and discussed. Moreover, this lack of involvement of the diabetologists resulted in a less conservative surgical approach being provided in the other departments .The mapping phase showed that the PISA-TH pathway for DF patients cared for by the DFOC was well staffed and organized. The DFOC included a team of podiatrists with resources and beds directly managed by the Diabetology Department. In addition, the DF-team performed minor and conservative amputations directly, with scheduled slots in the surgical rooms and in the cath-lab for revascularizations.However, in the complex organization of the Pisa-TH, some patients left or did not start this path. The lack of shared decisions and a defined pathway was because in the Pisa-TH there were several practitioners in both clinician-led and academic-led wards, thus multiplying the interactions between professionals and departments and increasing the chances of poor coordination and miscommunication. This confirmed the need for greater integration among the several Pisa-TH clinicians and services, and it raised concerns about equitable treatment for DF patients.Consequently, with the detailed analyses of patient pathways, the DF-team carried out internal audits with the other clinicians involved in DF care to map the internal pathway of each amputated patient; in particular, those who had not been previously cared for by the DF-team and had been hospitalized for amputations by the emergency department.The results were presented to the vascular surgeons and a multi-disciplinary audit was then carried out to share whether and when to perform surgical procedures. These results were also discussed by the DF community of practice in the plenary meetings.With regard to the integration between care settings, the key focus was to reduce the lack of coordination with Primary Care. The DFOC director decided to organize training courses for Pisa-LHA community nurses in charge of the DF screening phase. The initiative to overcome the TH boundaries and to interact with Primary Care structures of the Pisa-LHA area  confirmed the strong commitment to the Population Medicine approach.With regard to the integration between institutions, Pisa-TH fostered the overall coordination with the Pisa-LHA. The internal audits carried out by Pisa-TH clinicians were also adopted externally in order to map all the patient pathways that were shared by both institutions . Periodical meetings involving health clinicians and managers of the two institutions were thus organized.All these steps enhanced stronger collaboration and joint accountability by the Pisa-LHA and the Pisa-TH for the DRMAR results, thus overcoming organizational boundaries.Finally, initial evidence of outcome improvements was found in the DRMAR indicator: after the start of the project, the persistent increase in the Pisa-LHA DRMAR stopped and in 2014 the Pisa-LHA DRMAR registered an overall decrease of 38% with respect to 2012.Based on the study presented in this paper, some complementary steps should be carried out to tackle the barriers to integration and to drive consistent improvement in those pathways where Integrated Care is particularly related to outcomes .This approach includes: the use of a transparent and systematic PES along with stimuli for driving focus on geographic variation; the diffusion of a Population Medicine approach to shift professionals from a silo-working to Integrated Care practice; and the engagement of professionals as the key to promoting concrete improvement.The implementation of a Performance Evaluation System comparing benchmarking data and the use of effective tools to represent performance (dartboard and geographic maps) are the first steps in order to be able to highlight geographic variations and best practices. Public disclosure of these data raises professionals’ awareness, leading to a “reputational competition” 306263. H306225In addition, discussing analyses with clinicians comparing service utilization and outcomes with costs shows that, in most cases, it is possible to achieve greater quality of care and better outcomes without increasing costs. Indeed, financial sustainability can be achieved through resource reallocation rather than through across-the-board budget cuts. As in the case of the DF, fostering this issue in those multi-provider and multidisciplinary pathways where Integrated Care is strongly connected with quality of care, can foster value for money strategies and should become a financial priority.To implement improvement actions towards Integrated Care an engagement strategy 66 shouldThis approach actually enabled professionals to outline best practical models of Integrated Care and share improvement solutions. Hence, the community of practice allowed also to identify and reward the best performers through peer-reputation.Finally, the community of practices needs to share a common set of values that enables professionals to feel jointly accountable for the entire pathway and not only for the phase they are in charge of. In this respect, the Population Medicine approach embodies this key message and could be identified as the set of work values that should shape the professional culture in those organizations seeking more Integrated Care.The approach presented in this paper was framed specifically in Tuscany, and in a specific highly-specialized pathway, the DF care. However, our approach could be applied to all areas and to all care pathways where Integrated Care may be the leading factor to improve outcomes.In fact, for all those health services whose results are strongly linked to Integrated Care, a new specific category regarding the determinants of geographic variation could be identified. Wennberg and colleagues 1819, in 181718192021222324Based on our experience, ‘effective care’ should be split into two subcategories Table . In factTherefore, as in the case presented in this paper, it is possible to recognize services whose geographic variation is related to a lack of Integrated Care. For these services, Integrated Care and unwarranted geographic variation are connected and a comprehensive strategy to reduce equity gaps by diffusing integration should be carried out.In a Beveridge Healthcare System, which pursues universal coverage and equity, clinicians should be engaged in a cultural change where their work is less constrained by organizational boundaries. Clinicians should be steered towards the creation of overall value for patients in a population-based perspective and the adoption of Integrated Care as a systemic approach throughout the entire pathway.Services whose outcomes are particularly related to Integrated Care should be fully analysed by a stable community of practitioners in order to identify and tackle barriers to integration. This will create a healthcare system where clinicians share joint accountability for both the outcomes and the costs of the care pathways in which they are involved and not just for the patients they directly care for, the phases for which they are in charge of, or the productive factors they manage. This process enables healthcare professionals and managers to share their common commitment towards the principle of equity pursed by Beveridge healthcare systems.Click here for additional data file.


The scientific community has reported several cases of microbes that exhibit elevated rates of antibiotic resistance in different regions of the planet. Due to this emergence of antimicrobial resistant microorganisms, the use of antibiotics as promoters of livestock animals’ growth is being banned in most countries around the world. One of the challenges of agricultural immunology therefore is to find alternatives by modulating the immune system of animals in drug-independent safe food production systems. In this regard, in an effort to supplant antibiotics from bovine feeds, several alternatives were proposed including the use of immunomodulatory probiotics (immunobiotics). The purpose of this review is to provide an update of the status of the modulation of intestinal antiviral innate immunity of the bovine host by immunobiotics, and the beneficial impact of immunobiotics on viral infections, focused on intestinal epithelial cells (IECs). The results of our group, which demonstrate the capacity of immunobiotic strains to beneficially modulate Toll-like receptor 3-triggered immune responses in bovine IECs and improve the resistance to viral infections, are highlighted. This review provides comprehensive information on the innate immune response of bovine IECs against virus, which can be further investigated for the development of strategies aimed to improve defenses in the bovine host. Over the past decades, the global bovine production has been subjected to intensification, in order to improve efficiency of production because of the demand from a growing human population. The intensification of bovine production involved the application of confinement methods characterized by the concentration of animals in large outdoor feedlots or in specialized indoor environments. In confinement, the potential for transfer of pathogens among animals is higher, as there are more animals in a smaller space –3.Severe gastrointestinal infectious diseases causing malabsorption and diarrhea are important causes of discomfort and death in young calves, resulting in important economic losses to bovine producers. Gastrointestinal infectious diseases are able to cause significant economic losses to the cattle industry in big cattle-producing countries and can impair the development of cattle industry in small cattle-producing countries –3. In paProbiotics are defined as live microorganisms with the capacity to confer a health benefit on the host when administered in adequate amounts. Among them, those that are able to impact on human and animal health by modulating the mucosal and systemic immune systems have been called immunobiotics. It has been reported that immunobiotic lactic acid bacteria are able to generate protection against viral pathogens by differentially modulating antiviral immune responses in humans and livestock animals like pigs , 7. It iThe purpose of this review is to provide an update of the status of the modulation of intestinal antiviral innate immunity in the bovine host by immunobiotics, and their beneficial impact on viral infections. The results of our group, which demonstrate the capacity of immunobiotic strains to advantageously modulate Toll-like receptor (TLR)-3-triggered immune responses in bovine IECs and improve the resistance to viral infections, are particularly highlighted.Before weaning, dairy calves are highly susceptible to infectious diseases. For several years, antimicrobial compounds have been used to reduce the severity and mortality of infectious diseases and to improve economic benefits in terms of enhanced bovine performance and diminished medication expenses. However, the use of antibiotics in livestock animal management is in question because of the enhanced resistance of microbes to antimicrobial compounds. Therefore, there is an urgent need to reduce and finally eliminate the use of antibiotics in livestock and for this purpose many feed additives have been proposed including beneficial microbes –10. In fAs described for other livestock animals, the most critical stage in the bovine life is the period from birth to weaning. During this stage factors like nutrition can directly affect the immune system development and function and impact later in bovine performance . HoweverBifidobacterium pseudolongum M-602 or Lactobacillus acidophilus LAC-300 enhanced the gain of body weight and reduced diarrhea frequency in calves  (It is considered that an important step forward toward the understanding of the cellular and molecular interactions of pathogenic or probiotic microorganisms with the bovine host is the establishment of appropriate s (PRRs) .Primary cultures of small or large IECs have been used to evaluate the effects of microbial virulence factors, toxic compounds, and antimicrobial factors in cattle. Moreover, those primary cultures have been also used for the study of innate immune responses through PRRs signaling –33. SoftAs mentioned earlier, viral infections in livestock animals could cause a fatal disease that implicate serious economic loses. Therefore, the effective and non-costly control of this type of infections is a key factor for improving animal production. It is believed that the clear and detailed understanding of viral pathogenicity as well as host immune response in the bovine host is necessary to develop strategies capable of reducing infectious disease caused by these viruses. In this sense, a deeper understanding of the molecular interactions of virus with bovine IECs is necessary for the development of better prevention strategies to improve protection in animals.Bovine virus pathology and immune response have been studied mainly in heterologous systems including mouse models  and humaBovine primary IEC cultures have been of value to study the molecular mechanisms involved in diseases caused by pathogens. However, the cellular and molecular interactions of beneficial or commensal microorganisms with bovine IECs cells have been less examined. In addition, the intestinal cell lines established from adult cattle may have limitations in the study of infections with BRV, BVDV, or BCV, since these viruses infect IECs in the gut of young calves , 5.In order to understand: (i) the pathogenesis of bovine viral infections and the subsequent gastrointestinal diseases, (ii) the role of bovine IECs in the generation of mucosal immune responses, and (iii) the effect of beneficial microbes that may be used to advantageously modulate the antiviral immune response in bovine IECs; we have developed an immortalized bovine IEC line from young calves: bovine intestinal epithelial (BIE) cells .Bovine intestinal epithelial cells have an epithelial-like morphology and they grow forming a monolayer with cells that establish close contact between them . ScanninBovine intestinal epithelial cells also expressed the cell-to-cell adhesion molecules ZO-1 and beta-catenin . Both prSignificant progress has been made in the understanding of both the beneficial and detrimental roles of TLR3 in innate antiviral immune responses in mucosal tissues , 40. TheTherefore, to confirm these findings, we further examined the expression of TLR3 protein in BIE cells by immunohistochemical analysis and demonstrated that this PRRs is strongly expressed in the cytoplasm of BIE cells . Of notein vitro studies showed that the challenge of bovine intestinal tissues with BRV or BCV activated TLR3, upregulated nuclear factor κB (NF-κB) and increase IL-6 production  and an upregulation of type I interferon (IFN), and proinflammatory cytokines expression was detected. The changes in the expression of inflammatory factors induced by poly(I:C) in BIE cells correlate with the changes reported in various intestinal viral infections of cattle and other hosts. For instance, enhanced gene expression of CCL5 (RANTES), CXCL10 (IP-10), CXCL8 (IL-8), and CCL2 (MCP-1) were observed in rotavirus-infected HT-29 cells , 44. In in vivo or in vitro bovine systems. By performing an intestinal loop surgical technique, Aich et al.  demonstrated that viral infection significantly upregulated most of the IFN-inducible genes including IL-18, IFN-α-inducible protein 6, IFN-induced transmembrane protein 3, TAP1, DDX58 [retinoic acid inducible gene-I (RIG-I)], and 2′-5′-oligoadenylate synthetase (OAS) 1 as well as several cytokines such as IL-8, CCL5, CXCL10, and CXCL11 . Few stuh et al.  investigh et al. .in vitro tool for studying the interactions between BRV and bovine IECs. Therefore, we compared the infection capacity of four rotavirus strains in BIE cells including human (Wa), murine (EW), porcine (OSU), and bovine (UK), and we found that BIE cells can be effectively infected with the four rotavirus strains , upregulate the expression of hundred of antiviral proteins capable to reduce or inhibit viral replication and promote viral clearance. In this regard, transcriptomic analyses of bovine intestinal tissues after the challenge with BRV or BCV have shown that the expression of several IFN-regulated genes is reduced, supporting the conclusion that both viruses have developed mechanism(s) to inhibit immune responses mediated by IFNs  strains with the ability to increase antiviral defenses like L. rhamnosus LA-2, B. infantis MCC12 and B. breve MCC1274 and (ii) strains with anti-inflammatory capacities like L. casei TMC0409.In conclusion, the BIE cells Considering the mentioned results and that some recent research indicated that the presence of bifidobacteria in the gut of young calf is associated with a good health status , we nextL. rhamnosus GG reduced the mucin and IL-6 secretion response triggered by porcine rotavirus, diminishing the inflammatory damage   by which these immunobiotic bifidobacteria induce higher expression of IFN-β in BRV-infected BIE cells is an interesting topic for future research.We showed that BIE cells treated with bifidobacteria were more resistant to BRVs infection, and that MCC12 and MCC1274 treatments significantly increased IFN-β in BRV-infected BIE cells. This is in line with the observation that BRV replication is restricted in susceptible cells by preventive treatment with recombinant IFN-β . Likewisotavirus . Moreoven et al. , in prepProphylactic administration of low doses of antibiotics has been historically used to promote the growth and avoid infectious diseases in livestock animals. However, due to the emergence of antibiotic resistant microbes, several governments in countries around the world have prohibited the use of antibiotics as growth promoters for animals.One of the most important challenges of agricultural immunology therefore is to find alternatives for developing drug-independent safe food production systems by modulating the immune system of animals. The work reviewed here encourages the research of probiotics to beneficially modulate the immune system of the bovine host. This review provides comprehensive information on the innate antiviral immune response of bovine IECs against virus, which can be further studied for the development of strategies aimed to improve antiviral defenses. The analyzed data also suggest that beneficial microbes have a great potential to be used as antiviral alternatives able to reduce severity of infections in the bovine host.in vitro study systems for cattle such as BIE cells as well as the selection and characterization of microbes that exert beneficial functions specifically and efficiently in the bovine host are key points for the successful development of immunomodulatory feeds aimed to protect against infections and reduce or avoid the use of antibiotics.The development of specific All the authors contributed equally to the design, writing, and editing of the review article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This paper addresses the problem of reconstructing realistic, irregular pore geometries of lotus-type porous iron for computer models that allow for simple porosity and pore size variation in computational characterization of their mechanical properties. The presented methodology uses image-recognition algorithms for the statistical analysis of pore morphology in real material specimens, from which a unique fingerprint of pore morphology at a certain porosity level is derived. The representative morphology parameter is introduced and used for the indirect reconstruction of realistic and statistically representative pore morphologies, which can be used for the generation of computational models with an arbitrary porosity. Such models were subjected to parametric computer simulations to characterize the dependence of engineering elastic modulus on the porosity of lotus-type porous iron. The computational results are in excellent agreement with experimental observations, which confirms the suitability of the presented methodology of indirect pore geometry reconstruction for computational simulations of similar porous materials. Porous materials with unidirectional pores are a unique group of materials that contain elongated cylindrical pores of finite  materials ,2) or inThis study focuses on the characterisation of the base mechanical properties of lotus-type porous iron. Only a very limited number of experimental studies have been conducted so far in this regard ,9,10,11.Early computational models of lotus-type materials were rather simplistic and adequate only for coarse observations of deformation mechanisms ,14. The The motive for this study was to develop a novel computational approach for material characterisation, using indirectly reconstructed models of any porosity with a representative pore morphology derived from the morphological analysis of a limited set of real material specimens. The geometrical representative morphology (RM) parameter is introduced to describe the unique fingerprint of planar porous structure variation at a certain porosity. The RM parameter is derived from the statistical analysis of pore morphology in real material specimens. The presented methodology was used for the parametric computational study of lotus-type porous iron to determine the dependence of engineering elastic modulus on porosity, combined with the proper validation of computational results in comparison with the available experimental data. The study was focused entirely on determining the mechanical response in the transversal direction to pore orientation, since previous research has shown that unidirectional elongated pores cause an almost linear dependency of mechanical properties on porosity  and neglA was converted to pore diameter The procedure to define the computational models with realistic pore geometry was divided into three stages: (i) the acquisition of the specimen’s cross-sectional pore morphology data; (ii) statistical analysis of the acquired data for the derivation of representative pore morphology; and (iii) the indirect reconstruction of computer models with representative pore morphology. In the first stage, digital photographs were taken of the lotus-type iron specimen’s cross-sections oriented transversally to pore direction, as shown in For easier comparison between the data acquired from different specimen images, the pore diameters were normalised with the average pore size in the analysed cross-section. The normalised pore diameters were then classified into seven different size classes, ranging from the minimum to the maximum computed values (0–2.1). The percentage of pores in each size class was calculated by dividing the number of pores in each size class with the total number of pores in the analysed cross-section. These pore percentages were then defined as the representative morphology (RM) parameters, a unique fingerprint of the observed specimen’s cross-section with a certain porosity, following a similar methodology as described in . It was Eight different cross-sections of the lotus-type porous iron e.g.,  were anaAn algorithm for the indirect reconstruction of representative computer models with arbitrary porosity was developed to generate a finite set of pores with a certain porosity value. The model control parameters were the porosity, the average pore diameter and the model size. The model pore set was generated in the following way: for each new pore, a random function, weighted with the RM, was used to select a pore size class, from which an un-weighted random function selected the final pore size. This process was repeated until the chosen porosity was reached in the defined model size. The pores were assumed to be randomly distributed over the lotus-type material cross-section according to Wan et al. . TherefoThe total of 20 models with different porosities, gradually ranging from 0% to 72% were reconstructed. The percentage of large pores had to be slightly reduced in favour of a small pore percentage for porosities higher than 65%, since the simple linear extrapolation of pore percentages failed to satisfy the non-overlapping criterion of the pores. Twenty indirectly reconstructed models  were used for the computational characterisation of the engineering elastic modulus of lotus-type porous iron in the transversal direction. The finite element method (FEM) software system Abaqus/Standard  was usedThe results of the geometrical analysis of eight cross-sections of the lotus-type porous iron are shown in Pore geometry analysis of 22% average porosity lotus-type iron shows a very small percentage of small and large pores. Most of the pores are of an average normalised pore radius 1. The RMs of specimens at 22% average porosity roughly follow a normal distribution, with the exception of the third specimen. The largest differences in pore percentages can be observed in the class with an average normalised pore size of 1.05, where scattering reaches almost 50%. Specimens with 43% average porosity also have a majority of pores with an average normalised pore radius of 1, but the size concentration is more intensive than in 22% average porosity specimens. The scattering of pore percentages between different specimens is also smaller for 43% average porosity, with only 39% in the pore size class of 1.35. The highest percentage of pores is 33% in the 1.05 pore size class, and the lowest 0% in the 0.15 and 1.95 size classes. The largest value of average pore percentage at 22% average porosity is 37% in the 1.05 size class, and the lowest is less than 1% in the 0.15 size class. For 43% average porosity, the highest averaged pore percentage reaches 30% in the 1.05 size class, and the lowest lies between 1% and 2% in the 1.95 size class.The graph in 5 insertion attempts. Consequently, the percentage of smaller pores has to be manually increased to pass the linear extrapolation values, which yields successful model reconstruction. It should be noted that the engineering elastic modulus values at porosities higher than 50% estimated by indirect computational simulations have to be further validated by the experimental testing of real specimens of such porosity, when they become available. The question thus remains of how accurately the extrapolated pore percentages would represent the morphology of realistic lotus-type materials with very high porosity, since they have yet to be fabricated with technological advances. Even though the computational results can approximately predict the expected behaviour at higher porosities, it cannot be expected that the realistic material would have the same pore morphology. The question may be answered in the future, when the fabrication techniques are improved for the production of lotus-type materials with a porosity of above 50%. On the other hand, the need for the manual adjustment of pore percentages at high porosities indicates that linear interpolation and extrapolation is not the optimal choice for the reconstruction of models with extreme values of porosity. In the range of currently achievable porosities up to 50%, the linear relation provides for sufficient accuracy, since good correlation between experimental and computational results is observed. Conveniently, the presented algorithm allows numerous updates of the RM database with potential for the improvement of computational characterisation.The pore morphology of lotus-type iron specimens notably varies with the porosity, and pore sizes can be associated with normal distribution only for porosity values near 30%. At very low porosities (0–20%), the differences in pore sizes are smaller than at higher porosities. The majority of pores (up to 85%) are of the nominal pore size classes of 0.75 and 1.05. The diversity of pores grows with an increase in porosity, and at around 50%, a gap starts to form in the 0.75 size class. Afterwards, the majority of pores move away from the values of the average pore size. They become either small or large, while the number of averagely-sized pores decreases. At 60% porosity, it is estimated that already 70% of pores lie outside the 0.75 and 1.05 nominal pore size classes. This phenomenon can be observed in the model with 60% porosity , where sThe results of the analysed specimens at 22% average porosity show a greater scattering of morphology statistics than at 43% porosity. This statistical deviation might be caused by a smaller statistical sample due to the lower number of pores in the examined specimens. On the other hand, more space between the pores provides less restrictions on size and allows for easier development of statistical diversity during the fabrication process. However, the averaging statistics between similar porosities is considered to be necessary due to such deviations.The final pore percentages and porosities of reconstructed models differ slightly from the desired values in the reconstruction process. The indirectly reconstructed pore morphologies can differ from the target RM due to chosen randomness, but the statistical scatter decreases with the size of pore set used for geometry generation. The terminal porosity can also deviate from the target value; partly due to randomness in the pore selection process, and partly because the small portion of the generated pore set that stretches beyond the model boundaries is excluded from the final porosity calculation. Both effects decrease by increasing the model size relative to the average pore size. However, the discussed discrepancies did not compromise the computational characterisation, since the exact achieved porosity value was again calculated for each model after its generation.The computational characterisation of engineering elastic modulus with indirectly reconstructed lotus-type models is in very good agreement with the experimental results at comparable porosities, and the scatter of computational results is similar to that of the experimental results. The engineering elastic modulus was accurately estimated for the entire currently achievable porosity range of lotus-type iron. This proves the validity of indirectly reconstructed computational models and the presented methodology of indirect geometry reconstruction. Furthermore, the accuracy of models with indirectly reconstructed pore geometry is significantly better than that of models with simplified pore geometry. This confirms the importance of realistic pore geometry in the lotus-type material modelling, which is now simpler due to the validated indirect reconstruction algorithm.The algorithm for the indirect reconstruction of realistic pore geometries enables accurate computational prediction of a lotus-type material’s properties. It is based on: (i) data extraction through image recognition; (ii) statistical analysis for evaluation of the representative morphology (RM) parameter; and (iii) indirect reconstruction of computer models with statistically and therefore mechanically representative pore morphology.Statistical analysis of lotus-type porous iron’s cross-sections shows that pore morphology depends heavily on porosity, which in turn strongly influences the material’s elastic behaviour. Furthermore, the study confirms the findings of Wan et al. , that poAn example of the mechanical characterisation of lotus-type porous iron over the entire range of porosity was given based on indirectly reconstructed computer models with realistic pore morphology. There was very good agreement of the computational and experimental results in terms of the elastic modulus dependence on porosity for porosities up to 50% porosity validates the suitability of the indirect reconstruction methodology for the computational characterisation of the lotus-type materials. Furthermore, the accuracy of models with indirectly reconstructed pore geometry is significantly better than that of previous models with simplified pore geometries.The presented methodology can be used for computational analyses of other unidirectional porous structures with cylindrical pores, or for the characterisation of lotus-type porous structures of various base materials. Statistical analyses of their geometry shall reveal if the pore morphology is significantly influenced by the type of base material. In addition, the characterisation of other mechanical or thermal properties like yield stress, densification strain, hardening rate and heat conduction constants is also possible.


Aim: The aim of this paper was to describe the possible implications of topical (ocular) administration of Metamizole on vascular reactivity of the iris in Wistar rats. No other study regarding its topical use was found.Methods: Male adult Wistar rats were anaesthetized with Ketamine 100 mg /kg body weight - injected intraperitoneally - while maintaining spontaneous respiration and the blink reflex. After selecting the area of interest (long posterior ciliary artery – LPCA), manual adjustments of the image magnitude, clarity, and brightness were made, and the experiment began. The image recording lasted 10 minutes.Results: Metamizole induced a slight vasoconstriction that started with the initial moment for all the doses used. After the topical administration of Metamizole, we did not observe an increase of the vascular diameter of LPCA in a dose dependent manner. The saline solution used as a negative control did not modify the vessel diameter.Conclusions: Metamizole (dipyrone) is a non-opioid drug, which is commonly used in human and veterinary medicine. It is the most popular first-line analgesic in various populations. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug. The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders in humans and in animals.Abbreviations: COX = Cyclooxygenase; LPCA = Long Posterior Ciliary Artery; PRP = panretinal photocoagulation; PDR = proliferative diabetic retinopathy; Sec = second(s); VSPR = very severe non proliferative diabetic retinopathy  All the studies in the ophthalmological field focused on its effectiveness in reducing pain after laser procedures  . For example, it has been described that the use of 1000 mg of metamizole 40 min before PRP significantly reduces the pain associated with proliferative diabetic retinopathy (PDR) and very severe non proliferative diabetic retinopathy (VSPR) [2].Metamizole is a pro-drug, which spontaneously breaks down to structurally related pyrazolone compounds after oral administration. Besides its analgesic effect, Metamizole is an antipyretic and spasmolytic agent. The mechanism responsible for the analgesic effect is complex and most probably based on the inhibition of a central cyclooxygenase-3 and the activation of the opioid system and the cannabinoid system. The mechanism responsible for the spasmolytic effect of metamizole is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate . Although for years it has been claimed to be part of non-steroidal anti-inflammatory drugs (NSAIDs), apart from its analgesic effect, the medication has antipyretic and spasmolytic effects as well. The drug produces only a very weak anti-inflammatory effect, which is most probably the consequence of its weak inhibition on cyclooxygenase1 (COX-1) and 2 (COX-2) [5].This particular experimental model was chosen to observe the local effects of the topical administration of Metamizole on vascular reactivity. The reason for this choice was the diversity of effects Metamizole provides and the lack of similar studies from literature. Also, its systemic reactions are partially known, but there is no research made on its local effects associated with topical administration. Metamizole is a relatively safe pharmaceutical preparation although it is not completely free from undesirable effects. Among these side effects, the most serious one that raises most controversy is the myelotoxic effect. It seems that in the past, the risk of metamizole-induced agranulocytosis was exaggerated. Despite the evidence showing no risk of teratogenic and embryotoxic effects, the drug must not be administered in pregnant women, although it can be given to pregnant and lactating animals. The mechanism of action of Metamizole, especially the one responsible for the analgesic effect, is complex .The mechanism responsible for the analgesic effect of Metamizole most probably rests on the inhibition of a central cyclooxygenase-3 and activation of the opioidergic system and cannabinoid system; the mechanism responsible for the spasmolytic effect is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate [7]. Considering that Dipyrone is detectable in the serum for only about 15 min following the intravenous administration, and it is not detectable after oral intake [5], a considerable part of its side-effects can be avoided when using topical pathway.The topical administration of drugs is the most preferred route for the management of eye disorders because it provides higher ocular drug concentrations, avoiding powerful systemic side effects associated with oral administration [8]. Some studies suggested that the analgesic effect of dipyrone may be partly mediated by a dual mechanism of action: the inhibition of COX enzyme activity and the stimulation of CB receptors . Thus, further studies should focus on the neuropathic pain from Dry Eye Syndrome and the effects of topical Metamizole. Local side-effects of topical ophthalmic NSAIDs, which are often used in Dry Eye Syndrome, include transient burning, stinging, conjunctival hyperemia and corneal anesthesia [10].Our findings suggested a tendency towards the vasoconstriction on iris territory, probably via prostaglandin-induced vasoconstrictor tonus (at the level of LPCA), COX1-mediated, the latter being the main functional enzyme in the platelets which couples preferentially, with thromboxane synthase [10]. There might be many risk factors for NSAIDs-associated adverse reactions in diverse populations. Autoimmune diseases, such as and Sjögren’s syndrome, bacterial infections, rheumatoid arthritis, chronic dry eye syndrome and rosacea are common disorders associated with corneal ulcer-formation [11]. On the other hand, the side effects of NSAIDs are preferred over those of opioids, whose sedative and anesthetic effects could interfere with ocular homeostasis. That being considered, the use of topical Metamizole could exclude or diminish the numerous side effects of these two types of drugs and improve the outcome in those particular cases. For example, a comparative study that focused on the preemptive analgesia associated with the oral administration of metamizole versus ibuprofen in patients going through retinal laser photocoagulation stipulated that both medications are equivalent or equinumerous in controlling the pain produced by photocoagulation [3]. Keeping in mind the side effects of Ibuprofen, especially the gastrointestinal adverse reactions and the short period of drug administration, we could say that the first drug of choice should be Metamizole. It is now well established that inflammation plays a pathogenic role in age-related macular degeneration, diabetic retinopathy and diabetic macular edema, but clinical data demonstrating a therapeutic effect of NSAIDs for these diseases is limited and derived mostly from small, retrospective studies [12].According to relatively recent reports, a more severe complication involves the association of topical ophthalmic NSAIDs with indolent corneal ulceration and full-thickness corneal melting , which is excluded in case of topical (ocular) administration.- The greatest concern related to the administration of metamizole is the risk of causing agranulocytosis [- The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders  in humans and in animals.Conflict of interests The authors declare that they have no conflict of interests.


OBJECTIVE: The study compared two populations of patients undergoing bladder neck reconstruction using the silastic sheath in two major pediatric centers. The success with this technique was markedly different in the two centers. The purpose of the study was to determine factors that might explain the divergent results.PATIENTS AND METHODS: Fifteen patients treated in Indianapolis were compared with 94 patients treated in London with the silastic sheath technique of bladder neck reconstruction. Eighty-seven percent of the Indianapolis patients had myelomeningocele whereas 86% of the London group had exstrophy/epispadias. Median age of the Indianapolis patients was 11 years whereas it was 8.4 years in London. Seventy-three percent of patients in Indianapolis were female and 79% in London were male. Patients were followed for a minimum of eight years in Indianapolis and a mean of seven years in London. Similar surgical technique was employed in the two centers but, over time, the London approach included use of a non-reinforced silastic wrapped loosely around the bladder neck with the interposition of omentum. RESULTS: Both groups achieved continence rates exceeding 90%. Of the Indianapolis patients, two-thirds experienced erosion of the silastic at a mean of 48 months. With modifications in the London technique, the erosion rate of silastic was lowered from 100% to 7%. CONCLUSION: Direct, snug wrap of silastic without omentum around the Young-Dees tube as well as simultaneous bladder augmentation placed patients at increased risk for erosion. The silastic sheath technique may be less applicable to myelomeningocele patients. It seems most applicable to older male patients with exstrophy or epispadias undergoing Young-Dees bladder neck reconstruction who have the ability to void.


Giant cell tumor of the bones occurring in the first metacarpals frequently requires entire metacarpal resection due to the aggressive nature and high rate of recurrence. Bone reconstruction can be performed with autogenous bone grafts. Here we describe a new technique of reconstruction using a patient-matched three-dimensional printed titanium first metacarpal prosthesis. This prosthesis has a special design for ligament reconstruction in the proximal and distal portions. Good hand function and aesthetic appearance were maintained at a 24-month follow-up visit. This reconstructive technique can avoid donor-site complications and spare the autogenous bone grafts for revision options.  Giant cell tumor (GCT) of bones or osteoclastoma is a benign locally aggressive tumor. Metacarpals are uncommon sites of occurrence, accounting for 1% to 5.5% of cases . MetacarA 37-year-old female presented to our clinic with progressive painful swelling and restricted movement of the right thumb for a duration of 4 months. Radiographs revealed an expansile osteolytic lesion involving the entire length of the first metacarpal bone . The MRIThe en bloc resection was performed. The first metacarpal and the trapezium were excised, and the defect was temporarily bridged with bone cement. Six months later, a repeat MRI revealed no evidence of tumor recurrence. After a discussion with the patient regarding the reconstructive planning, she disallowed any option of using her autogenous bone grafts. A surgical treatment with patient-specific prosthesis was subsequently offered. A computed tomography scan of the patient's left metacarpal was done and used as a mirror image to create the custom mold by an Electron Beam Melting 3D printing technique. This mold was subsequently used to cast the entire titanium prosthesis. Multiple holes were designed in the proximal and distal portions of the prosthesis for the ligament reconstruction and temporary fixation .Intraoperatively, an incision was made over the dorsal aspect of the thumb metacarpophalangeal (MCP) joint, coursed along the radial insertion of the thenar muscles, curving ulnarly along the distal wrist crease, and extending longitudinally over the flexor carpi radialis (FCR) and palmaris longus (PL) tendon. The superficial branches of the radial nerve and artery were identified and protected. The biomembrane encapsulating the cement spacer was incised longitudinally. Once exposed, the cement spacer was removed and replaced by the titanium prosthesis. The ligament reconstruction was performed . The colPostoperatively, the hand was placed in the thumb spica cast for 4 weeks after which the cast was switched to a thumb spica removable splint for an additional 2 weeks. The K-wire was removed at 12 weeks under local anesthesia. At the latest follow-up, 2 years after surgery, the patient has no pain and there are no signs of tumor recurrence. Five mm shortening of the thumb was observed. The MCP and CMC joints were stable both clinically and radiologically . The patGCT of the first metacarpal bone always presents in the advanced stage, and surgical treatment with an extensive en bloc resection of the entire metacarpal is often required , 9, 10. The prosthesis in the present study had been manufactured to mimic the original first metacarpal bone using 3D printing technology. The prosthesis can be designed to have the same length as the original, and the articular section was anatomically contoured for the line to line contact with the corresponding articular surface. However, a proximal articulating surface was not used due to the loss of the trapezium. The soft tissue reconstruction and tendon interposition were performed to stabilize the CMC joint and maintain the proper length of thumb. The FCR tendon was passed through the proximal sagittal premade tunnel for reconstruction of the deep anterior oblique ligament and dorsal radial capsular ligament which are the key stabilizers of the CMC joint. The EPB tendon was inserted through the proximal posterior oblique tunnel for the posterior ligament reconstruction to create the force couple and maintain the prosthesis in an appropriate alignment. After the surgery, the prosthesis remained stable clinically and radiographically at the final follow-up. Preserving the mobility at the MCP and CMC joints may provide benefit for increasing the thumb range of motion and the ability of grasping and pinching.First metacarpal reconstruction with autogenous bone grafts from the iliac crest, fibula, and radius has been described previously , 6, 12. The advent of 3D printing technology is revolutionizing orthopedic reconstructive surgery , 17. BasIn conclusion, a patient-matched metacarpal titanium prosthesis appears to provide satisfactory functional outcome and aesthetic appearance. This could be a valid alternative for the treatment of the entire first metacarpal bone loss following the en bloc resection. Although the follow-up period is not sufficiently long enough to commit to longevity and retention of function, this reconstructive technique has the benefit of avoiding the donor-site complications and sparing the autogenous bone graft for the revision options.


Botulinum toxin (BTX) is a neurotoxin, and its injection in masticatory muscles induces muscle weakness and paralysis. This paralytic effect of BTX induces growth retardation of the maxillofacial bones, changes in dental eruption and occlusion state, and facial asymmetry. Using masticatory muscle paralysis and its effect via BTX, BTX can be used for the correction of malocclusion after orthognathic surgery and mandible fracture. The paralysis of specific masticatory muscles by BTX injection reduces the tensional force to the mandible and prevents relapse and changes in dental occlusion. BTX injection in the anterior belly of digastric and mylohyoid muscle prevents the open-bite and deep bite of dental occlusion and contributes to mandible stability after orthognathic surgery. The effect of BTX injection in masticatory muscles for maxillofacial bone growth and dental occlusion is reviewed in this article. The clinical application of BTX is also discussed for the correction of dental malocclusion and suppression of post-operative relapse after mandibular surgery. For the correction of malocclusion, the understanding of growth and development is a key component. Broken harmony between the maxilla and the mandible during growth influences dental occlusion . Most diDental occlusion is located in the border between the buccal shelf and the tongue. A patient with a narrow dental arch is treated using the appliance, which shields the action of the buccinator muscles. To prevent tongue thrust habit, an appliance can be used for treating anterior open-bite. In the case of pediatric mandibular prognathism, a chin cap, high-pull headgear, and other types of functional appliances have been used to restrain forward growth of the mandible. However, these efforts have often not achieved their treatment goals because most patients have shown relapse . CompareIf certain treatments can strengthen or weaken the power of specific muscles, they may replace unpleasant long-term usage of orthopedic appliances. Botulinum toxin is produced by bacterium and can weaken the power of specific muscles. If the rationale of the orthopedic appliance treatment is applied, BTX can be a highly effective treatment option for the correction of malocclusion-associated problems. Accordingly, recent knowledge regarding BTX on facial bone growth is reviewed in this article. Additionally, several frontier clinical applications of BTX are discussed.Botulinum toxin-A (BTX) is a family of BTX and is most commonly used in clinical practice . BTX revThe BTX injection in masticatory muscles influences balanced masticatory activity, including food mastication, swallowing, and breathing . The BTXIn this review, we introduced the balanced masticatory muscle function in normal masticatory activity and the role of masticatory muscles in the masticatory system. We investigated the effect of the BTX injection in masticatory muscles on the changes of maxillofacial bone growth, dental eruption, and occlusion. We also suggested the therapeutic application of BTX for the recovery and correction of dental occlusion.The masticatory system is a complex functional unit composed of the maxillofacial bones, masticatory muscles, teeth, tongue, and temporomandibular joint (TMJ) . This syMastication is a highly complex and organized neuromuscular activity involved with bone, muscles, teeth, and surrounding structure . This acMastication is rhythmic and repetitive chewing action and the beginning of digestion . The musNormal mastication activity and masticatory muscle function can influence the maxillofacial bone morphology . MandiblBalanced masticatory muscle function is closely related with maxillofacial bone growth and development ,35. ImpaBTX injection in masseter muscles decreases muscle activity and affects the maxillofacial bone growth in animal studies ,45. MassMasticatory muscle function has an important role in maintaining the bone density and quality of skeleton . DecreasBTX injection into the masticatory muscle may influence the growth of the mandibular condyle . BTX injIn animal research, trabecular bone density and condyle thickness are significantly reduced by the BTX injection into the masseter muscle , and theThe detailed mechanism for the change of the condylar cartilage has been unclear. BTX injection of the masticatory muscle influences the temporomandibular joint via altering masticatory loading and causes structural and cellular changes in the condylar cartilage . The groMasticatory muscle hypofunction caused by BTX injection decreases the bite force and affects the dental occlusion and tooth eruption ,20. The The application of BTX on the perioral area has been performed for cosmetic purposes or for the treatment of temporomandibular disorder . RecentlConsidering that post-operative relapse after orthognathic surgery is induced by the muscular tension, the strategy for reducing muscular tension can be an effective treatment option. In this aspect, BTX injection can be a solution for the postoperative relapse. Though the literature on this issue is scarce, there are several articles on the correction of open-bite after the treatment of trauma. The open-bite can be frequently found in bilateral mandibular angle fractures and the chin is depressed by the contracture of the digastric muscles . Most paIn the case of malocclusion patients, the anterior open bite has been frequently observed, and this protocol can be applied for these patients. The treatment of the open bite has been challenging because it has multiple etiological factors . The ope“Deep bite” is the opposite of open-bite. The status of malocclusion has been frequently found in mandibular retrognathism . For then = 7) received BTX-A injection into their masseter muscles along with two weeks of intermaxillary fixation. This group was compared to the patients (n = 11) who did not receive BTX treatment and the same period of intermaxillary fixation. The incidence of plate fractures was 14.3% in the BTX-injected group and 31.8% in the untreated control group (In the course of orthognathic surgery, patients usually prefer the intra-oral approach to the trans-buccal approach. However, compared to bi-cortical screws fixation, single plate fixation is less rigid fixation . Patientol group . As the The application of BTX in pediatric patients has been rare. In the progress of growth, the size of muscle fibers increases . In expeBTX injection into perioral muscle has been considered a relatively safe treatment. Except for periocular injection, complications related to BTX injection have been rarely reported. Recently, a case of temporary blindness has been reported after BTX injection into the masseter muscle . The bliBalanced masticatory muscle function is a key component of maxillofacial bone growth and development. The dysfunction of masticatory muscle influences the retardation of facial bone growth and disruption of dental occlusion. The BTX injection to the masticatory muscle induces reversible paralysis and weakness of muscle power. The injection of BTX in masticatory muscle disrupts the balanced function of mastication and can influence maxillofacial bone growth and dental occlusion when administered during the growth phase. The weakness of masticatory muscle activity by BTX induces the hypoplasia of maxillofacial bone in the zygoma, temporal bone, mandible, and condyle area, and the alteration of the tooth occlusion state.Clinically, the paralysis of masticatory muscle by BTX has an effect on maintaining mandible stability and preventing changes in dental occlusion after orthognathic and mandible fracture surgery. BTX injection in digastric muscle reduces the tensional force of mandible and prevents the counterclockwise rotation of mandible and open-bite of teeth. The BTX injection in mylohyoid muscle also prevents the deep bite of teeth and postoperative relapse after orthognathic surgery. Compared with a surgery-only patient, the patient in our clinic who received BTX in both masseter muscles after orthognathic surgery showed more stable dental occlusion. The BTX injection is an effective method for the correction of dental occlusion by inducing specific masticatory muscle paralysis without major complications. In an animal growth study, the injection of BTX in masticatory muscle has an effect on the growth potential of the maxillofacial bones. Additionally, this treatment could be an effective tool for the correction of facial bone and dental occlusion in the pediatric patient. Further study will be necessary for the therapeutic use of BTX in orthopedic treatment to correct abnormal jaw bone growth and malocclusion.