Objective: There are evidence-based practices in the field of family and patient psychoeducation for patients suffering from severe mental disorders. However, given the variation in resources and cultural contexts, implementation of these services, especially in low and middle-income countries is faced with challenges.This study aimed to review articles on family and patient psychoeducation of severe mental disorders in Iran and to find the characteristics of the main components necessary for the implementation of such practices in clinical settings.Method: All published studies on family and patient psychoeducation for severe mental disorders  conducted in Iran were searched up to May 2018; and key features and findings of each study were extracted and presented.Results: Forty-eight studies were included in this review, of which 27 were randomized controlled trials, and 20 were quasi-experimental. One study was an implementation and service development report. The main findings of these studies were a significant decrease in relapse rate and/or rehospitalization rate and a significant decrease of burden and distress of families.Conclusion: Despite a wide diversity in approaches, this review showed that different psychosocial interventions in which psychoeducation is one of their core and main components have promising results, demonstrating the significance of this intervention in Iranian mental health research. In our opinion, based on evidence, even with limited resources, it is no longer acceptable to deprioritize some forms of psychoeducation for patients and their families in clinical settings. There are evidence-based practices in the field of family and patient psychoeducation for patients suffering from severe mental disorder (SMD). Clinical trials and systematic reviews have demonstrated that psychoeducation significantly reduces relapse and rehospitalization rates in patients with SMD as well as burden and stress level of caregivers , 2, 3. HThe main issues to be considered in the implementation of psychoeducation in routine clinical practices are staff skills, training, and follow-up supervision, applicability of the intervention to the service users, economic costs, and mental health team’s values and preferences , 6. FurtLimited qualitative studies conducted in this area in Iran revealed that families of patients struggle with the lack of information on illnesses and how to deal with different issues related to them, while stigma is still a major concern for them , 9. In aBipolar disorder occurs in 1% to 3.7% and schizophrenia in 1% of the general population , 12. TheFor the past two decades, several studies have been conducted in the realm of patient and family psychoeducation in Iran. Finding information on different aspects of participants and programs, including level of education, type of intervention, and study design, can provide a framework for the implementation of such programs in routine clinical settings in LMICs.This article aimed to review studies on family and patient psychoeducation of SMD in Iran and to find the characteristics of the main components necessary for the implementation of such practices in clinical settings. Demographic data of participants and different aspects of intervention used in psychoeducational research can highlight the need for future research and can also be used as a roadmap for mental health services.All published studies on family and patient psychoeducation for SMD  conducted in Iran were searched up to May 2018. The electronic search was performed using PubMed, Scopus, Magiran, SID, PsychInfo, and Google Scholar. The following keywords in English and Farsi were used: psychoeducational family/patient intervention, family/patient psychoeducation, family/patient interventions, family/patient education and caregivers’ education/psychoeducation, combined with severe mental disorder/illness, schizophrenia, and schizoaffective bipolar disorder. The included papers were written in Farsi and English. Further, cross-reference searching for the purpose of obtaining more relevant studies was conducted. All studies on patient or family psychoeducation in SMD in Iran were included for this review. However, studies that developed a guideline were excluded. Both authors reviewed relevant studies and extracted data. Any disagreement was resolved by discussion. Where possible, authors of original papers were contacted for additional data. This review should not be considered as a systematic review, but rather as a review and description of key variables of studies supporting the implementation of psychoeducation for families and patients in routine clinical practice. Key features and findings of each study were extracted and presented in two tables. Data extracted on study characteristics included city of study, sample size, diagnosis, patients’ gender, relationship of family members to patient, family members’ education level, length and number of sessions, use of structured manual, attrition rate, type of intervention, personnel delivering intervention, study design, outcome measures, and main findings (family/patient). To collect information on different aspects of psychoeducational intervention from each paper, the following categorizations were employed to extract data on each variable:When different sections of a research were published in more than one paper, they were grouped together under 1 study with different dates/references. Sample size included the number of patients and/or family members participating in studies. The size of different arms of study were also reported if indicated in the paper. Patients’ gender was reported by percentage or number, the same as the original paper. Classification of the level of education in family members differed in studies and was presented by percentage or the majority of cases. Length of psychoeducational sessions showed the duration of psychoeducational intervention. Length of each session and number of psychoeducational sessions were also reported. Reporting of the use of structured manual variable was fitted into different categories. If the psychoeducational intervention was administered according to a manual, the manual reference was mentioned. If the content of the intervention was described based on each session, then “content of sessions described” was mentioned. Otherwise “information not given” was used. When pamphlets or other written materials were reported for psychoeducation, the phrase of “written information is given” was used.Given the wide diversity in reporting the attrition rate, it was stated the same as the original paper. Attrition rate included pre- and post-analysis dropout rates, response rate, and retention rate.With regards to type of intervention, all interventions other than “treatment as usual” (TAU) were listed. TAU usually comprised pharmacological treatment and inactive follow- up visits. Different interventions, including home visit/home care, social skills training, multiple family group” (MFG) psychoeducation, patient group psychoeducation, psychosocial rehabilitation, individual psychoeducation, telephone follow-up (TFU) and discharge planning, were reported. Whenever personnel delivering interventions based on different psychoeducational programs were mentioned in an article, they were included in this paper.Outcome measures used in each research as well as the main results of different interventions for patients and family members were reviewed. Main results were reported only where there were significant differences in outcome measures.A total of 48 studies were included in this review. The results were presented in two tables. The study design in 27 of the studies was randomized controlled trial (RCT) and it was quasi-experimental in 20. One study was an implementation and service development report . The intThe first study was published in 1995. Twenty-one studies took place in Tehran, 23 in the capital cities of provinces, two in towns , 69, andSample sizes ranged from 15 to 270 in the included studies. Diagnosis of participants was SMD in 13 studies , 68, 76,Fourteen studies included no information on patients’ gender , 78, 79 The participating family members were mostly parents, specifically mothers, followed by spouses and siblings. Family members’ education level is displayed in The length of each psychoeducation session varied from 45 minutes to four hours, but generally, it lasted between 90 to 120 minutes. The number of sessions varied from 1 to 14 sessions, and the maximum length of intervention was 12 months , 50, 64.Eleven studies used a structured manual for psychoeducation , 76, 79,Five studies focused on patient psychoeducation and did not provide family psychoeducation , 72, 79.One study reported service development , therefoThis is the first review of patient and family psychoeducation for patients suffering from SMD in Iran. Despite wide diversity in approaches, this review shows that different psychosocial interventions, with psychoeducation as one of their core and main component, have promising results, demonstrating the significance of this intervention in Iran’s mental health research.In 47% of the included studies, the diagnosis of patients was schizophrenia, however, the prevalence and number of beds in main psychiatric wards do not reflect the same statistics. Historically, family and patient psychoeducation first began with providing education to patients and families of patients suffering from schizophrenia. With a limited number of studies on patients suffering from bipolar disorder and first episode psychosis, there is a need to develop more specific psychoeducation interventions for these groups of families and their patients. The content of psychoeducation sessions in Iran was similar to programs in other parts of the world , 3, 11. MFG psychoeducation was presented without the presence of the patient. Cultural context plays a role in this format as families do not speak freely in front of the patients. Patients live with their families in Iran and families are the main caregivers, which is similar to other LMICs . With thThe prevalence of SMD is approximately the same for men and women. However, most participants in psychoeducation were male patients (27 studies out of 34 included studies that reported gender). Although the inpatient bed distribution is about 60% male to 40% female in psychiatric hospitals in Iran , research participants’ gender distribution still reflects a larger gap. Therefore, an investigation into the reasons why female patients’ participation rates are lower is important. For example, does stigma play a part in the gender participation rate ? Or, whyStudies were conducted at the capital cities of different provinces in Iran (12 provinces out of 31 provinces in Iran), and the majority were conducted in Tehran, the capital city of Iran. Some important questions are how many of the centers provide these services as a routine clinical practice? And how sustainable are psychoeducation programs? The specialty of those who delivered the services varied. In all studies, the intervention was delivered by professionals, except in 1 study in which family members delivered aftercare services, including psychoeducation . KeepingDuration of psychoeducation in studies reviewed in this article ranged from 1 session to 14. In a number of studies in which aftercare/home visits were provided, the education provided to patients and families was mentioned. However, the format and duration of each session were not reported, which makes it difficult to reach any conclusions. To be able to continue to support and help patients and their families for a longer time, booster sessions and self-help groups are recommended within planning psychoeducation programs for families and patients in community settings. The list of outcome measures shows a number of questionnaires that were used in different studies, which have been translated and validated for use in Farsi. A set of the same questionnaires for patients as well as their families exist, which were administered in the studies and can be useful for future research in this area. The main significant results are listed in Attrition rate is an important factor in planning the implementation of a program in clinical settings. Social and cultural issues can play a major role in the number of dropouts. Studies that were reviewed here reported attrition rates based on different definitions. Therefore, it is difficult to make a summary of the data. On the other hand, for each study that reported attrition rates, the number lied within an acceptable range compared to other research in this field. Research shows that culturally adapted interventions were more efficacious than the usual treatment in proportion to the degree of adaptation .Psychoeducation is offered in different formats and packages in community settings. Given the mixed method and the use of other interventions beside the psychoeducation, which were employed by the majority of studies included in this paper, it is difficult to make a generalized inference of the results. Also, we cannot infer that the outcomes are attributed to psychoeducation per se. However, significant results are promising with regards to a number of important variables that were measured as outcomes for included studies. Some of these include a low rate of relapse and rehospitalization for patients (in 16 studies) as well as the decrease of the level of burden and distress of caregivers (in 18 studies). Another important issue to consider regarding the implementation of a psychoeducation program is the cost-effectiveness of such interventions. Three studies conducted in this area showed a lower cost in intervention groups , 64, 61.The strength of this study is reviewing all interventions with psychoeducation as part of the package offered to patients and their families. Capturing all the core elements of psychoeducation intervention for patients suffering from SMD and their families is another strength of this study, which is useful in planning services. One limitation of this review is the lack of reported information on a number of variables, such as the educational level of caregivers, the relationship of caregivers to patients, the number of people who conducted the psychoeducational sessions and their professional capacity in several of the included studies. These variables are important in planning socially and culturally adaptable psychoeducation programs with limited resources. Another limitation is that the review did not include the research results of unpublished theses and dissertations topics in this area.ImplicationsThe main purpose of this review was to gather information on studies conducted in Iran to provide a roadmap for the implementation of psychoeducational programs for patients suffering from SMD and their families. This information can be used as an example for other LMICs.Our review has a promising capacity in the area of patient and family psychoeducation in Iran. However, the main issue is still the implementation of such programs. Few pilot studies conducted in the newly developed community mental health centers in Iran show promising trends for the future . HoweverOne of the barriers to feasibility in LMICs is the educational level of participants in psychoeducational intervention . In studBrief psychoeducational interventions in which patients and family members are provided with support and information about medication, the illness, and management strategies improve compliance, decrease relapse, and decrease readmission rates. This outcome is consistent in a number of studies included in the review as well as in other references .To overcome difficulties in the implementation of psychoeducation interventions considering the limited resources, the incorporation of a level approach can be one useful way to involve patients and families. Initial contact, assessment, and general education built on the patient and families’ acceptability of services and the engagement process can decrease attrition rates . DischarThere is a lack of information regarding training and supervision of mental health professionals while conducting psychoeducational sessions in most of the included studies. One study focused on service development with detailed information on training and supervision . UnfortuTranslating research findings into “real world” settings and improving the context of interventions plays a central role in the implementation process. To promote large-scale use and sustainability of an intervention, factors that describe various aspects of how the implementation of a program occurs and which important strategies facilitate the delivery are essential . UnfortuBased on studies included in this review, the majority of participants were male and the majority of the caregivers were female. Also, based on the results, low educational level should be considered in planning educational programs. Further, it was found that different methods of psychoeducation and mixed interventions are being used to provide psychoeducation to patients and their families. A number of possible contents are available in Farsi for psychoeducational sessions. In more than 40 studies, different mental health professionals were involved who could actively participate in capacity building and implementing psychoeducational intervention into routine practice in their workplace.This review included all studies that mentioned psychoeducation as part of their intervention. Although there are differences in the format and structure of education offered to families and their patients, the common factors of psychoeducation intervention provide a broad framework for future research as well as planning psychoeducation in community settings. To plan the implementation of family and patient psychoeducation, this review provides a basic structure including information extracted from studies on caregivers, interventions, manuals, and mental health personnel. This article has reviewed studies with a focus on the context and factors affecting implementation, such as the educational level of consumers and their families or the relationship of the main caregiver, which is important for the future planning of psychoeducational programs. Pragmatic and qualitative evaluations of appropriately adopted interventions that focus on feasibility and acceptance are necessary, given the promising outcome of studies published in Iran and other countries. Using information to guide the decision-making process for the service delivery of psychoeducation intervention for patients and their families is a priority for mental health services. In our opinion, based on evidence, even with limited resources, it is no longer acceptable to deprioritize some forms of psychoeducation for patients and their families in clinical settings. Future research with a focus on the implementation process and service development is much needed to facilitate the availability of psychoeducation to all patients suffering from SMD and their families in mental health settings in Iran.


The laws to secure intellectual property rights on plant germplasm have been strongly developed in parallel to the ongoing seed market consolidation. Germplasm as a commons, i.e., a natural resource accessible to all members of a society, receives almost no legal protection. On the other hand, the use of germplasm and released cultivars in breeding is increasingly restricted by intellectual property rights. In this study, approaches to open source plant germplasm are discussed, and the Open Source Seed (OSS) Licence is introduced and analysed. The OSS Licence was developed by an interdisciplinary working group of plant breeders, agricultural scientists, lawyers, and commons experts in Europe. The aim is to protect germplasm as a commons, support the free exchange of germplasm, stimulate plant breeding, reduce costs, and accelerate innovation. The OSS Licence is a legal tool and novel approach that extends its reach on derivatives of licenced germplasm. It is compatible with current seed laws. Effects on the access to plant germplasm, on breeding for diverse pedoclimatic environments, socioeconomic systems, and on biodiversity as a whole can first show after a few breeding cycles. The impact of open source germplasm on these aspects needs to be monitored carefully. This Community Page article presents the Open-Source Seed Licence, developed by an interdisciplinary working group of plant breeders, agricultural scientists, lawyers and commons experts in Europe. The aim is to protect germplasm as a commons, support the free exchange of germplasm, stimulate plant breeding, reduce costs and accelerate innovation. For millennia, crop seed has been a common good , and allThe loss of agrobiodiversity is critical. Plant genetic diversity is essential for food security as a means of adaptation to variable weather conditions, as it enhances social and ecological resilience against extreme events ,16,17. AWhile public sector plant breeding has undergone a steady decline in Europe , new staAlthough the International Treaty on Plant Genetic Resources for Food and Agriculture  recognizAs a new tool, the Open Source Seed Licence for plant germplasm  was developed by an interdisciplinary working group of the nongovernmental organization (NGO) Association for AgriCulture and Ecology (Agrecol). The primary target area is Europe. We will describe and discuss i) approaches to create open source plant germplasm, ii) the Open Source Seed Licence and the steps needed for its implementation, iii) the analysis of existing seed laws for potential conflicts with open source plant germplasm, and iv) potential effects of the Open Source Seed Licence on breeding for diverse pedoclimatic and social environments and on access to plant germplasm.The term “open source” is derived from computer science, for which it refers to free access to computer source codes. The open source concept is a development of the free software principles first articulated in the GNU General Public Licence  by RichaThe Open Source Seed Initiative (OSSI) was founded 2012 in the US by a group of academic and nonacademic plant breeders, farmers, nonprofit agencies, seed advocates, and policymakers as the first organization for the development of open source seeds . InspireThe Dutch NGO Hivos started the “Open Source Seed Systems Programme” . It invoThe Apna Beej Network in India also practices an “Open Source Seed System”. It works with a “material and knowledge transfer agreement” that allows members of the network to use their plant germplasm freely within the network .The German NGO Agrecol started work on open source plant germplasm systems in 2012 . An inteThe OSS Licence grants users many freedoms and demands little: the licensee is obliged to grant the same rights he or she has enjoyed to future owners of the plant germplasm. This obligation is “viral” and includes all derivatives of the germplasm. With the first licensing, a chain of contracts is started, which, in principle, is endless. Licensees become licensors, who pass on the germplasm with the same licence.Legally, the OSS Licence is a “sui generis contract” and falls under the General Business Terms and Conditions of German Civil Law , a prewrTo transfer germplasm under the OSS Licence, the licence conditions must, unambiguously, be disclosed. This means that any transfer is valid if the licensee is able to become aware of the terms and conditions of the licence. For traders, this means that an abridged version of the OSS Licence must be printed on the wrapping of small bags with reference to the online full-text version. For larger quantities, the licensors must ensure that a copy of the licence accompanies the material being transferred, and they must explicitly inform the recipient (the licensee). Licence infringements can be examined through a combination of measures. The most important one is to analyze the breeding process that the new cultivar has undergone. According to the Nagoya Protocol , a detaiThe OSS Licence was implemented on April 26, 2017, when Agrecol launched the service provider OpenSourceSeeds  and presOpenSourceSeeds started with two cultivars, a vegetable and a field crop. The tomato Sunviva was bred by the network of the Organic Outdoor Tomato Project launched in 2003 by the University of Göttingen. The project is based on participation and the free exchange of tomato genotypes and related knowledge . The proThe laws on securing intellectual property rights on plant germplasm have been strongly developed, whereas plant germplasm as a commons receives almost no legal protection. Thus, the possibility to license new cultivars as open source is new and unfamiliar. The release of the first OSS-licensed cultivars will stimulate further discussions and generate valuable experiences on the feasibility, acceptance, and impact of open source germplasm among plant breeders, seed producers, growers, plant genetic resources experts, and society as a whole.Being a legal tool, the question may arise whether the OSS Licence is in conflict with existing seed laws on seed marketing and plant variety protection. In the EU, national laws like the German Seed Marketing Act are based on EU regulations. The German Seed Marketing Act regulates the release of most agricultural and horticultural crops. The act is not in conflict with OSS licensing, but germplasm of the relevant crops can only be legally released when the cultivars are registered in the Plant Variety Database of the European Commission. The European Plant Variety Protection Act is not in conflict with open source germplasm because it only applies for cultivars under plant variety protection.Another issue to be addressed is the funding of a future plant breeding that needs to supply cultivars adapted to very diverse pedoclimatic conditions as a service for society. Financing models are to be further developed that are not based on royalties on intellectual property rights. In many developing countries, plant breeding does not follow a business model based on royalties, and even in industrial countries, there are private breeding companies that do not rely on intellectual property rights. Presently, many organic plant breeders in Europe finance their breeding work partly through “cultivar development contributions” that are negotiated between breeders, seed producers, and farmers. Some have, in cooperation with the food trade, developed a levy on food items, and most of them raise funds from government programs and foundations . The funIncentives for the application of the OSS Licence may be manifold. At present and after the first year of introduction, a significant demand from consumers can be observed. Interviews indicate that the public appreciates the possibility to contribute to an alternative to the dominant system of privatization and market concentration in the seed sector. Exemplarily, this can be observed with the OSS-licensed tomato cultivar Sunviva. Due to the growing demand in horticulture, more and more traders are offering Sunviva seed and its seedlings. Consumers could, therefore, create a significant pull effect. Other incentives may be identified in the following years. We expect that the increasing shortage of freely available breeding material will create a strong incentive for small and medium plant breeders to license their new cultivars open source and to contribute to a commons-based pool of plant germplasm.Expected impacts of the licence will have to be assessed in the following areas. Open source systems aim to allow plant breeders to operate and cooperate freely . It is aWe expect insights into the acceptance of the OSS Licence in the next few years because breeders and researchers can decide immediately how they release new genotypes. Monitoring the effects of licensing open source plant germplasm on other areas of major importance, however, will last much longer. Effects on the access of various stakeholders to plant germplasm, on breeding programs for diverse pedoclimatic and social environments and on biodiversity as a whole can first show after a few breeding cycles. A network meeting to evaluate first experiences with the OSS Licence will take place in 2019. We expect specific effects for different crop types , types of cultivars , and breeding systems . The impact of open source germplasm on the areas discussed above will have to be monitored carefully.


Poor intra-facility maternity care is a major contributor to maternal mortality in low- and middle-income countries. Close to 830 women die each day due to preventable maternal complications, partly due to the increasing number of women giving birth in health facilities that are not adequately resourced to manage growing patient populations. Barriers to adequate care during the ‘last mile’ of healthcare delivery are attributable to deficiencies at multiple levels: education, staff, medication, facilities, and delays in receiving care. Moreover, the scope and multi-scale interdependence of these factors make individual contributions of each challenging to analyze, particularly in settings where basic data registration is often lacking. To address this need, we have designed and implemented a novel systems-level and dynamic mathematical model that simulates the impact of hospital resource allocations on maternal mortality rates at Mnazi Mmoja Hospital (MMH), a referral hospital in Zanzibar, Tanzania. The purpose of this model is to provide a rigorous and flexible tool that enables hospital administrators and public health officials to quantitatively analyze the impact of resource constraints on patient outcomes within the maternity ward, and prioritize key areas for further human or capital investment. Currently, no such tool exists to assist administrators and policy makers with effective resource allocation and planning. This paper describes the structure and construct of the model, provides validation of the assumptions made with anonymized patient data and discusses the predictive capacity of our model. Application of the model to specific resource allocations, maternal treatment plans, and hospital loads at MMH indicates through quantitative results that medicine stocking schedules and staff allocations are key areas that can be addressed to reduce mortality by up to 5-fold. With data-driven evidence provided by the model, hospital staff, administration, and the local ministries of health can enact policy changes and implement targeted interventions to improve maternal health outcomes at MMH. While our model is able to determine specific gaps in resources and health care delivery specifically at MMH, the model should be viewed as an additional tool that may be used by other facilities seeking to analyze and improve maternal health outcomes in resource constrained environments. Every day, close to 830 women die of preventable maternal complications. Nearly all of these maternal deaths occur in developing countries, the majority of which occur specifically in sub-Saharan Africa –3. One iTo assess the burden of poor maternal health, the WHO has created the Maternal Severity Index (MSI), which indicates the probability of death amongst all severe maternal outcomes, and the Workforce Indicators of Staffing Need (WISN), which calculates the number of new health workers needed to meet the demand , 8. BothTo demonstrate its utility for a real maternal health facility, we have developed the model to reflect the structure and processes of the maternity ward at Mnazi Mmoja Hospital (MMH) in Zanzibar. MMH is the only public referral hospital in Zanzibar, a semi-autonomous archipelago of Tanzania. It receives referrals from other health centers to treat high-risk patients, but many patients without complications also self-refer to the hospital. As such, it serves a large portion of Zanzibar’s entire 1.3 million people population. The maternity ward in MMH is burdened with approximately 12,000 deliveries per year and limited numbers of skilled health workers and supplies . PreviouOur mathematical model incorporates these factors to analyze resource use and maternal mortality for a population reflecting that found at MMH. The purpose of this model is to provide a tool that enables hospital administrators and public health officials to generate quantitative data on how patient outcomes are impacted by resource allocation and availability within the maternity ward to help them optimize resource use. This model will be able to determine specific gaps in resources and health care delivery, and this information may be used for targeted and specific interventions to improve maternal health outcomes. With such targeted interventions backed by evidence from the model, hospital staff, administration, and the Ministry of Health can work collaboratively to enact policy and operational changes to improve maternal health outcomes.De-identified patient data spanning approximately six months was collected from medical records at Mnazi Mmoja Hospital. This research was approved by ZAMREC, the research authority in Zanzibar, Tanzania on July 18 2017; Protocol No. ZAMREC/0001/JUN/17. A stepwise, iterative, object-oriented program was developed to simulate the workflow and patient treatment process at the maternity ward at MMH. In order to ensure the algorithm accurately reflects a patient’s stay at the hospital and the resources used in treatment, it was developed in close collaboration with doctors, nurses, and clinical researchers at MMH. The model allows users to define resource allocations, patient load and incoming morbidity distributions over various shifts, as well as specific treatment plans based on patient status. A full list of key variables, classifications, and measures used throughout the model are summarized in In order to construct the model, patient records from the MMH maternity ward between July 2016 and September 2016 were anonymized and digitized to create a database of 343 patients with potentially life-threatening complications and 2,285 patients with uncomplicated deliveries. Potentially life-threatening complications included preeclampsia, eclampsia, antepartum hemorrhage, postpartum hemorrhage, rupture of the uterus, sepsis or systemic infection, cardiomyopathy, and anemia with a hemoglobin level below 7 g/dL. In addition to patient records, information on staffing levels over ten days at the hospital, staff scheduling, and ward inventory data detailing the stocks of all medications supplied to the ward was collected. Data on case fatality rates and causes of death were used from a previous clinical study at MMH’s maternity ward [To appropriately scope the model, only five complications—postpartum hemorrhage, preeclampsia, eclampsia, rupture of the uterus, and sepsis—were considered as discussed in the inclusion criteria set of the World Health Organization’s near-miss criteria –21. The The foundation of the model is an iterative simulation that accounts for the stochastic nature and nonlinear impacts of hospital admissions and condition severities, tracking both staff resources and medicines stocks in the process. Each iteration or cycle of the model represents fifteen minutes at the hospital maternity ward—the shortest duration necessary for a single intervention outlined in clinician treatment plans for each complication. Each cycle consists of four key steps:Admission of a new patientAllocation of resources to patientsEvaluation of patient health and resource redistribution to hospitalRestocking hospital resourcesBeginning each cycle, the model simulates the intake of new patients to the existing cohort based on a probability of admission that varies from morning, afternoon, to evening . These npc, is calculated under the simplification that each condition contributes independently to the patient’s health. For a patient exhibiting two simultaneous conditions with probabilities of mortality of p1 and p2, the probability of survival for each condition is (1-p1) and (1-p2), respectively. The total probability of survival is then (1-p1)(1-p2), making the total probability of mortality, pc, 1 –(1-p1)(1-p2).This composite probability of mortality is then utilized in the next section of the model to prioritize resource allocations to each patient.Once a set of probability of mortalities for an incoming patient has been randomly selected from severity distributions for each of the patient’s complication, a composite probability of mortality for the patient, Once new patients have been added to the cohort, the model determines the resources required by the cohort based on the assignment of treatment plans for each patient’s condition(s) . These tall medication and staff resources required by the treatment plan are available. If a single human or material resource is missing from the standard treatment plan, the patient will not be treated. Furthermore, doctors and nurses that are specified for consecutive treatment cycles in a particular treatment plan will stay with the patient and will not be returned to hospital staff resource pool until their visitation is complete.With a treatment plan and associated resources determined for each patient, the model begins treating patients in descending order of composite probability of mortality, with the patients with the highest probability of mortality being treated first; this is consistent with the standard protocol at MMH. Each patient is treated only if p, for each of her conditions decreases with each cycle based on the efficacy of her treatment plan, η. For each cycle that she is treated, the patient’s probability of mortality is calculated as p = pi(1—η), where pi is the probability of mortality at the start of the cycle and p is the new probability of mortality after treatment that cycle. Over successive cycles of treatment, this approach leads to a geometric decay of the probability of mortality with the form p(c) = pirc, where pi is the probability of mortality at c = 0, c is the number of successive cycles of treatment, and r is the rate constant and is related to the treatment efficacy by r = 1—η. The treatment efficacy for each treatment plan was calibrated by ensuring that with complete and timely treatment, a patient’s mean probability of mortality for each complication would decrease to zero by the end of a hospital stay .As the patient progresses through treatment, the probability of mortality, pi is probability of mortality for the condition at the beginning of the cycle, λ is the deterioration rate, and c is the number of consecutive cycles that the patient has not received treatment. Over successive cycles without treatment, this leads to a sigmoidal increase in the probability of mortality on the open interval of , with the form pi is the probability of mortality for the condition for the first cycle that treatment is not provided, c remains the number of successive cycles treatment is not provided and Γ is the mathematical gamma function. Deterioration rates for each condition were initially estimated qualitatively from patient records based on the mean length of time required for a complication to become fatal, after which they were adjusted to reflect expected mortality outcomes for each complication as observed in the patient files collected from MMH.In the case that enough resources are not available to carry out the treatment plan for a given cycle, treatment is not omitted that cycle, causing the probability of mortality for each complication to worsen according to pc, is considered their chance of death over the full length of their remaining hospital stay, a scaled probability of mortality, p, is used to reflect their chance of death within only the current cycle. This scaled probability of mortality is calculated based on a binomial distribution, where the composite probability of mortality is the cumulative probability of dying at any cycle and is given by n is the number of remaining cycles in the patient’s intended hospital stay. To solve for p, we may instead consider the probability of surviving, ps, where pc = 1 − ps, and by the binomial distribution in the case of k = 0 over n cycles, ps = (1 − p)n. Hence, we find that p is related to pc by In the third stage, the model iterates through the patient cohort and stochastically determines which patients survive based on the selection of a uniform random variate for each patient . If the The last phase of the cycle accounts for the hospital restocking its inventory, updates to on-duty staff based on shift changes, and for changing patterns of patient admission at different times of day  . If the In order to store the multi-dimensional data generated by the model in a flexible and organized format, the model outputs were stored in a JavaScript Object Notation (JSON) file. A user interface for plotting data and exporting the data to other file formats was developed in Java to enable efficient parsing of the JSON file and identification of trends of interest. The number of maternal deaths outputted by the model for each test case was obtained from 50 trials to capture the impact of stochastic variations.The model was calibrated by inputting current medication inventories  and not resupplied during the quarter to inspect the relative impact of the two medications on maternal mortality. Conversely, when varying hydralazine stocks, the initial oxytocin stock was set to 200 packs  and was not resupplied during the quarter. In all cases, the model was run with the staffing distribution and patient admission rates detailed in For oxytocin, our model shows that monthly restocking results in the greatest improvement on the number of maternal deaths over 3 months . It alsoTesting for hydralazine shows a similar trend in the necessity for restocking if smaller shipments are supplied, with the number of maternal deaths increasing over four-fold when 10 packs of hydralazine are not replenished over three months . The absAdequate monitoring of patients and timely interventions in the case of complications are crucial to preventing maternal deaths, and as such sufficient staffing of the maternity ward plays a key role in decreasing maternal mortality. Surveys of staff scheduling revealed that there are typically five nurses and three doctors on staff at the maternity ward, while at night there are on average two nurses and one doctor. However, additional reports from staff describe extremely limited staff availability—with only one nurse staffing the ward at times or no doctors available in the ward. Given this, we chose to examine the effects of staff capacity on maternal mortality and determine minimum staffing requirements necessary to minimize maternal deaths, keeping in mind the different rates of patient admission during the morning, evening, and night.The number of nurses and doctors available to staff the ward was varied between 0 and 10 and simulations were run over a 3-month period to determine the impact on maternal deaths. To explore the effects of different staffing schedules on maternal mortality, we varied the number of staff available on each shift from the existing distribution detailed in As the main referral hospital in Zanzibar, MMH receives a range of patients from self-referrals to patients who are referred from other health facilities. The spectrum of severity ranges from relatively uncomplicated and non-severe cases that ideally would seek care in the secondary or primary health care facilities, to severely complicated cases for which MMH is the designated hospital. The large influx of patients exacerbates delays in receiving care, stock-outs of medical supplies and shortages of staff. We examined the effects of decreasing the rate of patient influx to the maternity ward from 0.4 patients per 15 minutes to assess how this affects mortality outcomes for patients with potentially-life threatening complications. Conversely, the effects of a higher patient influx to MMH’s maternity ward were examined to determine if the ward could respond to higher patient volumes in the future without compromising health outcomes. Currently, approximately 50% of pregnant women in Zanzibar deliver in health facilities . With puSimulations indicate that a patient admission rate that is half of the current patient admission rates in the morning, evening and night, contributes to a decrease in mortality rate for patients with potentially life-threatening complications from 5.53% to 1.60% . IncreasThe health systems model described here was created for use in the Mnazi Mmoja Hospital maternity ward in Zanzibar, Tanzania. Yet, it provides a template for health systems modeling at other facilities, providing policymakers and hospital administrators with a tool to identify gaps and inefficiencies in maternal care that can be addressed in order to improve maternal mortality. The model has identified the following factors as contributors to a reduction in maternal mortality in this setting: (1) more frequent, monthly shipments of oxytocin and hydralazine to health facilities as opposed to larger, quarterly shipments, (2) an increase in the number of nurses working per shift, assuming the critical number of 3 doctors per shift has been met, and (3) a reduction of patient admissions by directing low-risk cases to deliver at primary and secondary healthcare facilities outside of MMH.While the model accounts for the staff capacity, medication inventory, treatment plans, and triaging of patients for six noted conditions, collection of additional clinical data likely will extend the utility of the model by accounting for the use of the intensive care unit, blood products, non-pharmaceutical consumables, surgical tools, and medical equipment. The model does not account for patients procuring their own medication and consumables for use in the event of stock outs (though this occurs at MMH), and operates under the ideal case of all medication being procured from Zanzibar’s Central Medical Store and purchased using funds from the government or aid agencies. Temporal changes in staff capacity and physical separation of antenatal wards, labor rooms, and postnatal wards were not included in this iteration of the model. Building on this framework to include these factors could extend the model for further use as a tool to optimize logistics and operations in the maternity department.Age and obstetric history of the simulated patients do not affect their initial probability of mortality in this iteration of the model, as further data must be collected to assess the relationships between age, prior complications in pregnancy, and mortality in order to be incorporated in the model. Accuracy of diagnosis was not incorporated into this version of the model, as it is assumed that if a patient has a complication that is what they are diagnosed with and treated for. Patients in the model can only have one of the five complications, if any, and cannot develop new complications as they progress through the simulation. Additionally, because there is insufficient data on how to weigh the impact of each resource prescribed by the treatment, all resources necessary for treatment must be available in the simulated ward inventory and staff pool for a patient in the model to be treated.Cesarean sections, hysterectomies, laparotomies, salpingectomies, and oophorectomies performed at the maternity ward are indirectly included in treatment plans but only specify the staff resources needed and the treatment efficacy; the average length of time of the surgery, the need for and availability of surgical tools and an operating theatre were excluded from this iteration of the model. Further, the potential for a patient’s condition to worsen due to complications arising from surgery was not included in the model due to a limited number of post-surgery complications becoming fatal. Abortions and anemia were not explicitly incorporated in the model as complications, though both occur in a substantial proportion of patients. Anemia has a relatively low mortality rate relative to other complications included in the model, and there was not adequate information on patient abortions in the medical records.Despite these limitations, we note that the model was able to capture the current trends and provide specific predictions that are relevant for understanding the complex operation of the maternity ward. We also note that by comparing the resource allocation and usage of human, pharmaceutical and capital resources, we are able to analyze the varying burdens on resources. Our model is unique from other generic tools for improving efficiency since it incorporates local challenges, patient trajectories and observations of staff. While the model is based on patient outcomes at MMH in Zanzibar, we note that the framework is modular and capable of adaptation to other wards and hospitals in low and middle-income countries using facility-specific inputs.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


Jonathon L Simon and colleaguesChild health guidelines must broaden in scope beyond under 5 mortality to facilitate improvements in child health and development necessary to meet the 2030 sustainable development goals, say  As the United Nations coordinating authority for international health, the World Health Organization has a vital role in producing scientifically valid and up to date global guidance. It is a challenge to keep the guidelines relevant and evidence based amid changing demography and disease epidemiology and expansion of scientific information and new priorities.The Integrated Management of Childhood Illness (IMCI) strategy was launched in 1995. It aimed to collate technical guidance related to management of the leading causes of childhood mortality in a holistic and child centred way. These guidelines were developed through review of evidence and based on expert consensus recommendations. Since 2007, a systematic review of evidence has been followed using the GRADE  approach, managed by an independent guideline review committee.Since the IMCI strategy was launched most countries have made substantial progress in reducing mortality among children under 5 years old. Overall, global mortality among under 5s has declined by an estimated 56% since 1990.Here, we discuss the changes needed based on the changing epidemiology and the analytical background papers and recommendations from the 2016 strategic review of IMCI and the results of the IMCI global implementation survey.At its inception in the mid-1990s, IMCI focused on countries where the mortality rate in the under 5s was higher than 40 per 1000 live births.Pneumonia, newborn sepsis, and diarrhoea remain among the top causes of death in young children. However, sequelae of newborn asphyxia and prematurity, congenital anomalies, non-communicable diseases, and injuries are becoming increasingly common causes of morbidity and mortality in countries where under-5 mortality has declined.WHO pocket book of hospital care for children.The initial IMCI case management guidelines, tools, and related training materials concentrated on the main conditions causing childhood mortality. Over time, countries have included other conditions and have adapted and updated the IMCI guidelines according to their regional and national epidemiological situation. The recent IMCI global implementation surveyAdaptations were widespread and country specific . RespondIt is a challenge to keep the IMCI guidelines up to date with the changing clinical epidemiology of disease, but they have contributed to reductions in deaths due to diarrhoea, pneumonia, and malaria over the past 20 years.One of the key recommendations of the child health strategic review was a call for WHO and Unicef to bring together existing guidance packages for newborns and children under 5 into one set of flexible, adaptable, and user friendly tools. The review also called for an approach that dealt with child health and development during the first 18 years of life. The life course approach, considers “childhood” as defined by the UN Declaration on the Rights of the Child (ages 0-18 years) and calls for a continuum of support and care where inputs at each age become the basis for improving the health and wellbeing at each subsequent age. This call for the redesign of the child health guidance within the context of this life course approach and the sustainable development goals is based on six identified factors that create changes and require a continued focus on child survival while also broadening the concept of global child health.Firstly, the change from millennium development goals to sustainable development goals has extended the programme. In addition to reduction of the mortality of young children, it now examines the social determinants of ill health and improved wellbeing. The Global Strategy for Women’s, Children’s and Adolescents’ Health emphasises the importance of an approach to ensure that children aged 0-18 years can survive and thrive.Secondly, changes in the timing and causes of child deaths suggest that greater attention should be paid to the first year of life. Focus on the first day, week, and month of life is key as this is when most deaths occur. Congenital abnormalities are increasingly dominant in settings where neonatal mortality from causes such as asphyxia, prematurity, and neonatal sepsis has been reduced. Identifying, testing, and communicating effective and feasible interventions to save lives and foster wellbeing of newborn infants at the differing levels of the health system requires robust research.Thirdly, the geographical distribution of deaths has changed markedly over the past 20 years. The largest demographic change in history is occurring as the world’s population is now predominantly located in urban and peri-urban areas. Not only does this change transmission dynamics and response to disease outbreaks , but it also changes health seeking behaviours as problems of geographical access are supplanted by economic problems. Urbanisation leads to rapid growth in use of the profit and not for profit private sectors for routine health services. In addition, increased recognition of the damage imposed by conflict and other humanitarian emergencies on the health of women and children drives us to improve our understanding of the locational problems associated with death and morbidity. These concerns are now poorly covered and attempts are under way to fill this gap.Fourthly, advances in clinical sciences and biomedical technology create opportunities to improve existing guidance. The introduction of new vaccines and antibiotics has changed the epidemiology, prevention, and treatment of several conditions. Old and new conditions and technologies would benefit from an updated review to ensure that they reflect the most recent scientific evidence. For example, research is under way to strengthen clinical recommendations for identification of children with signs of pneumonia who are likely to benefit from antibiotics. A continuous and careful review of new evidence, timely expert consultation, and a global guidelines process that facilitates rapid updates to current recommendations is therefore required. This will ensure that the WHO/Unicef guidance is up to date. Work into altering strategies for dissemination of WHO technical information is continuing. The use of digital platforms will help and facilitate more rapid updates of technical information and enable the democratisation of information. Some suggest that materials should be available to multiple audiences (including simplified versions for end users) as well as Ministry of Health policy and planning officers.Fifthly, changes due to complexity and variability in different areas are increasingly recognised as critical for effective programming, irrespective of the level of socioeconomic development. A consistent finding from the global survey was that epidemiological and health systems differ markedly across regions, countries, and within countries. Although intercountry differences are well recognised, intracountry variability is equally important. High risk and marginalised populations exist within every country and the commitment to increasing equity and universal health coverage requires that guidance reaches the most vulnerable populations. This forms part of the rationale for customising technical messages to better reach end users and service providers of marginalised populations to reduce information asymmetries.Across regions, countries have very different levels of health systems development and human resource capacity. In addition, with increasing awareness of the level of mortality and morbidity in children in conflict and emergency humanitarian settings, the need to produce materials to deal with the requirements of such children is immediate. Clearly, universal guidance and programming cannot hope to deal with the needs of these widely varying situations. WHO will seek to produce more guidance documents that are specific to the varying environments.Finally, the broad sustainable development goals and changes requiring guidance, such as urbanisation, climate change, environmental degradation, and increasing antimicrobial resistance, will need to be given priority. The broader agenda of child health and development thus requires integrated guidelines at each stage of life to consider health promotion, disease prevention, and the quality care and treatment of neonates, young children, and adolescents.Developing WHO technical guidelines to meet the sustainable development goals is challenging given the breadth of problems reflected in the 17 goals, with a broad definition of health being a core component of many of them. WHO and Unicef envisaged a child health redesign project to deal with these challenges through consultation with policy makers, programme managers, scientists, implementation partners, and civil society in all regions. This process has identified priority areas on which WHO and Unicef will focus. There is general agreement that the emphasis should expand beyond survival of children under 5. The changing patterns of mortality require a greater focus on interventions to reduce mortality in the first week, month, and year of life. Expansion of early child development activities in the first 3 years may help to ensure that children have the greatest chance to thrive and meet their potential. A strong focus on nutrition across all age groups, considering both undernutrition and overnutrition, is a priority. The largest gap to fill in guidance may be for children aged 5-9 years, a neglected group. For these children accidents and injuries are increasingly important causes of death, requiring the scope of guidance to be broadened. Furthermore, we acknowledge that integrating medical, health promotion, mental health, and social/behaviour interventions across the age groups and differing health settings may be a complex challenge.As a consequence of this expanded vision, three priority areas for guidelines and guidance work have been identified: updating current guidelines using the life course approach; identifying and filling guideline gaps, starting with children aged 5-9 and thrive interventions; and identifying innovative ways of making guidelines flexible and adaptable to local priorities. This work is large, broad, complex, and important. It will require WHO and Unicef, working with multiple stakeholders, to commit to many years of effort to listen, learn, and adapt as we change the way in which guidelines are devised, developed, and disseminated.The sustainable development goals have placed additional responsibilities upon WHO and Unicef to ensure that guidance meets the broader needs and deals with the newer questions that countries face as they respond to their global commitments. For child health, this means promulgation of a new vision, in which child health and development are dealt with in an innovative, evidence based, and balanced way. A major initiative to revise and update existing child health guidelines and create the new guidance necessary for the expanded goals is urgently needed.The transition from the millennium development goals to the sustainable development goals, and WHO’s continuing commitment to the health of women, children, and adolescents provides an opportunity to re-examine child health programming. The emphasis on child survival that marked the past two decades was justifiable, but a move to consider child health in a holistic and child centred way is of utmost importance to deal with the root causes of poor health and development and reduce inequities. Countries ascribe great importance to WHO guidance. Thus, the need to adopt state of the art thinking and science is both a huge responsibility and an opportunity for WHO. This is an exciting opportunity to refresh the world’s child health knowledge and, more importantly, use this information to accelerate the improvements in child health and development required to meet the 2030 sustainable development goals.•Many epidemiological and demographic changes affecting child health have occurred since the launch of the Integrated Management of Childhood Illness strategyThe sustainable development goals demand the focus to be widened beyond mortality among children under 5 years Guidelines need to be updated to take account of these changes as well as scientific advances A more holistic view of child health is needed that includes environmental and social determinants


Cancer is a leading cause of morbidity and mortality in the world. In Portugal, colorectal cancer is one of the most incident cancers; thus, it is crucial to act to fight it. Knowledge of the geographical distribution of the incidence and mortality of colorectal cancer can facilitate the execution of these actions and make them more effective.Our paper aims to describe and discuss the geographical patterns of colorectal cancer incidence and mortality in mainland Portugal municipalities (2007–2011). We used the Besag, York and Mollié (BYM) model to compute the relative risk (RR) and posterior probability (PP). We performed a cluster analysis with Global Moran’s Index and Local Moran’s Index (LISA). We ran a geographically weighted regression (GWR) to compare incidence and mortality patterns.Incidence and mortality have different distributions of RR values. The interval of RR concerning incidence was higher than the interval of RR concerning mortality. PP values reinforce the finding of higher heterogeneity of the incidence of colorectal cancer.The comparison of the cluster maps for incidence and mortality shows a few municipalities classified with the same cluster type in both maps. Additionally, the GWR results show that the percentage of RR mortality explained by RR incidence differs throughout mainland Portugal.From the comparison of our results with the prevalence of risk factors (at NUTS II level), the need to be aware of smoking habits, alcohol consumption and the unhealthy diet of the Portuguese population stands out.There are differences in the geographical distribution of the RR incidence and RR mortality of colorectal cancer in mainland Portugal municipalities. Likewise, it is relevant to highlight the cluster of two municipalities with high RR values concerning colorectal cancer’s incidence and mortality. Future research is necessary to explain the geographical differences in the distribution of colorectal cancer in mainland Portugal municipalities. Based on our findings, it may be interesting to examine the influence of smoking, alcohol consumption, diet and screening on colorectal cancer in greater detail. Additionally, it may be relevant to develop an analysis focused on municipalities where the incidence values explain the mortality values poorly (or well).The online version of this article (10.1186/s12885-019-5719-9) contains supplementary material, which is available to authorized users. Cancer is currently a major public health concern around the world. At the end of the last decade, it was estimated that approximately half of all deaths in Europe in the middle-aged population were due to cancer .Among all cancers, colorectal cancer is the third-most common in the world, and it has a higher incidence in more developed countries . HoweverIn Portugal, cancer mortality has been increasing in the last decades. Between 1960 and 1998, the crude mortality rate has more than doubled , and it Another important issue in cancer research is the association between cancer incidence and the occurrence of risk factors. Nevertheless, the long latency period of cancer, that is, the period between the exposure to risk factors and the diagnosis of the disease, hampers the study of these risk factors . ConcernIn this context, our paper’s main goal is to describe and compare the geographical distribution of colorectal cancer incidence and mortality in mainland Portugal municipalities between 2007 and 2011. Although our purpose is not to describe the occurrence of risk factors in detail, they are considered in the discussion of the obtained results.The flow diagram presented in Fig. A base map was constructed using Portugal’s official administrative cartography (CAOP) 2009 , correspThus, another map with NUTS II  boundaries  was constructed and overlaid on the maps of the municipalities. The names of each NUT II were indicated to facilitate the description of the results and the discussion. The NUTS II 1989  boundaryth revision of the International Statistical Classification of Diseases and Related Health Problems (10th ICD) [New cancer cases were collected at the Regional Oncologic Registries (RORENO  from the0th ICD) .Data were disaggregated by 278 municipalities, according to sex and age groups .Due to the recommendation to use large populations and data grouping over several years , a 5-yeaRegarding the Portuguese population, we gathered data at INE for 2009, the central year of the study period, disaggregated by sex and the age groups previously described.The Besag, York and Molié (BYM) model  was applIn the model construction, spatial adjacency was considered as neighbourhood criterion, and “Laplace” was adopted as the strategy of integration. Expected cases were computed based on the mainland Portugal population in 2009, aggregated as described above and multiplied by 5 .In result of model processing, we computed standardized incidence ratio and standardized mortality ratio  interpolation process. The legends of the maps were classified by seven classes, created by the method of equal intervals.Through the ArcGIS program , LISA waWe used GWR, performed in ArcGIS, to analyse the strength of association between colorectal cancer incidence and colorectal cancer mortality throughout mainland Portugal. GWR is a local regression method which applies an equation for each geographical unit under analysis.Assuming that there is no underreport of the incidence and mortality rate, our hypothesis is that if the lethality rate of the individuals with colorectal cancer is equal between municipalities we would observe a proportionality between the incidence rate and the mortality rate. Meaning that the higher the incidence rate, the higher the mortality rate would be. A lack of fit of the model in certain areas would mean a deviance from this hypothesis and that there is no proportionality between incidence and mortality rate.The RR concerning colorectal cancer mortality was assigned as a dependent variable, and the RR concerning colorectal cancer incidence was assigned as an independent variable. We assumed the adaptive kernel type and AICc bandwidth method.Incidence and mortality have different distributions of RR values, as shown in Table When comparing RR values between men and women, differences in RR values regarding incidence were found. The minimum RR value is the same (0.19), but the maximum RR value is higher among men than among women . This result is reflected in slightly greater mean values  and a much higher standard deviation (0.35 to men and 0.29 to women). Mortality values, in turn, are very similar in both sexes.In terms of the geographical distribution of the values, shown in Table However, if we analyse the extreme values, different scenarios in incidence and mortality are found. The minimum RR values for mortality are always higher than the minimum RR values for incidence, and the maximum RR values for mortality are always smaller than the corresponding RR values for incidence in the same region. Moreover, the standard deviation of the RR values for mortality present low values, and they are very similar in all NUTS II and both sexes. These results are also shown in Fig. Overall, the incidence maps (at left) show that the RR of colorectal cancer incidence tends to be higher in the Norte region and the coastal municipalities of the Centro, LVT and Alentejo regions. However, there are differences in maps by sex. There are more municipalities with high RR values in the Norte region to women than to men. In turn, there are higher RR values in the coastal Centro, the LVT and, more markedly, the Alentejo region to men than to women.In contrast, the mortality RR maps mostly present a more homogenous distribution of RR values in the entire territory than the incidence RR maps, with fewer municipalities classified in the extreme classes. The LVT and Alentejo regions, particularly, stand out as the regions with higher mortality RR values. These patterns are not as remarkable in the incidence RR maps.Figure One of the dominant patterns is the higher heterogeneity of RR incidence values in the Norte and Centro regions, particularly marked in the men’s scatterplot. On the other hand, the LVT and Norte regions are, at the same time, the regions with smaller RR mortality values.Additionally, it is interesting to highlight that the few cases of low RR incidence in the LVT region simultaneously register high RR mortality.In terms of RR mortality, for men, it is easy to identify Alentejo and, though less pronounced, LVT as the regions with higher values. These high values are, in general, associated with mean RR incidence values. In women, it is more difficult to highlight a region due to the greater heterogeneity in the distribution of values by region. However, it is apparent that some municipalities with higher RR mortality values are again associated with mean values for RR incidence.Concerning the situations in which the PP of the RR is higher than 1, the maps presented in Fig. LISA maps reveal much smaller clusters in incidence maps than in mortality maps Fig. . In geneIn addition, we overlaid incidence and mortality LISA maps and looked up municipalities classified as low-low clusters and as high-high clusters in both maps, as presented in Fig. There are few municipalities classified in the same way in both the incidence and the mortality RR’s maps. For those municipalities, we emphasize two groups that deserve special attention: (1) Among men, the set of two municipalities belonging to the high-high cluster in incidence and mortality maps, situated in the boundary of the Centro and LVT regions; and (2) In both men and women, the set of 6 municipalities classified in the low-low cluster in incidence and mortality maps, located in the boundaries between the Norte and Centro regions.To complement the comparison of RR incidence and RR mortality, we performed a GWR of these values for each sex. Residuals maps, presented in Fig. 2 map classes show that the incidence RR values explain no more than 75% of the mortality RR values  and 59% among men   for all screening tests and colonoscopies for FOBT-positive cases .There is a delay between the period of our analysis (2007–2011) and available data for screening (2015). This delay does not allow us to infer conclusions about colorectal cancer incidence or mortality and the occurrence of screening.Another important issue is the future research that must be performed to compare the colorectal cancer incidence and mortality patterns with the main known colorectal cancer risk factors. As mentioned in the introduction section, there are several risk factors identified as potentially related to the occurrence of colorectal cancer.In our study, we did not perform a detailed analysis of risk factors because the available data refer to a period too close to the time of collection of the cancer data, which does not allow us to consider the latency period. Moreover, the available data about referred risk factors have a high level of spatial aggregation. In fact, Portuguese national surveys adopt NUTS II or the Portuguese health regions as geographic units. It imposes the challenge of analysing data with different spatial scales, which is a common issue in spatial epidemiology . NeverthOne of the most important human carcinogens is tobacco smoking . The resAnother main colorectal cancer risk factor is alcohol intake. Alcohol consumption data from the 4th INS show that men drink more than women, regardless of age group or residence NUT II . FurtherBased on the 4th INS results , we veriAdditionally, we eventually need another indicator to study the effect of alcohol consumption on colorectal cancer. One indicator related to alcohol intake is binge drinking, defined as the intake of six or more drinks during a single occasion. There is already evidence reporting that binge drinking may increase the risk of colorectal cancer . UnfortuIn terms of dietary behaviours, there is an association between colorectal cancer risk increasing and the following: a) a low consumption of certain foods such as soup, vegetables and fruit  and b) aIn the 4th INS, data were collected on vegetable and fruit consumption but not on processed meat consumption . The resThese data are not sufficient to characterise the dietary behaviours of the Portuguese population and their effect on colorectal cancer rates. More geographically detailed data are necessary to improve this analysis. Nevertheless, it seems that Portuguese dietary behaviours tend to be unhealthier. This finding is consistent with those of previous studies, in which changes in Portuguese dietary habits were demonstrated to be a contributor to the increase in the incidence of colorectal cancer .Norte has clusters of municipalities with a higher incidence of colorectal cancer. In terms of risk factor behaviours, it is important to be aware of the effects of smoking, alcohol intake (particularly in women) and the reduction in fruit and vegetable consumption;Centro registers the highest RR values for incidence. This situation merits investigation in the future to determine the reason underlying that occurrence. Regarding risk behaviours, smoking is increasing among women, and there is a reduction in fruit and vegetable consumption in both sexes;LVT stands out as one of the regions with a higher RR mortality, particularly among men. The risk factors that must be tracked are smoking and alcohol intake (particularly in women) and the reduction in fruit and vegetable consumption;Alentejo is the other region with a higher RR mortality, particularly among men. In this case, high mortality is accompanied by a low incidence of colorectal cancer. Regarding risk factors, it is important to highlight smoking, alcohol drinking (particularly in women) and the reduction in fruit, vegetable and soup consumption;Algarve has the lowest RR values for incidence. In turn, the RR values for mortality are not very high. Nevertheless, the increase in alcohol drinking (particularly in women) and the reduction in fruit and vegetable consumption are two behaviours that must be combatted.In short, we would like to highlight some statements for each NUTS II that emerge from our findings:Colorectal cancer is an important public health concern in developed countries, where it predominantly affects people aged between 40 and 80 years old . It is iWhy is incidence higher in some municipalities?Why is mortality not high in some municipalities where incidence is high?Finally, why is mortality high in municipalities where incidence is not high?Our findings show heterogeneous patterns in the distribution of colorectal cancer incidence and mortality in mainland Portugal municipalities during the period 2007–2011. Some of these patterns warrant more detailed study in the future, in order to understand the following:To answer these questions, it is necessary to analyse risk factors as well as the availability and performance of health services.The evaluation of risk factors was not the aim of our research. Nevertheless, we highlight situations that can provide clues regarding more detailed studies in the future, specifically including the following: a) the possibility of a relation between opportunistic screening and high incidence; b) the high prevalence of smoking and alcoholic beverage intake; and c) the adoption of unhealthier dietary habits. Furthermore, we correlate the RR values for incidence with those for mortality. The results of this analysis allow for the identification of the municipalities where the incidence values poorly explain the mortality values. In those municipalities, it is possible that some risk factors contribute to a higher lethality of colorectal cancer.Furthermore, it is relevant to highlight the small cluster of municipalities that register high values for both incidence and mortality Fig. . It is iTo finish, we would like to reiterate that the fight against risk factors is the key to decreasing cancer morbidity and mortality . KnowledAdditional file 1:SIR and SMR of colorectal cancer in mainland Portugal, by sex. (ZIP 1260 kb)


The monitoring of caloric intake is an important challenge for the maintenance of individual and public health. The instruments used so far for dietary monitoring  are inexpensive and easy to implement but show important inaccuracies. Alternative methods based on wearable devices and wrist accelerometers have been proposed, yet they have limited accuracy in predicting caloric intake because analytics are usually not well suited to manage the massive sets of data generated from these types of devices.This study aims to develop an algorithm using recent advances in machine learning methodology, which provides a precise and stable estimate of caloric intake.The study will capture four individual eating activities outside the home over 2 months. Twenty healthy Italian adults will be recruited from the University of Padova in Padova, Italy, with email, flyers, and website announcements. The eligibility requirements include age 18 to 66 years and no eating disorder history. Each participant will be randomized to one of two menus to be eaten on weekdays in a predefined cafeteria in Padova . Flows of raw data will be accessed and downloaded from the wearable devices given to study participants and associated with anthropometric and demographic characteristics of the user (with their written permission). These massive data flows will provide a detailed picture of real-life conditions and will be analyzed through an up-to-date machine learning approach with the aim to accurately predict the caloric contribution of individual eating activities. Gold standard evaluation of the energy content of eaten foods will be obtained using calorimetric assessments made at the Laboratory of Dietetics and Nutraceutical Research of the University of Padova.The study will last 14 months from July 2017 with a final report by November 2018. Data collection will occur from October to December 2017. From this study, we expect to obtain a series of relevant data that, opportunely filtered, could allow the construction of a prototype algorithm able to estimate caloric intake through the recognition of food type and the number of bites. The algorithm should work in real time, be embedded in a wearable device, and able to match bite-related movements and the corresponding caloric intake with high accuracy.Building an automatic calculation method for caloric intake, independent on the black-box processing of the wearable devices marketed so far, has great potential both for clinical nutrition  and public health nutrition as a low-cost monitoring tool for eating habits of different segments of the population.DERR1-10.2196/12116 Obesity affects 650 million people worldwide and is strongly related to cardiovascular diseases, which are the main cause of death in Western countries ,2. ThereWith advances in technologies, studies have started to employ electronic wearable devices for monitoring caloric intake . WearablWearable devices equipped with motion sensors usually detect feeding-related gestures, translate gestures into a number of bites, and then bites into energy intake through the use of algorithms whose rationale is based on the existence of a relationship between the number of bites and the number of calories eaten . For exaThe main reason they are poor in associating bites to calories is because of their poor analytics, which are usually not well suited to manage the massive sets of data generated from these devices and with a limited accuracy in predicting caloric intake ,13-16. TThis section describes the protocol of the study “Measuring Caloric Intake at the Population Level” (acronym NOTION), approved by the Bioethics Committee of the University of Torino, Torino, Italy, on July 12, 2017 (#256091).The study will last 14 months from July 2017 with a final report by November 2018. Data collection will occur from October to December 2017.The study will capture four individual eating activities outside the home over a 2-month period. Twenty healthy Italian people will be recruited from the University of Padova with email, flyers, and website announcements. The eligibility requirements include age 18 to 66 years, no eating disorder history, and absence of allergies and food intolerances. Potential participants will complete a Web-based initial form to collect a preliminary assessment of the fulfillment of the inclusion criteria. Those who appear eligible will meet with the research team members who will describe the study, answer questions, and obtain written informed consent to determine final eligibility. Participants will receive an eating activity schedule, a device, and written instructions.Each participant will be required to eat a minimum of four meals on weekdays in a predefined cafeteria in Padova .2); body density (g/cc) will be calculated by Durnin and Womersley equations, adjusted by age, using the logarithmic sum of four skinfolds using a Holtain 610 Caliper (accuracy: 0.1 mm): biceps, triceps, subscapularis, and iliac )The purpose of this study is obtaining an estimate of caloric intake from the movements of the wrist. To achieve this objective, we will exploit accelerometer data because it is known to be a suitable adoption for this kind of problem ,32. CompBuilding an automatic calculation method for caloric intake independent of the black-box processing of the wearable devices marketed so far, has great potential both for clinical nutrition  and public health nutrition as a low-cost monitoring tool for eating habits of specific segments of the population.From this study, we expect to obtain a series of relevant data that, opportunely filtered, could allow the construction of a prototype algorithm able to estimate caloric intake through the recognition of food type and the number of bites. The algorithm should work in real time and be embedded in a wearable device able to match bite-related movements and the corresponding caloric intake with high accuracy. The challenge will be refining the algorithm to recognize an extended number of foods on a large sample of multiethnic participants.The estimation of caloric intake is a topic of great interest in the field of nutrition ,2. MonitTo handle the challenges of big data from wearable devices, new statistical thinking and computational methods are needed. The use of machine learning techniques, able to grab all the available information to solve complex learning tasks such as classification, clustering, and numerical prediction, represent a possible advancement.This study will address these existing challenges and make the following innovative contributions:Build a detailed and objective picture of eating activity under seminaturalistic conditions, as a reliable and robust basis for the subsequent analytical steps.Use cutting-edge advances in machine learning for big raw data generated by inertial sensors.Implement a prototype algorithm for caloric intake, independent on the wearable device used at the development stage, which will hopefully improve dietary monitoring.We acknowledge that the whole system is still premature for real-time implementation and that future work will require a broader range of food items, a larger sample size, and a free-living condition. Furthermore, we will need to check the hypothesis that the type of food rather than other participant and food characteristics  is the best proxy of caloric intake. Moreover, we will have to investigate whether the signals recorded by the wearable devices actually hold promise in measuring caloric intake. Nevertheless, this ambitious project has great potential to empower dietary monitoring.