The access to various forms of support during the disease trajectory is crucial for people with cancer. The provision and use of Internet health services is increasing, and it is important to further investigate the preferences and demographical characteristics of its users. Investigating the uptake and perceived value of Internet health services is a prerequisite to be able to meet the needs in the targeted group.The objective of this study was to investigate health-related Internet use among people with cancer.The health online support questionnaire (HOSQ), examining the incentives for health-related Internet support use, was administered in two Swedish outpatient hospital clinics. Of the 350 copies of the questionnaire handed out, 285 (81.4%) were returned, answered by persons with cancer who had completed treatment or were under active surveillance or another medical treatment.P<.001), more likely to have a partner (P=.03), and had a higher level of education than nonusers (P<.001). The most common health-related activity on the Internet was searching for information , and users searched significantly more immediately after diagnosis compared with later on (P<.001). Use of My Healthcare Contacts was considered the most valuable Internet activity. Having a university degree (P ˂.001) and being younger in age (P=.01) were associated with a significantly higher frequency of health- related Internet use.A total of 215  participants reported Internet use since being diagnosed with cancer. Internet-users were younger (People with cancer turn to the Internet for informational support that enables them to influence their care and to stay in touch with friends and relatives. Demographical differences regarding the uptake of Web-based support remains. This indicates a need for research on how to bridge this digital gap. By learning more about the use of health-related support on the Web among people with cancer, adequate support can be offered and potential strain reduced. The treatment of cancer has gone through some important changes the past decades and one of them is an increase in outpatient care services coupled with a decrease in inpatient care ,2. This Internet-based technologies such as patient portals, websites, and apps managed by health care institutions, have been recognized as a significant lever to improve cancer care coordination . InterneThe use of the Internet as a source of support is a trend that has increased rapidly among cancer patients during the past decade . MotivesThe access to the Internet in Europe has increased significantly during the past decades and is high in the Northern countries . HoweverDue to potential long lasting effects of the disease and treatments, people with cancer are at a higher risk for comorbidities and psychosocial problems throughout their life . An undeThis study aims to investigate health-related Internet use and the perceived value of this among people with cancer. A further aim is to describe the incentives for Internet use and to explore associations between Internet use and medical and demographic variables.A convenience sample of persons with cancer was included from November 2014 to February 2015. Subjects were consecutively recruited at a scheduled visit to an oncology or urology outpatient clinic at a university hospital in Sweden. The inclusion criteria were an age of 18 years or older and completion of the initial treatment  or currently undergoing either hormone treatment, active surveillance or other medical treatment. This was in order for them to have gained some perspective on how they had used the Internet after being diagnosed. Exclusion criteria were inability to understand Swedish, cognitive impairment, or participation in an ongoing Internet-based intervention (U-CARE) at the hospital that could influence the reported use of support on the Internet . EligiblEthics approval was granted by the regional ethical review board in Uppsala .The first question in the questionnaire asked about whether the patients had used the Internet. The group of Internet users was defined as the group who reported that they had used the Internet on a computer, mobile phone or a tablet, at least once or twice since being diagnosed with cancer. Internet users were asked if they had visited information sites; social media sites such as Twitter, Facebook, and Instagram; discussion forums and blogs regarding health, diseases, treatments, lifestyle or similar; and whether they had created their own blogs and/or discussion threads and/or commented on others. The questions were rated from 0=never, to 1=once or twice ever, 2=at least once a year, 3=at least once a month, 4=at least once a week, and 5=daily or almost daily. Subjects were further asked a question about the use of an eHealth service  that allows patients to request, cancel, or reschedule appointments; read their medical record; and renew their prescriptions. This question was rated from 0=never, to 1=sometimes, and 2=several times. The questions regarding the frequency of using the apps were asked in relation to both the time immediately after diagnosis, and later on. All patients gave their own definition of how long the time immediately after diagnosis was. How valuable they considered the use of different apps to handle their health situation was, was rated on a scale ranging from 0=not valuable at all, to 10=very valuable.The incentives for Internet use were investigated using the health online support questionnaire, (HOSQ) . The HOSDemographic data on age, sex, civil status (having a partner or being single), birth country, educational level, diagnosis, time since diagnosis, and cancer treatment  were collected using project-specific questions answered by both Internet users and nonusers.The statistical analyses were performed using IBM SPSS Statistics (version 20.0).P ≤.05.The level of significance in this study was t-tests (age). Comparisons between the use of apps  immediately after diagnosis and later on were conducted with Wilcoxon signed rank test due to positively skewed data. Correlations between age and the HOSQ total score and the subscales were conducted with Spearman rho. The associations between Internet use and demographic and medical data were analyzed with multiple logistic regressions including age, sex, education, civil status, and completion of treatment as independent variables. This analysis was done on the HOSQ total scale and separately for each subscale. Due to positively skewed data, all HOSQ scales were dichotomized based on the median of the respective scale.Internet use, the perceived value of this, and the incentives for Internet use were analyzed descriptively. Statistical comparisons between groups were conducted with chi-square tests  and In total, 350 questionnaires were handed out and 285  were answered and returned. Three were excluded due to missing data. Two hundred and fifteen  of the participants reported Internet use after being diagnosed with cancer. Internet users were younger, more often had a partner, and had higher education compared with nonusers. The most common type of diagnosis was prostate or breast cancer and the median time since diagnosis was 3 years .The median score of the HOSQ reading subscale was higher compared with the HOSQ interacting subscale median score .P=.01) and the reading subscale (P ˂.001). Having a university degree was significantly associated with a higher score on all three scales  compared with elementary school. Completion of treatment was significantly associated with a lower score on the HOSQ reading subscale  reported that they had used the Internet to search for health information. Forty five  had visited health-related discussion forums, 39  had visited blogs, only one  had taken part in psychological treatment on the Internet, 73  reported use of social media. My Healthcare Contacts had been used by 82  and 38  of them had taken part of information and test results in the medical e-record services, 8  had scheduled appointments, 12  had renewed prescriptions, and 5  had chosen a general practitioner (GP). My Healthcare Contacts was considered the most valuable Internet health resource  compared with information sites , forums , blogs , and social media .P<.001. One hundred and twelve  considered the length of the time immediately after diagnosis to be somewhere between 1 day and 3 months. The total range of reports was 1 day to 5 years and the median time was 3 months. No differences were found regarding use of other apps than information between the time immediately after the diagnosis and thereafter. The vast majority of users visiting information sites (86%) and discussion forums (81%) did so regarding their own health. Use of the other apps was less related to their own health .The daily use of information apps immediately after diagnosis was higher  than later on , This study found that the persons with cancer who use the Internet for health-related support mainly search for information that enables them to improve their overall health and get the best possible health care. The health care delivered tool My Healthcare Contacts was considered very valuable among the ones who used it, hence, seems to be a satisfactory app on the Web. Younger and higher educated used the Internet significantly more than the older and less educated.Information sites were the most frequented sites compared with social media, discussion forums, and blogs. This finding converges with other studies on health-related Internet use ,20,24. RPeer support is often referred to as an important factor for people with cancer, even though it is not considered as one of the most important health activities on the Internet . The useThe demographic factors found to predict Internet use in this study were young in age and having a university education. The variables that frequently appear to influence health-related Internet use are age, gender, educational level, perceived health, and socioeconomic and civil status ,20,28. AOne third of the Internet users reported use of My Healthcare Contacts, where taking part of information and finding out test results in the medical e-record services, was the most frequent activity. This was the app that was reported as the most valuable. There are findings suggesting that the majority of cancer patients consider improved access to their medical records as something that should be prioritized  ScheduliDespite just over 20 years of Internet, the number of people using it is still expanding in Sweden. The access as well as Internet use is still increasing even though the vast majority of people in Sweden already use the Internet. In particular, the group of younger pensioners using the Internet is growing. Currently, almost 100% of people between the ages of 12-55 years, and approximately 90% of people aged 60-65 years use the Internet in Sweden . Future The response rate was high (81%) and 75% of the participants were Internet users. To avoid selection bias the questionnaire was handed out at the clinic instead of being administered in a Web-based context to Internet users only. This way we were able to compare demographic and disease-related variables between the Internet users and the nonusers. The heterogeneity regarding diagnosis, age, educational level, and sex was satisfactory. Thus, the results may be fairly representative for people with cancer but limited to patients that have completed their initial treatment. However, there is a need for diagnose specific studies as well.Many of the patients who chose not to answer the questionnaire said that they did not use the Internet, hence, did not think it was relevant for them to respond. Therefore, the percentage of Internet users in this study may be higher than what is representative for the population examined.The patients’ definition of the time immediately after the diagnosis varied greatly. Therefore, results showing that the need for information was significantly higher immediately after diagnosis compared with later should be interpreted with caution, since the time “immediately after” the diagnosis might overlap the time “later on.”A recall bias among the Internet users should also be taken into consideration since the median time since diagnosis is 3 years, meaning that the frequencies of Internet use may be under- or overestimated, which decreases the reliability of the findings.The questionnaire used in this study, the HOSQ, has not been used previously, so the validity and reliability are uncertain. However, it has been psychometrically tested and validated regarding face and content validity in two samples where the response pattern revealed expected differences both between the interaction and reading scales and according to age, gender, education, and health problems .According to UTAUT , there aThis study has found that patients turn to the Internet primarily for informational support that enable them to improve their overall health, make more informed decisions, and to get the best possible health care. Also to stay in touch with friends and colleagues and take part of other peoples’ experiences of a similar situation. Instrumental support such as searching for scheduled appointments, phone numbers, and addresses to health care was also something that they used the Internet for. The perceived value of the apps examined in this study was generally high. The use of instrumental support such as My Healthcare Contacts was considered the most valuable activity on the Web. Internet use was associated with having a university degree and being younger. This may indicate that the threshold for health-related activities on the Web is higher for older and less educated individuals, which needs to be addressed in future research.A better understanding of health-related Internet use in different groups is a prerequisite to the provision of adequate Internet delivered support. By learning more about the incentives for health-related Internet use in various contexts of people with cancer, we may be able to develop tailored support that may alleviate potential distress, save costs, and reduce health care workload.


Response to Intervention (RTI) was accepted in the early 2000s as a new framework for identifying learning difficulties (LD) in the U.S. In Finland, a similar multi-tiered framework has existed since 2010. In the present study, these frameworks are presented from the viewpoint of the role of assessment and instruction as expressed in documents that describe the frameworks, as it seems that these two components of RTI are the most disparate between the U.S. and Finland. We present a suggestion for the Finnish framework as an example of support in mathematics learning that incorporates principles of RTI . Finally, recommendations are presented for further refining and developing assessment and instruction policies in the two countries. Why do we need educational frameworks and guidelines for providing support? Why can teachers not rely on their education and knowledge of learning and provide sufficient instruction and support for all students in need of something extra? These are the questions we discuss in the present paper. Different countries have different approaches to these matters, but we choose to compare the multi-tiered frameworks for support in learning used in the United States and Finland, as interesting similarities and dissimilarities exist. In the U.S., Response-To-Intervention (RTI) has long been a suggested framework for identifying students with disabilities. It provides guidelines for early prevention and for delivering evidence-based instruction with intensifying tiers of support. Close monitoring of student progress is also at the core of the U.S. RTI. Informed decision making at all levels within the system .The U.S. school system consists of public and private schools. The average school age ranges from about age 5–18 years. The Finnish school system is public; there are basically no private schools. Children enter the compulsory schooling system the year they turn seven years old. Compulsory schooling lasts nine years, until the child reaches the age of 15 or 16 (depending on the time of year the child was born). The overall educational standards are run by the Ministry of Education, Science, and Culture, but the schools may relatively freely implement support in their own curricula , the implementation of RTI after the Individuals with Disabilities Education Act, IDEA, , enactedIn Finland, the Ministry of Education, Science, and Culture formed a steering group in 2006 to focus on developing a strategy for special education in basic education. Several tasks were to be achieved: developing ways to analyze the need for the amount of special educational services, developing legislation concerning special education, developing teacher education, developing administrative procedures in special educational services, and developing other areas related to special education. Consequently, a new strategy for special education was published in 2007.Based on this strategy document, a renewed Basic Education Act was introduced in 2010 and was officially implemented in August 2011 in all Finnish schools  are major reasons for the need of extra support in learning  comparing the US. and Finland. After that, we will present a model for providing individual support in mathematics according to Finnish RTI framework and legislation.no formal guidance on performing screenings within the RTI framework. Some type of universal screening might (once or twice per year), however, be performed according to a school's and municipality's own system. Finnish teachers may freely decide when, how, and with which the screenings are performed. The frequency of screening is normally three times per year in RTI, but once again, it is not clearly localized within the Finnish framework.See Table The latest addition to the screening procedure in the U.S. RTI framework was suggested by Fuchs et al. . Originaoptional learning plan is suggested . The intervention programs may be selected from a bank of research-proven interventions based on school resources in the U.S. The concept of progress monitoring (CBM) and a resource bank of suggested intervention methods are not mentioned at all in documents defining the Finnish framework.According to Fuchs and Fuchs , in the obligatory learning plan at this level of intensified support in which the support a student receives is reported by teachers. No description of frequency or type of progress monitoring exists in the Finnish framework at the level of intensified support. The learning plan document consists of descriptions of different forms of support provided for a student. Large variation exists, as there is no guidance on time for support.In the U.S. RTI, Tier 2  belongs to general education as an instructional service. In Finland, this level called “intensified support,” including assessment as well as instruction, is organized via consultation and collaboration between teachers. In the U.S. RTI, assessment is instruction-based and skill-specific. The Finnish framework provides no formal guidance for assessment (in the sense of frequency). However, Finnish schools may, for example, decide whether to do a skill-specific assessment of students in need of extra support in learning. The Finnish framework provides for an Multi-professional consultation is made in problem-solving RTI frameworks. Evidence-based protocols are used by reading specialists, special education teachers, and paraprofessionals in some RTI versions. Tier 2 within the RTI framework is an important stage between Tier 1 and the intensified Tier 3. Therefore, instruction on Tier 2 is evidence-based as well as performed in short periods to allow for the instruction to be modified in a timely manner . This form of instruction resembles in many ways the flexibility and degree of individual assessment and instruction that exists in the Finnish framework; teaching methods are individually adjusted. However, what is missing from the background of the Finnish framework is a research-based resource center that would actually validate using individually adjusted instructional methods.Tier 3 RTI in the U.S. has an interesting feature: individualized data-based instruction  with plans for instruction would be drawn up with the participation of the student, caregivers, school psychologist, classroom teacher, and special needs teacher. We suggest that approach to instruction during a school year would consist of several cycles. The current situation in schools is that each teacher  decide on the frequency and content of support. This results in differing practices, and the rights of suitable instruction provided for each individual student in need of support in mathematics are not addressed adequately.To correct this situation, we suggest that each cycle of support lasts for 5–7 weeks, and that the support is provided 3–4 times per week (each session duration 30 min of intensive work). starting from making sure very basic math skills are learned . By viewing the support as cycles throughout the school year, groups/pairs of students participating in Tier 3 support could work together regardless of age. We recommend that students work in pairs or small groups, maybe occasionally even provided with fully individualized support. This means that based on “what works” literature .We cannot expect severe mathematics learning difficulties to be “cured” even by repeating several cycles of support during a school year; instead, support would need to be provided over several school years. The teaching contents during these support sessions would include basic arithmetic and estimation skills, according to individual needs, for as long as deemed necessary. Continuity of the support would be ensured by keeping a record of the support and assessment given to each student. Giving many alternate suggestions for intervention programs to be selected from as the instructional basis for this support cannot be done at this time. This is due to the fact that, to date, only a few intervention programs for mathematics are available in Finland  should be continuous, cyclic, individual, and based on evidence-based intervention programs. Support can be provided in many different contexts, but it must be systematized and modifiable between cycles.In this paper, we presented the RTI framework and the three-level Finnish educational support system from the viewpoints of assessment and instruction. The models were implemented based on similar background philosophies: the right to receive the best possible preventive support for learning and participation. Tohe recent Finnish reform ; the National Center for Intensive Intervention .Within education systems there are always possibilities for improvement, even after reforms take effect. The present analysis contributes to this goal and to the research literature by identifying similarities and differences between two countries with significant experience of RTI-like frameworks. Because formal identification of learning disabilities is not a central part of the current Finnish framework, it is understandable that it resembles those RTI systems that take a problem-solving and consultation-based approach  should take steps toward establishing similar centers. However, we continuously seek funding to make the Although the RTI framework seems to be clear, the IDEA legislation leaves too much room for multifaceted interpretations, a situation that leads to, for example, seven-tiered RTI models and the impossibility of comparing the uses of RTI across the U.S. On the other hand, the three-tiered Finnish framework is clear in its background philosophy and purpose (Sabel et al., What follows from revealing these differing profiles of assessment and instruction within the two countries are some modest suggestions for concluding remarks. For the RTI model used in the U.S., it would be useful to simplify the RTI models in use (see also, Fuchs and Fuchs, PB has been the major contributor of this paper. LF and DF have provided information on the U.S. RTI. TK and MA have reviewed the paper several times, commented and contributed to the discussion.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.


The prevalence of genital piercing among women is increasing. As the popularity increases, the number of complications from infection, injury, and retained jewelry is likely to rise. Techniques to remove embedded jewelry are not well described in the literature. The purpose of this report was to describe a case of a patient with a retained clitoral glans piercing, discuss a simple technique for outpatient removal, and review current evidence regarding associated risks of clitoral piercings. A 24-year-old female presented to the emergency department with an embedded clitoral glans piercing. Local anesthetic was injected into the periclitoral skin and a small superficial vertical incision was made to remove the ball of the retained barbell safely. In conclusion, among patients with retained genital piercing, outpatient removal of embedded jewelry is feasible. While the practice of female genital piercing is not regulated, piercing of the glans of the clitoris is associated with increased injury to the nerves and blood supply of the clitoris structures leading to future fibrosis and diminished function compared to piercing of the clitoral hood. Genital piercing is increasing in frequency among many demographic groups. Genital piercings are unique as they may have a functional role in addition to aesthetical value, with some women reporting heightened sexual arousal and increased orgasm potential after clitoral piercings . In womeA 24-year-old female presented to the emergency room with pain at the site of her clitoral piercing for 1 day. She reported that earlier that day, she noted that the piercing did not move freely on with touching the area. The patient was sexually active one day prior. The patient's own attempts to remove the piercing were unsuccessful due to pain. She had also returned to the tattoo parlor where the piercing was performed 8 months earlier who recommended she seek medical care. On examination, the labia were normal without lesions. There was a straight metal barbell protruding at a perpendicular angle from the glans of the clitoris. On closer inspection, one of the removable balls was missing from the barbell externally and on palpation, the other ball attached to the straight barbell was appreciated underneath the glans of the clitoris. There was no drainage, bleeding, or evidence of infection. There was no evidence of scarring or keloid formation at the site of the piercing. The patient was unable to tolerate initial attempts to remove due to pain. She gave consent for attempted removal of the piercing in the emergency department. She was premedicated with 0.2 milligrams of intramuscular hydromorphone and the area was thoroughly cleansed with betadine. Then, 3 cc of 1% lidocaine without epinephrine was injected into the periclitoral skin and tested to ensure analgesia. A #11 scalpel was used to make a 2-millimeter superficial incision within the nonkeratinizing squamous epithelium overlying the clitoral glans over the embedded ball of the piercing . The embGenital piercing is not a new phenomenon. There are historical records of male genital piercing from as early as the 1st century B.C., and this practice has been alluded to in writings from the Mayan, Victorian, and World War II eras . While gThe practice of female genital piercing is not standardized. Common anatomical locations for female genital piercings include the labia majora, labia minora, and clitoris. The clitoris may be pierced through the prepuce, either horizontally or vertically or through the glans of the clitoris. Alternative female genital piercing locations that have been described include a vertical clitoral piercing exiting superiorly on the mons pubis, placement of a ring entering through the urethra and exiting between the urethral and vaginal openings (“Albertina Piercing”) , 8, and For clitoral piercings specifically, piercings through the clitoral hood or prepuce are associated with decreased rates of infection, injury to the clitoris, and fibrosis. Genital piercing of the clitoral glans has been associated with higher rates of loss of sensation and diminished sexual function due to increased risk of damage to the nerves and vascular structures that supply of clitoris  .Traumatic injuries occurring at the time of insertion or afterwards, such as during sexual intercourse, are not uncommon , 8. SurgEmbedded jewelry from piercings has been reported in other areas of the body, most commonly for lingual piercings. Piercings of the tongue and clitoris are alike as barbell jewelry is commonly used in both which consists of a central stud with two peripheral balls , 8, 10. Healthcare providers should be aware of the increasing prevalence of genital piercing and the complications inherent to this practice. Complications after genital piercings are common, reported in over 50% of patients who had genital piercings. While the practice of female genital piercing is not standardized or supported by a wealth of evidence based literature, prior studies do suggest that piercing of the glans of the clitoris is associated with higher rates of injury to the neurovascular structures leading to future fibrosis, decreased function, and injury , 8. Ther


In Latin American and Caribbean (LAC) countries, the number of cases of dog-mediated human rabies is at its lowest since the onset of the Regional Program for Rabies Elimination in 1983, a commitment from LAC countries to eliminate dog-mediated rabies coordinated by the Pan American Health Organization. Despite minor setbacks, the decline in the number of human cases has been constant since 1983. While many LAC countries have significantly reduced rabies to a level where it is no longer significant public health concern, elimination has proven elusive and pockets of the disease remain across the region. In the 33-year period since 1983, the region has set and committed to four dates for elimination . In this paper, we ponder on the multiple causes behind the elusive goal of rabies elimination, such as blanket regional goals oblivious to the large heterogeneity in national rabies capacities. Looking ahead to the elimination of dog-mediated rabies in the region, now established for 2022, we also review the many challenges and questions that the region faces in the last mile of the epidemic. Given the advanced position of the Americas in the race toward elimination, our considerations could provide valuable knowledge to other regions pursuing elimination goals. In 1983, when dog-mediated rabies in the American region was the cause of over 200 human deaths and 12,000 dog cases per year, representatives from the countries, gathered at the first Regional Meeting of Rabies Program Directors (REDIPRA)  .The development of a systematic evaluation framework of the countries capacities is thus critical. Such a framework would require the definition of regional standards and indicators as well as clear requirements regarding the nature and quality of the evidence needed to support control and elimination claims. A PAHO review of indicators used by the countries to monitor the performance of their rabies programs identified large heterogeneity, in the number of indicators per country, from just a few to more than 100, and in the nature of them, from process indicators to outcome indicators .The importance of the regular REDIPRA meetings, which constitute the strategic governance platform of rabies programs in the region, cannot be underestimated. Group dynamics prevalent at these meetings exercise great influence on strategic issues that cannot be replicated remotely. Specifically, we stress the importance of peer-pressure among countries. In addition, regional coordination requires formal structures to facilitate regular networking in the interval between REDIPRA meetings, e.g., via working groups around specific products such as interlaboratory proficiency exercises .On coordination, we must mention stakeholder engagement, even if briefly, and specifically one of the most salient actors in recent years, i.e., animal rights groups. The engagement of officials with these groups was not always productive and, at times, led to departures from the real focus on rabies control. But a change at both camps appears evident in recent years. Both sides have learned to moderate their message, and now understand that negotiation and not confrontation leads to better outcomes for all. Official programs start to recognize that these groups need to be brought to the discussion table at the planning stages, as they can deliver niche-specific approaches to local problems.The impact of interventions can only be monitored with reliable data. Since 1998, PAHO has been collecting data via questionnaires to the countries on their programs’ performance prior to the regular REDIPRA meetings. It was only at the most recent REDIPRA in 2015 that a thorough analysis of the data could be presented (Earlier reports stated that a number of Latin American and Caribbean (LAC) countries were conducting excellent rabies surveillance . These rThe investigations that followed the recent occurrence of multiple dog cases in Brazil , spanninThe regional rabies database, SIRVERA , despiteA prolonged epidemic tail, consecutive goal failures and farther in time goals, contribute to investors’ fatigue . It is a well-described fact that short-term goals lead to greater willingness to invest . The oppEfforts to attract investment must also recognize that at the end game, there is little room for inefficiencies. As a result, optimization of regional and national resource allocation schemes, e.g., by country or geographical area vs. by capacity, merits study to prevent underperforming assets from receiving undeserved support , 11. ThiNotwithstanding occasional problems, all countries in the region, except for those that have been free from rabies for years, plan the purchase of vaccine (for humans and dogs) in their annual budgets. This, in comparison with other regions, is a feast. Not all, though, manage to acquire the vaccine at all (most notably Haiti), or in the quantities and timelines needed. The insufficient deployment of vaccine, whether in control or elimination stages, is the ultimate reason as to why rabies persists in some of those countries. Insufficient dog vaccine deployment, due to deficient population coverage, untested vaccine quality, mismanagement of batches, and non-compliance with protocol, translates into failure to consistently achieve herd immunity in a number of scattered locations that remain endemic, even if undetected. Occasional donations and exchanges of vaccines between countries, whether brokered by PAHO or not, have been the norm in the past to supply vaccine to areas in acute need , 12. ThiFollowing on our remarks about the limited appetite for inefficiencies at the last mile, dog vaccine application must seek ways to reduce repeated vaccination of easy-to-reach animals. Beyond the financial implications, these animals contribute to vaccine coverage indicators, despite bringing no additional immunity, and may lead to a false sense of achievement about herd protection in the targeted dog population.Rabies programs across the region have benefited from the incorporation of human rabies vaccine in the countries’ regular acquisition of biologicals through PAHO’s purchasing mechanisms. In 2014, following recommendations from REDIPRA , PAHO alDespite seeing the lowest human case count in over 30 years, the demand for human rabies vaccine is on the rise. If human vaccine sold by PAHO’s purchasing mechanisms is a good proxy for the overall use across the region, bearing in mind that not all the LAC countries buy through PAHO, we have noted an average increase of over 55,000 doses of human vaccine every year for the period 2005–2015. In 2015 alone, circa of 900,000 doses were acquired via PAHO’s revolving fund. Although alternative dog surveillance systems, such as those based on tracking exposures after reported bites, could lead to more efficient PEP application , rabies In contrast to the evident scars left by smallpox, or other diseases with obvious sequelae, rabies does not leave living bearers to remind us of its occurrence. Together with the declining incidence, awareness of the disease will wane. This phenomenon will only get worse, and it would be important to regularly monitor the levels of awareness among the population in risk areas. Activities to that effect, e.g., knowledge-attitudes and practices surveys, may deliver collateral benefits by capturing heightened risk perception among the population that may provide sufficient reason, in the absence of adequate surveillance, for policy intervention.A decrease in awareness may also lead to reduced uptake of preventive measures as seen in other diseases, e.g., measles vaccine. For rabies, the impact might be twofold: leading to reduced dog vaccination, and PEP uptake and prescription by health staff after exposure. The latter was the target of the recent rabies alerts issued by PAHO after a number of cases in the region . HoweverIt has been said that the regional rabies elimination program is a victim of its own success, as reduced disease incidence leads to relaxation of controls, and new evidence needs at the end game challenge attitudes and practices that worked well during the control phase, but may not do so well during the last mile. Given the regional success, some resistance to accept innovations tested in other settings, as is the case of intradermal human rabies vaccine or the use of capture–recapture methods to estimate dog vaccine coverage, is expected. Transferring successful approaches from well-controlled projects in local settings elsewhere is not without difficulty as managers tend to dismiss them as generated from different contexts of little applicability to their own. This may be true, given well-known limitations in external validity of even the most robust investigations . HoweverBasic problem structuring theory identifies two types of complexities in every problem and decision setting to its resolution: technical or analytical complexities, and organizational complexities . For rabImprovements are underway. The regional program has now developed a framework for evaluation of rabies capacities, commissioned research to robustly guide dog surveillance requirements  and clasReaching out to countries to promote reporting as per the new data standards and to support the shift in focus toward monitoring capacities and vulnerabilities, and not just cases, will require increased resources by the regional program. The additional resource will have to be distributed across endemic, at risk and free areas. Although the most obvious targets are the endemic and at risk classes, the region must also capitalize on those areas that achieve freedom. To that effect, the regional program needs to formalize the processes around rabies elimination and maintenance of such status and demand thorough risk analysis by countries that contemplate interventions beyond their borders in collaboration with areas still posing a risk.Good as a planned approach may be, elimination requires more than cold preparation. Failure to reach the 2015 elimination goal should have generated a state of crisis to justify major transformational changes in the regional program. Without such changes, in the form of a state of urgency to propel the commitment to prompt elimination, the risk of apathy is real. Without consideration of the intangible benefits stemming from elimination, mostly of a political nature, the cold calculations around the diminishing returns of additional disease control measures at this stage may lead to the perpetuation of the current situation. This would betray the vision of those colleagues over 30 years ago. Without the pressure of an imminent goal, there are no regional consequences as a result of a new case, beyond the tragic death of a human being by a shameful disease.The recently approved “Plan of Action for the elimination of neglected infectious diseases and post-elimination actions 2016–2022” , should VV conceived and wrote the work. All the authors have critically reviewed and revised the manuscript and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors MV and states that the process nevertheless met the standards of a fair and objective review.


Pulmonary arterial hypertension (PAH) management has been transformed in recent times with the advent of cheap and effective diagnostic tools and therapy. Sildenafil, a phosphodiesterase-V inhibitor, has been at the centre of this treatment, and its success in treating PAH has led to its widespread uptake in adult and paediatric pulmonary hypertension (PH), as a first line treatment choice. This might apply to persistent pulmonary hypertension of the newborn (PPHN) or bronchopulmonary dysplasia, as well as to more complex diseases, such as idiopathic pulmonary hypertension. Although recent data regarding long-term mortality and the repeal of Food and Drug Administration (FDA) approval has complicated the issue, Sildenafil continues to be the major treatment option for paediatric PH for patients in a variety of contexts, and this does not seem likely to change in the foreseeable future. In this review, we provide a summary of pulmonary hypertension in infants and children and the use of Sildenafil for such diseases. Pulmonary hypertension (PH) is a chronic pathology with a progressive nature that, without treatment, can cause various complications, such as right-sided heart failure and death . Often sThere are a large number of aetiologies that can lead to PH, and although nowadays the majority of the risk factors are known, there are still an important number of cases in which the cause has yet to be discovered. In all cases, PH is a result of the increased resistance to blood flow through the lungs, which is sometimes due to the increased volume of pulmonary blood flow. Therefore, any change in either or all of these variables will consequently cause an increase in pulmonary arterial pressure  4]..4].Five groups of conditions have been classified as leading to PH: (1) pulmonary arterial hypertension (PAH); (2) a reaction to left-sided heart disease; (3) illnesses that emerge from either lung diseases or hypoxia; (4) chronic thromboembolism and 5) a grouping for unclear, unknown, multifactorial mechanisms . Se. Se30]. The guidelines of the European Society of Cardiology (ESC)  for PH rThe use of Sildenafil in Persistent Pulmonary Hypertension of the Newborn (PPHN) is controversial and needs further investigation, mainly due to the high risk of hypotension that was observed in IV administration. Therefore, it is highly recommended that it should be administrated in a slow IV infusion to reduce the occurrence of such hypotension. Sildenafil has been shown to improve arterial oxygenation by 16 mmHg  in patieBronchopulmonary dysplasia (BPD) is a chronic lung disease, more frequently seen in premature infants. Prematurity is observed in 10% of all births and BPD is seen in approximately 10% of these, of whom PH is found in 30–45% of these cases ,35. AbouSome studies have shown that PDE5 inhibitors normalize lung development, decrease right ventricle peak systolic pressure and improve outcomes ,38. SildPulmonary hypertension associated with congenital diaphragmatic hernia (CDH) in infants and children is a challenging condition to treat. Firstly, the enteral administration of Sildenafil is compromised in the majority of cases, mainly because of the delay in feeding and the food intolerance that can occur . SecondlEisenmenger’s Syndrome is defined as an untreated septal defect that leads to increased pulmonary vascular resistance (PVR) and subsequently to PAH, due to the reversed or bidirectional blood flow through the defect ,41. AccoSildenafil in the treatment of lymphatic malformations represents a new therapeutic avenue, although this indication needs further studies. After 20 weeks of therapy, one patient who had obstructive sleep apnoea, airway occlusion and the right ear canal infiltrated by a lymphatic malformation, showed improved symptomatology. Additionally, symptoms improved in 6/7 patients treated for this condition, suggesting a potential significant efficacy. There were no serious adverse effects in any of the patients and none of them had to stop their treatment .There have also been a variety of other causes of PAH where children have been treated effectively with Sildenafil. For the patients who experienced high PVR after heart transplant, Sildenafil treatment improved the right ventricular dysfunction and decreased PVR . This isFollowing the Fontan operation, for children and adolescents with functionally univentricular hearts, some patients have decreased pulmonary vascular compliance. In the absence of true PAH, but PVR is increased, Sildenafil or Bosentan therapy administered before and after Fontan surgery, has appeared to benefit such patients. This is now standard therapy both early on in intensive care, but also later in the “failing Fontan” period ,48.Five children who underwent haematopoietic stem cell transplant developed PH at a median of 2.5 months post-transplant. One of the children (the only one who survived) received Sildenafil therapy for 11 months, and was off oxygen and doing well after two years from the transplant. Although is an isolated case, this could open the door for Sildenafil use in many more conditions and underlines the importance of further investigations on the subject .Due to the increasing variety of pathologies in which Sildenafil is being used, and to the high number of comorbidities that are found in some of the paediatric patients, a unique dose regimen is almost impossible to establish, often leaving this matter to the judgment of the paediatric cardiologist. However, the approved and recommended dose regimen for oral administration varies according to body weight. In recent studies (STARTS 1 and 2), children were randomized in 4 dose groups of Sildenafil  and comparison was made for survival between these groups. In total, a death rate of 16% was found, while the low dose category had the lowest percentage of deaths, at 9%. The medium category was found to have a death rate of 16%, and the high dose group had the highest mortality, as 22% of the patients died, who were treated with a high dose. Interestingly, regardless of the up-titrations that were conducted in the low dose group, the number of deaths in this group was found to be far less than the other groups [Therefore, all patients over 1 year and under 20 kg should receive 10 mg of Sildenafil, three times a day. Even though it might be expected that older children should receive a higher dose, there have been concerns from the US that there was an excess mortality in children receiving high dose Sildenafil for PH . As a reSildenafil cannot be used in severe cases of hypotension because of its vasodilatory effect. Its use is also contraindicated in left ventricle outflow obstruction, in PAH associated with sickle cell anaemia, as well as in pulmonary veno-occlusive disease. Due to the relative potency of Sildenafil on PDE6, it also cannot be indicated in ischaemic optic neuropathy and in hereditary degenerative retinal disorders . AlthougTreatment of PAH in infants and children represents a real challenge and sometimes requires a combination of drugs in order to improve patient outcomes. Regardless of the aetiology of PAH, WHO FC and clinical parameters showed improvement after treating the patients with Sildenafil and Bosentan . HoweverNegative interactions have not yet been established when combined therapy of the newer endothelin receptor antagonist Macitentan and Sildenafil was used to treat PAH in adults or paediatric patients . The firTo this date, the effect of Sildenafil on the mortality of infants and children with PAH is not clear and further studies are still needed. After an average treatment duration of 4–12 months, the known mortality rate today is still between 5–30%. An insufficient number of studies have been conducted for a clear rate to be determined, but many studies have contributed to a more accurate image of how Sildenafil can be used as a potential therapy, in order to turn the risk and benefit balance in favour of the paediatric patient .The PDE5 inhibitor Sildenafil is a valuable pharmacotherapy that can be used to treat children and infants with PAH, both in monotherapy and combined therapy, as well as for additional related diseases. Nowadays, Sildenafil is approved in Europe for the treatment of PAH in children aged 1–17 years, although with some caution required. The problematic matter of researching new drugs on children is one of the main limitations for the use of Sildenafil, because without proper RCTs being performed, researchers and clinicians cannot be fully aware of the detailed treatment effects or consequent side effects. So far, the use of Sildenafil in the treatment of PAH in infants and children has shown potential benefits and improved patient outcomes. One of the most pressing questions that remains is at what dosage regimen patients can fully benefit from its favourable effects with the minimum possible adverse reactions. As previously mentioned, frequency and severity of adverse effects appear more often at higher doses  of Sildenafil and are correlated with higher mortality. At the opposite pole, the administration of low doses (10 mg) were less effective, but have a much lower mortality risk.Aside from the common aetiology, PAH as a result of cardiovascular surgery and haematological disorders has been alleviated with the use of Sildenafil. Although the haemodynamic and morphological aspects of cardiac transplantation and univentricular heart surgery have been subjected to statistical analyses, in order to assess the efficacy of the PDE5 inhibitor, the data on stem cells transplant remains scarce. The only existing information is from a study with a small group of five children, of whom, the survival of one patient was attributed to the Sildenafil administration. Other indications, such as in PPHN, BPD, CDH and Eisenmenger’s syndrome, have also had positive outcomes of Sildenafil therapy, through the improvement of cardiorespiratory physiology, but the variation in results among paediatric departments renders the need for further evaluation. Additionally, the reports on lymphatic reductions also require further analysis, due to the reduced number of patients in recently conducted studies.In all cases, it is quintessential that the selection and monitoring of patients has to be thorough, and that every aspect should be evaluated to establish clear criteria of Sildenafil administration, as well as evidence-based data regarding dosage, in order to accomplish the best possible outcome.It can be clearly seen that Sildenafil has been proven as a significant potential therapy which can provide beneficial effects in contributing to the improvement of a large variety of conditions. However, the currently available evidence-based data has inconsistent data, inconclusive pharmacological evidence and a lack of exact protocols in different aetiologies of PAH, still create an obstacle for the assessment of the role of Sildenafil, in spite of the recent advances that appear to demonstrate its effectiveness. The potential of Sildenafil alone, and also in combination with other current PAH therapies, requires additional exploration in order to find the correct treatment strategy for the challenging paediatric pathology that is PH. Further research is needed to conclude the ideal posology of Sildenafil and to establish its place in the future developments and therapies in the field of paediatric cardiology.


Selective breeding and intensive management of farm animals have increased their productivity. At the same time, the ability of the animal to cope with challenges from its environment has decreased. The manner in which the animal interacts with its environment influences its ability to cope. In recent models of brain function, neural tissue is understood to predict the sensations that arise from behavioural activities. The brain also predicts sensory input from physiological activities and from at least some activities of the immune system. An ability to predict and control sensory inputs provides the animal with agency, while a continuing discrepancy between predicted and actual sensory inputs leads to stress and negative emotional states. Through these processes, aspects of the environment acquire a negative or positive character: that is the environment becomes valenced. Predicting and controlling its environment gives the animal agency. Mutualism may represent a further step towards closer synchronisation between animal and environment. A better description of the environment from the animal’s perspective could improve our understanding of how cognition, behaviour, temperament, immune functions and metabolic activities are linked, and improve strategies to enhance farm animal welfare.Genetic selection of farm animals for productivity, and intensification of farming practices have yielded substantial improvements in efficiency; however, the capacity of animals to cope with environmental challenges has diminished. Understanding how the animal and environment interact is central to efforts to improve the health, fitness, and welfare of animals through breeding and management strategies. The review examines aspects of the environment that are sensed by the animal. The predictive brain model of sensory perception and motor action (the Bayesian brain model) and its recent extension to account for anticipatory, predictive control of physiological activities is described. Afferent sensory input from the immune system, and induction of predictive immune functions by the efferent nervous system are also in accord with the Bayesian brain model. In this model, expected sensory input  is reconciled with actual sensory input through behavioural, physiological and immune actions, and through updating future expectations. Sustained discrepancy between expected and actual sensory inputs occurs when environmental encounters cannot be predicted and controlled resulting in stress and negative affective states. Through these processes, from the animal’s perspective, aspects of the environment acquire a negative or positive character: that is the environment becomes valenced. In a homeostatic manner, affective experience guides the animal towards synchronisation and a greater degree of mutualism with its environment. A better understanding of the dynamic among environmental valence, animal affect and mutualism may provide a better understanding of genetic and phenotypic links between temperament, immune function, metabolic performance, affective state, and resilience in farm animals, and provide further opportunities to improve their welfare. The application of quantitative methods to the selective breeding of farm animals and the intensification of animal management in the second half of the 20th century have led to impressive improvements in productivity. At the same time as meat, milk, fibre, and egg production have increased, the animal’s capacity to stay healthy and fertile in a diversity of environments has diminished . The cauThe relationship between the animal and its environment is central to all these aspects of farm animal biology. Is the environment a concrete, invariant, objective reality that shapes the animal, or do animal and environment engage in a more interdependent manner? This brief review examines animal environment interaction and its relationship to neural, behavioural, physiological and immune functions of the animal. As the central integrative modulator of these processes, it is suggested that affective state provides a barometer of mutualism in the dynamic of animal environment engagement.Does the environment exert a mechanical influence on the animal in its everyday life? This materialist conception of an instrumental environment shaping the animal was challenged in 1909 by the Estonian biologist von Uexküll who proposed that the animal is immersed in its surrounding world. Writing in German, he termed the surrounding world “Umwelt” and proposed that the animal and its environment constitute a functional interacting unit, or function circle ,11. Von provides or furnishes, either for good or ill [emphasis in original]” (p. 127). In Gibson’s view, affordances are features of the environment that provide opportunities for action. Affordances can be surfaces to stand on, to lie on or to rub against, objects to chew, air to breathe, and so on. For a goat climbing on a cliff face to access plants and salt, the crevices and ledges are affordances, but for cattle (for example) these same ledges may provide no affordance [In 1977, the American psychologist JJ Gibson introduced the concept of “affordances” to describe the resources available to the animal in its environment ,13. Gibsfordance . Opportufordance . Two spefordance . In contfordance ,18. Despfordance ,21,22) hRecognition of animal/environment as a dynamic system starts from a consideration of the animal as a whole functional entity. Asking how the animal’s sensory systems enable it to engage with its environment begins to break the animal down into functions or activities, and leads to questions of how senses enable neural control of behaviour and physiology. The brain is physically isolated from the external world yet requires information to regulate engagement of the animal with its surroundings. The senses of sight, hearing, touch, taste and smell as well as the senses of position and motion of the body send afferent signals to the brain reporting the animal’s interaction with the external environment . The braRecent models of neural function suggest that rather than operating as a stimulus response network, the brain generates expectations from prior experience of the train of sensory input noted above that it is about to receive. Discrepancy between expected and actual sensory input can lead both to sensorimotor actions and to a change in subsequent expectations ,26,27. HAs well as controlling engagement with the external environment, the brain maintains the internal environment of the animal in a physiological state conducive to surviving, thriving, and reproducing ,32. SensAn important feature of interoception is its influence on the affective state of the animal ,43,44. WThe immune system of vertebrates recognizes short sequences and three dimensional conformations of molecules through two sets of receptors. The first is a germ line encoded set that binds predominantly with molecular structures common amongst microorganisms. These receptors provide innate immunity. A second set of receptors are generated throughout the life of the animal by somatic hypermutation of a small number of genes and provide adaptive immunity. A vast network of messengers produced within the immune system regulates its activity . In addiTwo important questions are firstly whether immune activity as a sensory input to neural tissue can be linked to anticipatory behavioural and physiological functions, and secondly whether the brain can exert anticipatory and predictive control over activities of the immune system. The role of the immune system as an afferent sensory arm of the brain is well recognised. For instance, immune activation by a wide variety of immune stimuli induce sickness behaviours that modify foraging and rest ,52, a neThe other arm of the Bayesian model is initiation of predictive actions. This is the second question. Can the brain exert predictive control over immune functions? Indeed a large body of evidence indicates that a wide range of immune functions can be entrained by classical Pavlovian conditioning to non-immunological cues such as ingestion of a sucrose syrup in rats ,56,57. IIn the formulation given above of animal/external environment as dynamic process, there is no discrete boundary between the animal and the environment that determines where the animal ends and the external environment begins . This isAs the internal physiological environment is contained within the animal, a consideration of its boundary with the animal need not concern us in detail here; however, the nature of the immunological boundary poses a more interesting problem. The boundary between the animal and the environment is described by immunologists to arise from a distinction between self  and non-self  . FurtherThus, whether examining the animal as a behavioural agent sensing sounds, smells, light, movement and pressure, or as an immunological agent sensing molecular structures, there is no clear boundary between the organism and the environment. Within the environment of affordances and the environment of molecular structures, the organism and environment combine as a dynamic process.The Bayesian account sees behavioural, physiological and immune functions as processes in which expectations are continually updated to better match environmental conditions. Expectations are generated endogenously from prior experience and from drives and needs arising spontaneously from neural activities. Yet environmental conditions are rarely static and the capacity to reconcile expectations with actual afferent sensory inputs can be limited by the ability of the animal to predict change in, or to exert influence over its external, physiological and immune environments. An inability to predict and control environments results in changes that are recognised as stress ,65,66. IWithin the dynamic of animal/environment interaction, the capacity of the animal to balance sensations with expectations is not necessarily stable over time. When actions are unable to provide prediction and control, the environment can be considered to exert an instrumentality that shapes the actions of the animal. As an object of environmental effects, the animal is in a state of objecthood. When the animal can command its interactions with the environment through prediction and control it exerts agency ,67. As rYet acting as agent may not itself represent the optimal outcome for the animal of the animal environment interaction. As noted above, the dynamic of interaction generates affective experience. From this realisation developed the concept that, from the animal’s perspective, the environment is valenced and provides a landscape of affective experience ,44,68,69Farm animals are managed in a diversity of environments extending from naturalistic rangeland pastures to intensive housing in close confinement with conspecifics. Availability of environmental resources and freedom to fulfil needs and drives are recognized as fundamental requirements for good animal welfare . The neeFrom many lines of enquiry comes a view that the animal needs a cognitive, affective, physical and immunological grasp on its environment in order to survive, thrive and reproduce. While substantial progress has been made, an improved understanding of aspects that enable farm animals to predict and control their environment has the potential to further improve definition of traits such as temperament and resilience, and to further improve design of the farm animal environment. In outbred populations like farm animals, individuals differ in their response to conditions and challenges that to the scientist’s eye may appear identical for each animal ,82,83. B


Research has demonstrated a reduction in olfactory functioning in patients with schizophrenia. This research has led to examination of olfactory functioning in other mental disorders, such as depression. There is a great deal of variation in the results generated from such research, and it remains unclear as to how olfactory functioning is associated with or impacted by depression.The current review examined the literature in accordance with PRISMA guidelines in order to generate a better understanding of this relationship and to identify if and what aspects of olfactory processing are altered. Through examination of the available literature from the databases PubMed, Ovid Medline, CINAL, and PsychINFO, 15 manuscripts were selected to determine if there was a difference in olfactory processing—specifically central and peripheral processing—between depressed individuals and non-depressed controls.p < 0.05).The comparison of the 15 studies showed that the majority of studies  found a difference in overall olfactory functioning between depressed individuals and non-depressed controls (There is still a lack of definitive conclusions due to variation of which olfactory process was altered.Given the differences in the methodology and design of these studies, a possible solution that could eliminate the lack of clarity and reduce variation would be to adhere to a single, thorough methodology that examines and separates central and peripheral olfactory processing. Future research employing a uniform and validated methodology could provide more definitive conclusions as to how and if olfactory functioning is related depression. Within the global population, approximately 15% of the worldwide burden of disease is attributed to mental disorders  and 8–12Within the adult brain, the OB and hippocampus are the only areas that demonstrate postnatal neuroplasticity –15. MousThere is uncertainty regarding the connections observed, and if the therapeutic/restorative effect of antidepressant medication can be observed in the OB volume and neurogenesis of depressed humans. Based on findings previously observed in rodents, researchers have suggested that the use of antidepressant therapies including pharmaceutical and psychological interventions could also improve olfactory function , 40, 41.Despite the growing interest in this area of research over the last two decades, inconsistent results and no clear conclusion as to if and how olfaction is altered in depressed patients still remain. In order to more clearly understand the relationship between depression and olfaction, we have systematically examined the available literature and evaluated the olfactory data available comparing depressed patients to non-depressed controls. The goal of this study is to provide further understanding and overview of the studies that have been conducted over the last few decades with regards to this topic and to generate a conclusion with regards to the relationship between depression and olfaction.A search of the literature was conducted according to PRISMA guidelines  see Fig using thA total of 928 manuscripts were yielded from a search of the databases. These 928 studies were entered into EndNote™ Basic, where duplicates of the studies gathered were identified and eliminated to give a total of 698 manuscripts. The manuscripts were then reviewed using titles, with 142 manuscripts reviewed by abstracts, and finally 51 full manuscripts were reviewed. All titles, abstracts, and manuscripts were reviewed independently by two authors . All disagreements were discussed and reviewed by both authors until a consensus was reached based on inclusion/exclusion criteria. The references of the reviewed manuscripts were also examined for other studies of relevance. Of the full manuscripts reviewed, 17 were screened for inclusion/exclusion criteria with 15 meeting the criteria.For inclusion, all studies must have included data on a quantitative difference or loss of olfactory functioning in depressed and healthy control groups. All studies must have included subjects between the ages of 18 and 70, in order to exclude results due to age-related olfactory loss. Those studies that focused on primary olfactory dysfunction included patients with neurocognitive or neuropsychiatric disorders other than depression or employed patient self-report or subjective olfactory data were excluded.Each of the included studies were evaluated for quality in accordance with the Critical Appraisal Skills Program (CASP) criteria—a quality assessment tool for qualitative data in review studies that focuses on the following three elements: rigor, credibility, and relevance. The CASP is a 10-item questionnaire and the studies must meet all of the criteria in order to be included. 17 studies were examined under quality review based on these following questions: (1) clearly focused, (2) appropriate method, (3) cases recruited acceptable, (4) controls recruited in an acceptable manner, (5) accurate measurement and minimized bias, (6) confounds are addressed and accounted for, (7) results are precise, (8) results are believable, (9) can be applied locally, and (10) fir other available evidence. Of these 17 studies, 15 met criteria while 2 did not , 48. TheHT extracted the data from those studies meeting criteria. The information gathered was as follows: number of cases and non-depressed controls; methodology employed for measurement of olfaction and the specific aspect of olfaction focused on; demographics; correlations, means, SDs, and conclusions regarding depression and olfaction; as well as any other relevant or pertinent information.p > 0.05, see Table S1 in Supplementary Material for specific statistical values)  between the two groups, with depressed scoring significantly lower than controls  , 48, 50.controls , 40, 48.p = 0.037) with depressed scoring lower on the discrimination tests. No significant difference after a psychotherapy program. The remaining studies did not find any significant difference in the olfactory discrimination scores in depressed compared to control.Only four studies examined olfactory discrimination , 31, 41.p < 0.05)  , 51, 53.Methodology used for the measurement of olfactory functioning varied. Olfactory parameters were measured using three testing paradigms: Burghart’s Sniffin’ Sticks, University of Pennyslvania Smell Identification Test (UPSIT), and the use of varying concentrations and/or a variety of chemicals with differing odors. Four of the fifteen manuscripts employed the Sniffin’ Sticks Extended Test to measure threshold, discrimination, identification, or a combination of any of those three , 52, 53.A lack of understanding of the relationship between olfaction and depression is seen throughout the literature for many different aspects of olfactory functioning. The goal of our study was to examine the available literature pertaining to the topic of olfactory dysfunction in individuals with a primary diagnosis of depression, including major depression disorder, seasonal affective disorder (SAD), and bipolar depression (BD)/disorder. A comparison of the fifteen studies which met criteria shows that nine of fifteen (60%) studies found significant differences between depressed and non-depressed controls on some aspect of olfactory functioning, with depressed having scores that reflected poorer olfactory functioning. However, the remaining six found there was no significant difference at baseline between depressed and non-depressed controls. Upon further examination of the results, it is important to note that while the results of some are not significant, in some studies the depressed patients performed poorer than non-depressed controls on average , 52. An The aspect of olfactory functioning with the most agreement with regards to a significant difference between depressed and non-depressed controls was the aspect of olfactory threshold, also termed as olfactory sensitivity in some studies. Four of the eight studies that examined threshold found that was a significant difference between the olfactory threshold of depressed and that of non-depressed controls , 48, 52.One aspect of the literature that was of particular interest was the alteration in olfactory functioning before and after treatment for depression. Of the fifteen studies examined, only four used an experimental design involving an interventional protocol of either antidepressant medication , 53, psyOverall, we do indeed find that olfactory functioning is impaired in depression; however, the variation in what aspect of olfaction is impaired remains mixed. Kohli et al.  suggestsMany studies examined only one or two of threshold, discrimination, or identification using either the UPSIT, Sniffin’ Sticks or a lab-made procedure. The variation within the testing procedures likely contributes to the inconsistency in the literature and further hinders the formation of a clear conclusion as to the nature of the relationship between olfaction and depression. We assert that a solution to this issue is tangible and obtainable by researchers adhering to a single, consistent methodology that involves testing all three of: threshold discrimination, and identification. Measuring all three aspects of olfaction allows or differentiation of the processing systems and closer examination of which, if not both, systems are impacted in depression.The majority of the studies available in the literature examine olfaction at only one time which may be the etiological or contributing factor for the variation and confusion as to the relationship between depression and olfaction. While some researchers find no relationship between the two as there is no significant difference between non-depressed controls and depressed patients, many of the patients were already under treatment and how the olfaction changes at the initiation or over the course of this treatment was not examined. Observation of how olfactory processing, especially central processing, is altered in conjunction with treatment of depression could further substantiate and provide evidence for the theory that OB volume and neurogenesis restoration can be observed in depressed humans after improvement of depression severity. The improvement of depression severity is believed to be linked to an increase in neurogenesis in the hippocampus , 15 and In addition to inconsistency in the methodology employed and small sample sizes, the age range of the participants may have an impact in the results. All of the studies included participants within the age range of approximately 20–70 years, with some variation in the exact range throughout . We included studies with participants in this age range in order to control for age-related decline in sensory functioning and to focus primarily on adults rather than elderly individuals. While this would allow for a more inclusive study, the maximum age still poses a specific problem with regards to the impact of aging in olfactory functioning. In particular, the inclusion of participants over the age of 60–65 and the comparison of the olfactory functioning of such participants to those younger represents a limitation and a possible explanation for the variation in the results and a lack of significance. A decrease in olfactory functioning is a common occurrence and consequence of aging with age having a strong influence on the results of psychophysical tests of olfaction . Within Within the literature, there are very few reviews on the topic of olfactory functioning and depression. However, of those that have been published, a recent publication by Kohli and colleagues  focusingWhile conducting the literature review and analysis of the results, we encountered a number of limitations. The largest limitation we encountered was during the meta-analysis phase of the review. We intended to conduct a meta-analysis of the four studies that examined olfaction before and after treatment, with the goal of finding a common conclusion through the combination of the data. However, we were unsuccessful in doing so due to the variable methodology and reporting employed by the researchers, the manner in which the data were analyzed and presented by the researchers, and the small number of studies included in the analysis. Of the four studies, only two used the same methodology , 53, whiIn assessment of depression, particularly at the onset of depressive episodes, many clinical scales—such as the Montgomery–Asberg Depression Rating Scale and Hamilton Depression Inventory—measure a loss of appetite as an indicator of hedonic evaluation. However, the underlying mechanisms and representation of hedonics in the sensory system are not measured further  and ofteOlfaction is a sense that individuals often take for granted and do not notice when there is a reduction in their ability to smell. However, olfaction is greatly involved in quality of life through ability to enjoy surroundings, involvement in appetite and taste quality of food, and heavily integrated into memory storage and recall , 61. ExaWhile there is variation in which aspect of olfaction is altered, our review of the literature found that there indeed is an alteration to olfactory functioning and processing in individuals with depression at baseline and after treatment. Focusing specifically on those studies that employed an interventional methodology, we find that depression and olfaction changed over the course of treatment with an overall improvement in olfactory functioning and depression severity , 40, 53.All authors contributed substantially to the conception and design, as well as agree to be held accountable for all aspects of the work. HT drafted the article and revised it critically for important intellectual content, as well as gave the final approval of the version to be published. HT and CW contributed to the acquisition, analysis, and interpretation of the data. CW and RM revised the article critically for important intellectual content, as well as gave final approval of the version to be published.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.


In this study, we analyzed healthcare provision and health expenditure across six Mediterranean countries that adopt the National Health System (Beveridge model) and that form part of the European Union (EU) with the main aim being that of analyzing and comparing out-of-pocket health spending in countries with a European Mediterranean connection. To this end, we considered various economic indicators and statistics to derive commonalities and differences across these countries and also compared trends in these indicators to those observed across the rest of the EU. We then analyzed these findings in light of other data related to the quality of healthcare delivery and the infrastructure of the health system and discussed recent developments in healthcare within each country and the main challenges faced by the respective health systems. The results show that on average, Mediterranean countries spend less on total healthcare expenditure (THE) than the EU average, both as a proportion of GDP, as well as in per capita terms. This is primarily driven by lower-than-EU-average public funding of healthcare. The 2008/2009 macro-economic and financial crisis had a significant impact on the countries under review, and explains the persistent reductions in public health spending as part of the austerity measures put in force across sectors. On the flipside, Mediterranean countries have a higher presence of private health providers in total funding, thereby explaining the higher Out-of-Pocket (OOPs) health expenditures in these countries relative to the EU-average. With regard to the overall health infrastructure in these countries, we observed that although the supply of physicians is largely in line with the rest of the EU, there is under-supply when it comes to hospital beds. This may be symptomatic of lower government funding. Nonetheless, all countries score highly in the evaluation of the quality of health services, as recorded by international rankings like the WHO's 2000 metric, whereas health system performance indicators, namely mortality rates and life expectancy reveal favorable health outcomes in the Mediterranean EU countries. The findings in this paper may be seen in light of the Mediterranean region's lifestyle in terms of diet, health behavior, health beliefs and shared culture. In particular, the higher out-of-pocket expenditure may reflect the tendency for one-to-one relationships with private clinicians and the pursuit of person-centered care . Additio In most countries, the level of expenditure on healthcare is increasing over time, largely due to their allotment of a higher proportion of the national financial budget –4. In faVarious theoretical and empirical studies such as those by Ogura and Jakovljevic  and DielAcross the Mediterranean countries , health expenditure varies considerably and as in other parts of the world, the demand on healthcare in this region is on the rise. Since the 2008 macro-economic crisis, health spending was markedly reduced across the EU after years of continuous growth. The substantial variation in the distribution of health expenditure across European and Mediterranean countries is reflected in different types of expenditure, whether public, private or insurance-based. The Mediterranean countries adopted a number of measures to contain healthcare costs, namely changes to public funding, the introduction of user charges, changes in entitlements, the introduction of health technology assessment and the restructuring of healthcare services [e.g., In our comparative research of these countries, we aim to demonstrate the extent to which structure and finances vary or are similar, especially in relation to out-of-pocket spending in the health sector. We explore whether the countries in this region offer similar health services and have similar influences in terms of culture, traditions, climate and diet. In this manner, we will be able to determine whether these influences play a major part in the decisions related to health expenditure. Moreover, the paper aims to uncover trends over time in these countries that may be useful for developed, developing and underdeveloped countries for future readiness and forecasts .The methodology of this research was based on a detailed analysis and evaluation of a series of data indicators related to health expenditure patterns in each country. Indicators related to health expenditure reflect performance of health systems, albeit the extent to which health expenditure could influence health system efficiency is still debatable . We haveNational expenditure on healthcare has trended upwards for the last quarter of the twentieth century, noting spiked investment in the industry from both the private and public sectors . An incrFigure It is interesting to note the relationship between public health spending and OOPs among European countries. As seen in Figure We now turn to a more in-depth analysis of the economic indicators of the countries under consideration. In Malta, THE as a percentage of GDP increased from 5.7 to 9.7% between 1995 and 2014, the highest of any Mediterranean country. Furthermore, Malta also experienced the highest growth in THE per capita among the Mediterranean countries considered, with an increase of almost 242% from US$898.48 in 1995 to US$3071.63 in 2014 , this has been on a downward trajectory since 2011. The public sector's share in total healthcare expenditure has risen from 70.8% in 1995 to 75.6% in 2014, while the private sector's share has fallen from 29.2% in 1995 to 24.4% in 2014.Greece's THE trajectory has largely mirrored the country's economic fortunes, particularly in the aftermath of the global financial crisis. In fact, as a percentage of GDP total healthcare expenditure actually fell slightly over the period 1995 to 2014, from 8.3 to 8.1%, with the decline mainly concentrated in the 2009-2014 period. Health expenditure per capita did increase over the period under review, from US$1266.563 in 1995 to US$2098.05 in 2014, the smallest increase in the Mediterranean, mainly as a result of a steep decline from US$3012.66 in 2008, coinciding with the economic crisis and subsequent austerity program. It is interesting to note the sectoral share of healthcare expenditure in Greece over this period, since in 1995 the private-public shares were relatively similar at 48 and 52% respectively. Since then however, the public sector's share increased to 61.7% in 2014, while the private sector's share has fallen to 38.3%.The results presented above point toward a number of key similarities shared by the Mediterranean countries as regards healthcare expenditure. More specifically, we observed that THE, both in per capita terms and as a percentage of GDP, is lower in these countries relative to the EU average, mainly as a result of lower-than-average public health spending, albeit in most cases this has increased over time. OOP health expenditure is also higher in these countries relative to other European countries , underliFurthermore, with the exception of Malta, THE across these countries has stalled somewhat in recent years (both in per capita terms and as a proportion of GDP), which can be linked to the 2008-09 global macro-economic and financial crisis and the impact that this had within these countries in terms of dampened economic conditions, as well as austerity measures to control public finances .When analyzing whether these salient characteristics have had any discernible impact on the actual quality and infrastructure of healthcare in these six Mediterranean countries, we take note of , and practitioners are allowed to participate in the private system, as well as the public system. The public or government healthcare platform is free to all Maltese and European citizens . HoweverPortugal's healthcare system is driven by subsystems that merge the objectives of both the private and public healthcare systems . Some ofIn Spain, the publicly-funded Spanish Health Service (or SHS) provides free medical treatment for all patients, who undertake a consultation with a doctor who is recognized by or affiliated with the Spanish State Health Service , with coCyprus has a dual healthcare system which, uniquely to the rest of the European countries, is largely skewed toward the private sector, although in recent years public health provision has grown in importance. Cyprus is the only EU member state without (near) universal public health coverage, with around 83% of the population in 2014 covered by free healthcare . The natHealthcare in Italy is largely operated by the public sector, and has the second highest-ranked health service in the world according to the World Health Organization . The natIn Greece, public healthcare is provided by the National Healthcare Service (ESY), built on the principle of universal coverage . A publiDespite the high number of physicians per 1,000 people, the Greek public health system has long been plagued by inefficiencies in management and organization, requiring significant reforms . The gloThe study incorporated information from different sources to ensure that it maintained accurate information for the analysis required. However, the time period considered, 1995-2014, is an accurate long-run indicator. Additionally, one must also take into account the unique factors that characterized both the last quarter of the twentith century, including mass development of industries, cities and economies , as wellIt is also arguable that the reports filed by individual countries through their various agencies might be fixed and, therefore, unreliable . We sougWith this study, we have sought to analyze healthcare provision and expenditure across six Mediterranean countries  forming part of the European Union. To this end, we considered various indicators and statistics in order to derive commonalities and differences across these countries. We compared their overall trends to those observed across the rest of the European Union. We then analyzed these findings in light of other data related to the quality of healthcare and infrastructure within these countries, before looking at recent developments within each country and the main challenges faced.The results show that on average, the Mediterranean countries spend less on total healthcare expenditure than the EU average, both as a proportion of GDP as well as in per capita terms. This is primarily driven by lower-than-average public funding of healthcare, which must be considered in light of the economic crisis which had a significant impact on the countries under review, and reductions in public spending due to austerity measures. On the flipside, the Mediterranean countries have a higher presence of private health providers in total funding, while OOP health expenditures are higher in these countries relative to the average in the EU.With regard to the overall health infrastructure in these countries, we observed that although the supply of physicians is largely in line with the rest of the EU, there is under-supply when it comes to hospital beds, which may be symptomatic of lower government funding and thus driving higher OOPs. Nonetheless, all countries score highly when it comes to evaluating the quality of the health services, both according to independent international rankings like the WHO's 2000 metric as well as other indicators like mortality rates and life expectancy, which all point toward favorable health outcomes in the Mediterranean.Many of the countries analyzed in this paper have undertaken significant healthcare reforms in recent years, with the aim of improving efficiency and quality in healthcare provision and thereby decreasing the high out-of-pocket healthcare spending. The economic crisis has stifled these reforms to some extent, since in many countries like Greece and Italy significant cuts to public health expenditure were enacted in order to rein in rising debt levels. Therefore, a major challenge faced by these countries is to ensure maximum coverage for citizens, particularly the most vulnerable members of society, all while faced with tightening public health budgets. This further emphasizes the importance of public sector reforms in terms of ensuring improved efficiency, governance and management of public health administration. Furthermore, increased decentralization and autonomy of public health management at the regional level, which is a feature of many countries in the Mediterranean and indeed across Europe, brings new challenges like ensuring coordination across regions and consistency of quality standards to avoid the creation of regional disparities in healthcare provision, which in turn may exacerbate existing disparities in economic and social outcomes.Besides these financial and administrative challenges, various socio-economic and cultural developments across the Mediterranean may have important implications for healthcare systems in these countries. One such development is increased migratory flows from North African countries, which have grown significantly over the last two decades and which place further pressures on public healthcare and the need for universal coverage . AnotherThese findings further serve to emphasize the commonalities observed in this group of EU Mediterranean countries, who despite their diversity have clear similarities in terms of socio-demographic developments, health outcomes, total health expenditure patterns as well as the relative importance of private healthcare providers in these countries. It is the intention of the authors to invite future research, most likely using the health care utilization model or related health sociology models to explain the likelihood for people in these countries to go for OOP expenditure.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer KK and the handling Editor declared their shared affiliation.