The incidence of zoonotic cutaneous leishmaniasis (ZCL) makes it the most widespread parasitic disease in Tunisia and the Arab world. Yet, few studies have addressed its psychological and psychosocial effects. The purpose of this study was to examine the psychosocial impact of ZCL scars among Tunisian women.We conducted an exploratory study, we administered Revised Illness Perception Questionnaire (IPQ-R), World Health Organization Quality Of Life-26 (WHOQOL-26) and Psoriasis Life Stress Inventory (PLSI) to a group of girls and women with ZCL scar in the region of Sidi Bouzid. This group was randomly selected from volunteers who came to primary health care facilities to seek for treatment for any pathology.Descriptive statistics showed that the collected scores from the three scales exhibit heterogeneous distributions: IPQ-R , PSLI , WHOQOL-Physical , WHOQOL-Psychological , WHOQOL-Social , and WHOQOL-Environmental . The correlation analyses performed on Inter and intra-subscales showed that the emotional representations associated with ZCL were correlated with the loss of self-esteem and feelings of inferiority . In addition, high education level and the knowledge about ZCL are positively correlated with cognitive and emotional representation in the IPQ-R . "Rejection experiences" and the "anticipation and avoidance of stress" were respectively negatively correlated with age . Correlations between the scores on IPQ-R domains and PLSI factors were significant. The results showed that anticipation of rejection and avoidance of stress are strongly correlated with a negative perception of ZCL. Quality of life scores were not correlated with either age, education level, time of illness, or the number of facial or body scars. However, the correlations between quality of life scores and the multiple IPQ-R domains were all insignificant. Finally, there was a negative correlation between the scores on the perceived quality of social life and the knowledge about ZCL .This makes it vital to strengthen preventive health education. Conducting studies on ways to establish a holistic support system for managing ZCL, a system that covers the psychological challenges and the barriers it causes to women’s social and professional integration, is a vital first step. Zoonotic cutaneous leishmaniasis (ZCL) is the most common form of leishmaniasis in Tunisia. The disease is not severe and heal spontaneously with a definitive scar causing a social impact mainly when the lesion occurs in the face. Yet, few studies have addressed these psychological and psychosocial effects. To examine these issues among Tunisian women suffering from ZCL, we administered Revised Illness Perception Questionnaire (IPQ-R), World Health Organization Quality Of Life-26 (WHOQOL-26) and Psoriasis Life Stress Inventory (PLSI) to a group of girls and women with ZCL scars in the region of Sidi Bouzid. This study demonstrated the wide range of psychological effects  and psychosocial impacts  of ZCL permanent scars; mainly when it is located in the face; among women and girls. This study suggests the need of social and psychological support and professional integration for women and girls in rural remote areas first and second conducts studies on ways to establish control measures for ZCL, mainly in vulnerable exposed population. Cutaneous leishmaniasis is the most common form of leishmaniasis. It is a skin infection caused by a unicellular parasite transmitted by infected sandflies that feed on the blood of rodents bred in caves or burrows in degraded environments. It is known also as Oriental Sore, Biskra Button, Aleppo boil or Tabaa Sidi Bouzid, depending on the geographic region concerned.Cutaneous leishmaniasis is endemic in many parts of the world. There are about twenty different species of Leishmania capable of infecting humans. The distribution of cutaneous leishmaniasis is very closely related to the geographical characteristics and the ecological specificities of the endemic areas.Cutaneous leishmaniasis always heals spontaneously, but leaves permanent scars. New treatment options and new molecules are still in the process of getting validated. ZCL is the most widespread parasitic disease in Tunisia. It mostly affects people who live in the central and south-western parts of the country.ZCL is not a fatal disease, but it causes significant changes in victims that affect their psychosocial condition and quality of life. Work done in Pakistan and Afghanistan  suggestsThe theoretical framework for this study is the self-regulatory theory framework by which Leventhal, Meyer & Nerenz  explain identity: what the illness is called and the symptoms that affect the patient and are associated with the illness; the cause: the patient’s opinion on the causes of the illness. An illness with no identifiable cause is a devastating experience that causes impotence and difficult adjustment; the timeline: chronic, acute or cyclical; the consequences: for the patient and his entourage; and cure and control: this domain refers to personal perceptions of one’s potential power to control the illness and its spontaneous development or treatment.According to Leventhal, Nerenz and Steele , there aemotional representation, relating to all the negative feelings caused by the illness or the coherence of the illness, a metacognitive domain relating to the general understanding of the illness and to the degree of integration of its various dimensions, symptoms and causes.Apart from these five domains of illness perception, there are other domains such as Our study intended to evaluate the psychological and social impact of ZCL on women with facial scars in the region of Sidi Bouzid. Understanding perceptions of ZCL and quality of life among patients with ZCL and ZCL scars can help us develop psychosocial intervention strategies to fight against stigma and self-deprecation, and to develop strategies for preventing harmful behaviour patterns on ZCL.The study was conducted in Sidi Bouzid, a predominantly rural or semi-rural region with scattered groups of extended families attached to their farmland. Sidi Bouzid is a region that provides over 20% of the country's agricultural production. There is no psychological services available for this population. For the facility and the feasibility of this first study and the disponibility of the population, the sample was made up of 41 girls and women from El Hichria (n = 31) and Ouled Mhamed (n = 10) in the Sidi Bouzid Governorate . We condTo assess the perception of health and illness, we used the "Revised Illness Perception Questionnaire (IPQ-R )." This The IPQ-R contains 71 questions rated on a four-level Likert scale on level of agreement with the item . It explores the illness identity, timeline, consequences, cure, control, and coherence domains and the emotional representation domain.During scaling and scoring, we did reverse recoding of several items. The results for the domains are expressed in percentages.The assessment of the psychosocial impact of leishmaniasis was done using the Psoriasis Life Stress Inventory (PSLI) questionnaire . The queTo assess the quality of life of adolescents and women affected by ZCL, we chose to use the World Health Organization Quality Of Life-26 (WHOQOL-26) scale . This scFour major factors of quality of life were examined to enable us to have a sufficiently comprehensive perception of the perceived quality of life of the respondents according to four domains: 1. The physical domain, which covers items on physical pain feeling, the need for any medical treatment, energy for everyday life, sleep satisfaction, functional capacity, energy and work capacity; 2. The psychological domain, which contains items exploring aspects of perceived satisfaction about the meaning of life, the capacity of concentration, the bodily appearance, self-image, and negative feelings; 3. The domain of social relationships, which includes items related to satisfaction about personal relationships, sex life, and social support; 4. The environmental health domain, which comprises items related to perceived safety in daily life, financial resources, information availability, leisure activities, condition of living place, accessibility to health services, and transportation.The questionnaires were administered in the following order: the IPQ-R, the PLSI and WHOQOL Bref.Statistica 6 software after verifying that it was entered properly. We performed statistical analysis using parametric tests after checking for the normal distribution of variables. The correlation analysis were done using the Pearson correlation coefficient. For comparison, we used Student’s t-test or variance analysis. We didn’t perform multivariate analysis because of the small sample size.The information gathered was processed using The questionnaires were administered by a psychologist and/or a health educator on ZCL patients in their homes or at the local clinic. All persons who participated in this study did so willingly. The study was approved by the "Ethic committee of Pasteur Institute of Tunis (IPT)".All women provided informed consent, and parents of any child participant provided also informed consent on their behalf. The informed consent given by all subjects was oral since the majority of them were illiterate, the psychologist and the health educator explained the aim and the procedure of the study and asked them for consent. The "Ethic committee" approved the study since we didn't need any clinic or biological investigation from all subjects with the guarantee from the research team about confidentiality and the respect of individual information. The response on the questionnaire attest the oral consent of participants.For the respondents in the survey, this disease, "leishmaniasis", is linked with sand flies. All the respondents stated that they consider ZCL scars as marks of the disease, and that the number of scars varies from person to person. Seventy-eight per cent considered that ZCL is sex-specific. Seventy-eight per cent declared that it is seasonal and spares no age group. Seventy per cent believed the insect bites eventually become scars. The respondents had different views on whether this disease was found recently (56%) or a long time ago and on the possible disappearance of the scars over time (51%). Further, 68% stated that ZCL is dangerous.Concerning perceptions on the causes of ZCL, the respondents mentioned the human responsibility for the environmental changes. The majority considered that ZCL is not hereditary (80%). It was not related to the quality of food (92%), or stress in everyday life (78%). However, 73% linked the environment (stagnant water) and physical activity  with the incidence of ZCL. About 66% thought extreme temperatures contribute to the incidence of ZCL. Close to three quarters (73%) saw a correlation between stagnant water, sand flies and the incidence of ZCL. About fifty percent made a link between ZCL and abundant rainfall that frequently ends by forming stagnant water. This may be because these events rarely occur in Sidi Bouzid. The summer is usually very hot and associated easily with sand flies and increased risk of sand fly bites and illness.Almost 71% of the respondents mentioned the notion of vectors and reservoirs. Close to two thirds linked rat’s sand flies to ZCL transmission. Yet, barely 43% said that killing rats and sand flies vectors is relevant to preventing risk of exposure to ZCL.Eighty five per cent of the respondents thought that sand flies are responsible for the disease. Eighty seven per cent admitted there is a correlation between working with animals and exposure to ZCL. None of the subjects believed that the sandfly that are related to ZCL are small and almost invisible. Seventy per cent said that the sand fly that are linked to ZCL are the same size as other mosquitoes.We found that the respondents’ perceptions on the time it takes for scars to develop ranged from an uncertain period (some scars are permanent while others appear and then fade away) to chronicity, sometimes with an increase in the number and appearance of the scars. Almost half the number of respondents stated that the scars do not fade quickly, but they were carefully optimistic that the scars would fade gradually with time.The respondents said unanimously that ZCL has had no positive effects on their lives. The consequences have rather been negative. About 73% suffered social exclusion and stigmatization. Their relationships have been broken and they face more interpersonal conflicts in society, regardless of the context . The consequences were seen also in their chances of getting employment. ZCL affected women who stay at home more than those who study or are already working. It reduced marriage prospects for men (75%) and women (59%). The consequences were felt also on aesthetic features, for the scars alter women’s beauty (58%).With respect to individual ability to control ZCL, the most common perception was an absolute lack of power to control and cure the disease. The respondents thought there is nothing useful they can do to control the disease, its symptoms or its progress. Drugs were seen to have little or no effect, and the risk of getting the disease again is still likely.When it comes to understanding the problem, we noted that patients still cannot explain how they contracted ZCL. There is little understanding of the problem, and respondents keep asking themselves "why am I the one who is infected".We found that the emotional representations associated with ZCL were associated with the loss of self-esteem, feelings of inferiority and the idea that the disease is equal to an obvious social disadvantage. There was also a strong sense of shame.The inter-correlation matrix for multiple IPQ-R domains  showed tThis correlation analysis suggested also that patients who have a more coherent perception of ZCL do have stronger emotional reactions  and face more severe consequences . Finally, those who are more inclined to perceive ZCL as an illness with negative consequences were more likely to claim that they experience severe emotional difficulties .All these significant correlations are maintained even after testing them on the "age" variable and the "education level" variable, using partial correlations.The descriptive data focused more on anticipation of a negative reaction from others and the efforts made to display anticipatory avoidance behaviour meant to deny such reactions, than on convictions from the presence of negative experiences that patients have had through social interactions on the state of their skin ."Rejection experiences" and the "anticipation and avoidance of stress" were respectively, significantly and negatively correlated with age . The younger the subject, the higher the number of experiences tied to stigma; and the older the subject, the more such feelings are dismissed. Thus, the correlation analysis showed that stigma assessment indices were not correlated with level of education, "total knowledge" score, or time of illness. They were correlated only with age: the younger the subject, the more they tend to experience stigma.Furthermore, there are moderate correlations and just around the significant level between the total number of body scars and "rejection experiences" , and between the number of facial scars and the scores on "Anticipation and avoidance of stress" . It is important to note that this correlation between the number of scars and stigma indices was at the same threshold of significance when checked against age-related variations. Hence, the number of body scars had a strong link to experience with stigma, regardless of a patient’s age.We also noted correlations between the scores on multiple IPQ-R domains  and PLSI factors . Environmental quality of life is seen as significantly less fulfilling (p<0.001) than quality of social life. According to the respondents, it appeared to be far less fulfilling than (p<0.001) the physical quality of life. Quality of mental life did not differ much from environmental quality of life. However, it is said to be significantly more impaired than quality of social life (p<0.001) and the physical quality of life (p<0.001). The physical quality of life was not described as significantly different from quality of social life .Quality of life scores were not significantly correlated with either age, education level, time of illness, or the number of facial or body scars . In addiOn the other hand, quality of life scores had interesting correlations with PLSI scores on stigma Figs  and 4. TFinally, there was a significant and negative correlation between the score on quality of social life and that on "Total Knowledge". It seems that the higher a person’s knowledge of ZCL, the less likely they are to view their quality of social life in a negative manner . The quality of knowledge seems therefore to be tied closely to the quality of social life .It was important also to note that the correlation between scores on 'Rejection experience" and on mental quality of life index was on the verge of the threshold of significance . Mental quality of life tends to be perceived negatively, if the subject claims to have suffered many rejection experiences. The mental quality of life index tended to be associated with the total stress and stigma score .The objective of this study is to explore the perceptions of ZCL, the stigma associated with the disease, and the quality of life of people with ZCL in Sidi Bouzid.We studied the perceptions of CL based on the theoretical model by Leventhal et al. , which ith of February, 2016, we found that ScienceDirect contained 1 758 articles on "IPQ-R" and 21 831 articles on "leishmania", but no entry on "IPQ-R" and "leishmania".It is the first time this type of model, and the assessment tool associated with it (IPQ-R), is applied to study CL. For example, on the 18It is the first time also that the psychological and psychosocial aspects of CL are studied in the Arab world, which is one of the areas with the highest number of cases of CL in the world. All works dealt basically with the epidemiological and/or biological aspects of the issue. Despite the originality of this work, our results should be taken with caution and have to be confirmed because we only did an explanatory study on a small sample size.Based on the results from the IPQ-R, we see that patients tend to consider ZCL as a disease that affects entire generations and is more rampant in some regions more than others. The disease mostly affects women and spreads in cyclical trends, caused by "mosquito" bites associated with the presence of rats, and related to climate change and the favourable ecological context in Sidi Bouzid. The patients were incline to think ZCL has negative consequences on their personal, family, social and professional life. They generally believe that ZCL considerably alters their natural beauty and reduces their prospects of getting employment, getting married and being valued in society. They see ZCL as a mysterious, incurable and uncontrollable disease.After analysing the responses we had gathered under the “causes” domain in the survey questionnaire, we were able to identify patients’ beliefs on the underlying causes of ZCL. The contents relate basically to biological and/or ecological causes. The patients did not talk about irrational, supernatural and magical causes, as was the case with some patients in Colombia .ZCL patients think that living with the disease is a steady source of stress that forces them to develop anticipatory avoidance behaviour against rejection. They try to anticipate stigma primarily out of feelings of inferiority in society. These problems bring about a huge sense of injustice and anger to the point where there is little sympathy with other girls or women with ZCL. These difficulties can lead to depression and anxiety. The patients think their scars are degrading and this increases their feelings of shame. They describe their feeling of isolation, that is, they think subjectively that they are inferior to other members of society, that they are not fully fledged individuals, or that they have an "impaired identity" and suffer discrimination, which includes rejection and isolation from others. Anticipated stigma is a subjective experience that could negatively affect psychosocial and professional development and adjustment among patients. These results largely confirm the findings from similar studies conducted on patients with vitiligo .The psychological effects of ZCL tend to reduce as patients get older. The more educated a patient is, the more his knowledge of the disease develops, and the more he tends to analyse the consequences of the disease and display dramatic emotional reactions. A high level of education and high levels of knowledge are associated with greater cognitive sensitivity (perception of consequences) and emotional sensitivity .After calculating our correlation analysis, the results we obtained were consistent with the theoretical construct on illness perception in Leventhal’s model . We noteMoreover, there is a high level of consistency between perceptions of CL in the IPQ-R and stigma indices in the PLSI. Anticipation and avoidance of stress have a strong correlation with a patient’s perceptions of the "consequences", "coherence" and "emotional representation" of the disease. The more patients see ZCL as a disease with severe, unambiguous consequences that have harmful emotional effects, the more they tend to expect to be rejected by others, and the more they would be inclined to form avoidance attitudes towards others. These conclusions do not concern the relationships between these variables and the patient’s age, level of education, or knowledge of the disease.The correlation between the level of stigma and the number of lesions is not related to the location of these lesions on the face or elsewhere on the body. This rather surprising result confirms the work of Papadopoulos et al.  who repoOur results also suggest that the nature of stigma that patients experience are associated with certain general fears and anticipation of rejection, rather than the possible rejection that patient truly experience from society. However, this is not the case in some countries like Pakistan, where Afghan refugees with CL face stigma and are excluded from social groups , or in AThe respondents believe that ZCL has a generally negative impact on quality of life. But our results show that ZCL has differential impacts on the four domains of quality of life in the WHOQOL-26. The quality of life of ZCL patients is largely unsatisfactory in two domains: environmental quality of life and quality of mental life. The respondents are inclined to think that the environmental quality of life is the more degraded of the two. It includes availability of financial resources, freedom, security, access to and quality of housing, opportunities for acquiring new information and skills, opportunities for recreation and leisure, as well as the availability and quality of transport facilities. We are assuming that ZCL patients are not the only ones dissatisfied with this domain. The entire population shares this dissatisfaction with the environmental quality of life in the region of Sidi Bouzid.For the respondents, the quality of mental life is lower than physical quality of life and the quality of social life. It suggests that they are dissatisfied with their self-image and appearance, with the negative sentiment displayed towards them, with their self-esteem and their cognitive abilities . This latter result is frequently described in literature on skin infections .None of the domains on quality of life is closely correlated with the scores that reflect patients’ perception of ZCL in the IPQ-R. However, the quality of social life domain is significantly and negatively correlated to the "Anticipation and avoidance of stress" factor in the Psoriasis Life Stress Inventory (PLSI) questionnaire. The more a person expects to face rejection and stigma, the lower the quality of social life they have when it comes to personal relations and social support. These dynamics have been observed already in patients with psoriasis .ZCL got little attention for long because, apart from the aesthetic effects it has, the disease is neither contagious nor fatal, and causes no major health concerns. However, it can have adverse socio-economic effects. ZCL is a health problem in developing countries because of the social and economic challenges it causes . The disThese results show that public health officials, in planning control programmes, should pay attention to the gaps in knowledge perceptions, the vulnerability of women to cutaneous leishmaniasis, the ways of preventing their exposure and the psychological support to reduce the psychosocial effects .With the Leventhal model , we haveIt is crucial also to take preventive measures, given the importance of behavioural aspects in the onset of the disease. Byrne et al.  have desS1 Table(XLSX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


The target of this investigation was to determine the effectiveness of neurofeedback in promoting reading in deaf kids after cochlear implantation. This research was an analytical example of 8 kids (5 sons and three girls) grown 8-14 years old by an IQ of eighty, based on Wechsler exam scheduled on the student’s list. Next recognizing the students according to specific standards, parents and their kid engaged in the research, which happened in Ava square in Ilam, and, afterward heard the stories about the way they could manage the trade themselves. No past of seizure disorders, epilepsy and brain trauma was recorded. No past of seizure disorders, epilepsy and brain trauma was recorded. The cochlear implant was done in 18 months and highest twenty-four months. The members were randomly split into a test collection and a check collection. The experimental group got neurofeedback therapy for twenty sessions of forty minutes any (3 sessions by week). The means used in this research were a demographic questionnaire , a reading disorder test, and the neurofeedback devices. The capability to read the neurofeedback collection recorded that the reading problems in the experimental group were lower. Also, the functional groups, relocation, replacement and reverse readings improved. According to this definition, a person whose hearing has been damaged needs special procedures to understand the spoken words of others. The Education act has defined hearing disability as an audition impairment, which goes beyond so that the student will not be able to process the others’ verbal information without a hearing help. Hearing impairment has been reported among 28 million Americans, of whom, 1% has been seen with severe hearing impairment [1]. With regard to the investigations undergone by practitioners of the education center, in average, about 50% of the children require an education program and people with a hearing handicap require special aids. In this area, the main problem lies in how to train individuals who face limitation. Children with a hearing impairment cannot set relationships with others, thus the feelings such as isolation, failure and loneliness will dominate them, whereby this problem will complicate the issue of education for them [2]. Hearing loss is a reality throughout the world, which dates back to the literature on Exceptional Children. Factors, which have been considered in the area of deaf children, include discussion and exchange of ideas about sensorineural hearing loss, the oral methods, oral method with finger movements, oral (lip-reading) method, both sensory and multi-sensory methods, single sensory methods. Each of the proposed educational procedures for deaf children had consistent evidence; thus we could witness diversity in the educational styles in working with deaf children, where hopeful outcomes concerning efforts made to date could be observed [3]. About 30%-40% of deaf or hard-of-hearing babies have been seen with nerve growth status or mental retardation. According to the statistics research board, the most common statuses in hearing impairment include mental retardation, learning disabilities, and attention problems. Further, some disabilities might not emerge until childhood or adolescence, resulting in an increase of these figures. Despite the exposure with some similarities with mentally retarded children and children without mental retardation, in investigating general issues related to deafness in children, it could be observed that deaf children pass cognitive and linguistic stages similar to normal children, who repeated mistakes the same as mistakes by normal children at certain stages of evolution of language. Almost 30% of the kids with a hearing disorder, in addition to hearing loss, also have other disabilities including mental retardation, significant vision impairment, learning disabilities, and attention deficit disorder. Furthermore, emotional or behavioral problems, cerebral palsy, bone problems might also occur with lack of hearing. Looking into the previous experiences at the area of fostering children with newly diagnosed hearing impairment indicated that the early diagnosis of hearing disorder and use of intervention programs could be the best way to help for progress. To use the advantage of ductility of the central nervous organization, maximize treatment, and reduce functional defects, the intervention must be started, followed by the diagnosis. Children with an early hearing-loss detection and interruption related to the kids with late hearing-loss detection have better cognitive, social, and linguistic skills and all these factors help the children attend in normal conjunctive classes and open environments. In recent decades, intervention programs have been increasingly expanded to prevent behavioral disorders and healthy of mental problems of deaf children. Some of these programs could train the children with the required skills such as response inhibition, knowledge of impulsive behavior, emotion regulation. The committee of exceptional children and the council of deaf children have had some standards for teachers of deaf children for over one decade, in which all the needs required for deaf children were considered. Studies have shown that the kids who attended training courses for executive functions one or two years earlier, presented a huge progress in their social skills, skill of problem-solving and cognitive performance, such that all these progress related to executive functions [4].Regular hearing implies the capability to recognize the spoken words of others without any need to treatment aids or special procedures [5] formulated a test to evaluate the reading skill, in which deaf students in the age group 14-16 years were asked to read some sentences and apply the instructions to the read the text, whereby the results indicated that the deaf students in the age group 14-16 years had the same function as the 7 years old students. In the procedure of knowing the reading comprehension input that was the text, finally, the semantic output was produced, whereby the meaning of the text was understood; thereby, the talent of reading without understanding the concept of terms was not accounted as a complete process to achieve the ultimate aim of reading, that was, the knowing of the meaning of the text. The linguistic processing must be fulfilled during special stages at different levels covering syntactic, phonological, and morphological words, thus the required ability for reading implies phonological awareness, reading comprehension and dominance on reading the words [6]. Due to deficits in working the memory, deaf students have a poorer comprehension and reading [7]. Learning subjective subjects and theoretical contexts cannot be practicable, which is difficult for the character with a hearing disability and the reason for this is the impairment in speaking, thinking, and visualizing. Hence, it can be told that hearing impairment causes pseudo-academia and laziness. The studies on the academic performance of kids with hearing disability indicated loss academic performance of these children. In this regard, Peter Rimmer quoted from Saeedi in his studies, stating that he had perceived these children under their education level for 5 years. Using the Stanford Achievement Test (SAT.HT), which was standardized in 1972 on 6871 kids with hearing disability, Kretschmer found disorders of reading in these students. Reading is important education skills; it can be said that learning, knowledge, awareness, and advance in all the educational courses rely on the skill of reading. Reading, in all age groups, is one of the most influence methods of enriching language and expanding words, syntax, semantics, and language use. Reading disorder is one of the most common disorders in learning. Largest of the people with a reading disorder have been seen with loss progress in their brain cells and expanding problems in their reading derived from visual and auditory problems. This derives from problems in neurons, which have formed a network in the brain, deemed allocating for time changes. Reading, while one of the talents and abilities acquired in school, plays a major role in the individual growth of a character and his attendance in society. Reading is a cognitive and linguistic process, which has a familiar association with another linguistic process including speaking, writing, listening, which the child acquires. Notably, children with a hearing impairment face problems in their subjective activities such as processing, storage, and retrieval of data. A variety of studies have been conducted in the area of problems of reading comprehension among deaf children. In 1916, two English scholars [8] indicated that 0.95 of the deaf students who graduated from school, were deemed as 7 years old students regarding reading comprehension. The outcomes of the research quoted by KakuJoybari [8]. Deaf education is the education of students with a variety of hearing levels, which dates back to a long time ago; teaching reading and writing is an unavoidable necessity to increase communication skills of hearing-impaired children. Reading is one of the cognitive skills that was developed as the result of the interaction between the nervous system and cultural experience [9]. Reading comprehension is a complicated procedure that requires coordination and combination of skills of word recognition and understanding the meanings [10]. Reading is one of the most important skills for children in learning courses. Proficiency in reading through speaking and listening or writing and reading comes to be realized by the use of signs and symptoms [11].Additional investigations determined that the deaf students face substantial problems in their life regarding verbal communication skills, such as understanding the meanings of words, speaking, reading comprehension, and writing [12]. Neurofeedback is a treatment model for changing or modifying cognitive, emotional, and physiological processes in patients. The results of studies indicated that neurofeedback fosters the brain for activity or proper pattern during various sessions. However, a variety of studies on treatments for learning disabilities concerning neurofeedback have been conducted; in a study it was indicated that children with learning difficulties are different from other children in terms of EEG indicators. One of the methods for the normalization of the brainwave of children with learning disabled (LD) can use Valproate Sodium. Neurofeedback therapy is another technique that normalizes brainwaves. Neurofeedback regards to the method of factor conditioning in which the individuals learn to change the electrical activity of their brain [13]. Neurofeedback aims to treat EEG abnormalities, whereby improvement of cognitive or behavioral performances will result. Neurofeedback is inhibited as a form of conditioning the electrical action of the brain. It is believed that neurofeedback recalls growth and brings about alterations in brain cell surfaces, which supports the brain function and the cognitive/ behavioral performance [12].Studies in the meaning of deaf children’s reading comprehension have had disappointing results. It must be regarded that these results do not indicate an intellectual disability of deaf children, but the weakness in the reading comprehension in this group derives from the factors with cognitive nature. Reading comprehension is both a cognitive and linguistic process, which has a close relation with the another linguistic processes including speaking, writing, listening, which the child acquires. Notably, the children with a hearing impairment face problems in their subjective activities such as processing, storage, and retrieval of data. Since reading comprehension and learning reading skill require the acquisition of visual recognition of linguistic elements including letters, words and sentences, thus recognizing strengths and weaknesses in both cognitive and linguistic areas, it seems that essential brain waves depending on the frequency are classified into four groups: Delta (1 to 3 Hz), theta (4 to 7 Hz), alpha (8 to 13 Hz) and beta (14 to 30 Hz). We can witness alpha activity when a person is relaxed, but alert. Yet, when a person involves in a cognitive activity or problem resolving, we can witness beta waves. Delta waves are recognized when people are in long sleep or in a coma, and theta waves are seen when the person is in light sleep  mentioned that brain circuits that are used to regulate a subjective practice are those used to regulate a physical practice, i.e. The sensorimotor cortex works out in conducting physical and mental processes, and this cortex is more likely used for sensorimotor functions. Hence, the clients who have difficulties in understanding their cognitive tasks can use the neurofeedback education in their treatment process. Neurofeedback education using the systems which deal with emotion, feeling, attention and working memory, develops the energy source, movement, reasoning and thinking. Regarding the SMR area, in another explanation for finding of this research, it can be told that the activation of neuronal circuits involved in cognitive processes comes to be realized. Previous investigations have explained that the working memory depends on a neuronal circuit, which is acquired from the interaction between the attention control system in the prefrontal cortex and the sensory information storage in the dorsal prefrontal association area. In current research, a part of. In current research, a part of the protocol was applied for the destruction of theta waves, and the related works showed that theta relates to poor performance, and the outcomes showed that the suppression of theta waves caused a better cognitive performance. In other words, neurofeedback education has positive effects on the individuals’ subjective performance and cognitive processing, confirming the conclusions of this research. Further, Ratey . To date, this method has not been used to improve the comprehension in deaf children. In this research, the writers tried to get an approach to increase the reading comprehension of deaf children so that to help improving the educational, communicative, and social abilities of deaf children, besides other educational approaches of deaf children. Another explanation for the effect of neurofeedback thalamus, regarding the early changes in the activity, more likely occurring via neurofeedback, mentioned that these changes might modify EEG through thalamocortical circuits. Hence, changes in the EEG were deemed as the result of complex reorganization of neuronal activity. A variety of studies have been conducted in the area of effectiveness of neurofeedback in developing the students’ reading difficulties, whereby significant results have been obtained  was used to diagnose kids with reading problems. According to this test, three clinical characteristics including mistakes in reading, speed of reading and reading knowledge of students were measured. According to this test, a score was given to each participant per any error, and the sum of scores of the member was recognized as his total errors; further, a score was awarded to each participant per any response to the reading knowledge problems. Finally, the time spent by the participant from the start to the end of reading the text, was regarded as the index of speed of reading; further, coefficients of reading validity of 0.56, 0.61 and 0.68 at third, fourth and fifth grades were obtained [17].The reading disturbance exam developed and normalized by Nesfat et al. . In the second protocol, theta (407) and hyper-beta (22-30), suppression of SMR (subset of beta) in encoding dynamiv and cognitive responsibilities helped the cerebral cortex, adding that the encoding of dynamic and cognitive responsibilities helped the cerebral cortex in brain circuits. Brain circuits which were used to regulate a subjective practice, were those used to regulate a physical practice. Hence, the clients who had difficulties in understanding the logical sequence of cognitive tasks could use the neurofeedback therapy in their sensorimotor cortex of the right hemisphere (C4) to recall their emotions and feelings. Education in midpoint or Cz facilitated a mixed response. In other words, increasing the activity at the central cortex was followed by increasing the activity in skills of both hemispheres as a precondition for a prosperous understanding and attainment of the reading skills. Neurofeedback sessions were organized until the twelfth session during three sessions in a week, and sessions of 12 to 19 were organized during two sessions in a week. Treatment processes: the participant was sat on a chair in front of a computer screen in a room in a total silence; he prepared tulip ear-tips and areas C4, C3, Cz by using alcohol and gel, for which Alpha-theta protocol was performed. To this, the active electrode was transferred to point Cz. Feedback of alpha-theta protocol was in the form of voice (sound of waves in ocean - River), that the participant used to hark to the sound with his eyes closed, and if he fell asleep, the device had to be alerted. In this protocol, the person found the ability to establish a balance and coordination between alpha and theta, where this protocol was performed in any session during 20 minutes. The next 20 minutes were considered for training protocol SMR, where theta waves of 4-7 Hz and beta waves of 22-30 Hz were suppressed, and SMR waves were strengthened. Finally, the threshold was written down for the next session.The second protocol: the SMR protocol was implemented in C3, C4 areas. In this protocol, SMR (subset of beta) was strengthened for 12 to 15 Hz, and theta was suppressed for 4 to 7 Hz. These two protocols were repeated during all 20 education sessions. Since session seven, any student seen with progress, received a CD box. They also received a CD in the thirteenth and nineteenth sessions. The rational reason for the treatment used in this research relied on the factors below: in comparing EEG in normal and LD children, the highest amount of EEG frequency was in LD children by increasing the theta activity , who believes that reading comprehension in deaf children is poorer compared to normal children. Besides all the studies on exceptional individuals, on linguistic, cognitive and verbal abilities of deaf individuals and their comparison with normal individuals to examine the differences, have been more likely drawn into attention in scientific communities. bout the ability of deaf individuals concerning the achievement of life skills, attention to training these individuals is important. Deaf children often cannot foster the courses and concepts relating to language in them. If hearing impairment occurs at the early childhood, the deaf child might find some of the various sorts of learning impossible. As the early experiences of the kids are often visual and tactile, their first dialogues are generally through sign language and gestures. The children who have hearing difficulties, learn in their early childhood how to talk with so much difficulty, because proper dialogue relies on copying from others’ speech. Hearing impairment affects the formation of a concept. Progress in reading has a slow trend in person including a hearing disability [19]. It was revealed that there is a meaningful distinction with common children and children affected by a reading disorder concerning EEG waves. Neurofeedback seeks to train the individuals to normalize their brain waves reaction to the stimulants. Neurofeedback can be applied to stimulate or regulate the exercise of the brain. Neurofeedback is also used for normal individuals’ neurofeedback causes increasing the capacity of working memory and attention to education performance, and besides, neurofeedback had significant results in LD treatment. The therapists enabled to indicate that training neurofeedback could cause an enhancement of the cognitive functions. These results are relevant and similar to the conclusions of the research by Vernon et al [5]. A section of the protocol applied in this research was regarded as the increase of Cz. To define this finding, it can be said that neurofeedback education affects three sensorimotor cortexes. Therefore, it can be assumed that neurofeedback facilitates information processing because SMR reduces the voluntary direction of the motor system interference in Cognitive Information Processing.The studies in the two recent decades have given use of absolute responses, the responses that have confused the teachers and have obliged them to have a revision on their methods about fostering deaf children. By studying brain injuries and their complications on reading, some researchers called important brain activities involved in brain injuries. A special electroencephalogram (EEG) pattern has been observed in children detected with dyslexia [


We investigated the short-term impact of Typhoon Haiyan, one of the strongest typhoons ever to make landfall, on the pattern of admissions in two hospitals in Eastern Visayas, the Philippines.This study took place at Eastern Visayas Regional Medical Center (EVRMC) in Tacloban, and Ormoc District Hospital (ODH) in Ormoc. We determined whether there were differences in the pattern of admissions between the week before and the three weeks after Haiyan by using information on sex, age, diagnosis, ward and outcome at discharge from patient records.There was a drop in admissions in both hospitals after Haiyan as compared to before. Admissions climbed back to the baseline after ten days in EVRMC and after two weeks in ODH. When comparing the period after Haiyan to the period before, there was a relative increase in male versus female admissions in ODH , but not in EVRMC. Patients aged ≥50 years and 0–14 years had the highest relative increase in admissions. There was a relative decrease in admissions for the ICD10 group ‘Pregnancy, childbirth and the puerperium’ , and an increase in ‘Certain infectious and parasitic diseases’ , mainly gastroenteritis, and ‘Diseases of the respiratory system’ , mainly pneumonia, compared to all other diagnosis groups in ODH. Out of all reasons for admission within the study period, 66% belong to these three ICD-10 groups. Data on reasons for admission were not available for EVRMC.The observed reduction in patients after the Typhoon calls for ensuring that hospital accessibility should be protected and reinforced, especially for pregnant women, by trying to remove debris in the direct hospital vicinity. Hospitals in areas prone to tropical cyclones should be prepared to treat large numbers of patients with gastroenteritis and pneumonia, as part of their disaster plans. Tropical cyclones are called typhoons if they occur in the northwestern Pacific Ocean and hurricanes in the Atlantic and northeastern Pacific Ocean. Damage due to this type of event occurs because of strong winds, which in turn can lead to storm surges, a tsunami-like phenomenon. These types of events can have a large impact on the number of hospital admissions, as well as on the cause for hospitalisation, as has been shown in previous studies. The number of admissions within six hospitals in Hampton Roads, Virginia (USA), increased on the day of Hurricane Isabel, but recovered to the baseline level the day after . HoweverThere is very limited research on the impact of tropical cyclones on hospital admissions in low- and middle-income countries. Patient data collected from a field hospital in Banda Aceh, Indonesia, after the 2004 tsunami showed no increase in cholera, malaria and dengue in the four months following the event [th of November 2013, the Philippines was hit by Typhoon Haiyan, which was the strongest typhoon ever to make landfall on a major island in the western North Pacific Ocean [On the 8ic Ocean . The impic Ocean . The citic Ocean , due to ic Ocean . In the ic Ocean  and chroic Ocean , and peric Ocean .This study investigated the short-term impact of Typhoon Haiyan on admissions in two hospitals that remained operational during and after the typhoon in Eastern Visayas, Philippines. We examined whether there were differences in the pattern of admissions between the week before and the three weeks after Haiyan in terms of age, sex, the ward in which patients were admitted, their diagnosis and their outcome at discharge. The general assumption is that women and children are mostly affected by disasters, but until now there is almost no evidence to back this up. The results of this study help to fill the existing gap on the impact of tropical cyclones on hospital admissions in low- and middle-income countries, and it is essential for preparation of hospitals for future events.Eastern Visayas Regional Medical Center (EVRMC), a tertiary hospital in Tacloban, and Ormoc District Hospital (ODH), a secondary hospital in Ormoc. The capacities of EVRMC and ODH in 2013 were 250 and 100 beds, respectively. In EVRMC, there was an operational disaster plan in place, which was not the case for ODH. Although both hospitals remained operational, they were partly damaged by the typhoon. EVRMC was hit by strong winds as well as a storm surge, while ODH only experienced strong winds [The study was carried out in the region of the Philippines that was hardest hit by the typhoon, the Eastern Visayas. ng winds . DespiteData from patient records were collected from centralised hospital registries. Patient records were summarised in logbooks in EVRMC and in Excel files in ODH. The research team collected data on all admissions that took place in November 2013, one week before (baseline) and approximately three weeks after Typhoon Haiyan. Admission date, sex, age, ward in which the patient was admitted, final diagnosis and patient outcome at discharge were available from patient records. In EVRMC, the research team entered patient data from logbooks in September 2016, using the software EpiData 3.1.We grouped age in four categories: 0–4, 5–14, 15–49 and ≥50 years old. The research team reclassified all diagnoses according to the International Classification of Diseases, ICD-10 version 2016, up until the third level [th in the period after the typhoon. The hospitals were located on different sides of the island, and they were affected by different weather phenomena. EVRMC is a tertiary hospital and ODH secondary, so the number and complexity of cases they receive is different. For the above reasons, we decided to analyse and present the results separately.We made a descriptive overview of the study variables for the baseline week (November 1–7), and each week after Typhoon Haiyan . We carried out logistic regression, comparing variables between the baseline period before Typhoon Haiyan (November 1–7) and the period after (November 8–30). As Haiyan occurred in the early morning of November 8, we included the 8For EVRMC, data on diagnosis and patient outcome at discharge were available for only 25% of the cases. Therefore, we decided not to include these variables for the EVRMC analyses, but instead we used ward as a proxy for diagnosis (e.g. Obstetrics ward for diagnoses related to pregnancy and childbirth). All other variables had few missing values for both hospitals (>90% complete).Patient data were used anonymously. Ethical clearance was waived by the Institutional Ethics Review Committee of EVRMC, since it was a retrospective study using chart records.The daily number of admissions before and after Haiyan for both hospitals is shown in The numbers of admissions per week in terms of sex, age, ward, patient outcome at discharge and diagnosis are presented in Tables We tested whether there was a proportional increase in admission characteristics in the period after Haiyan (November 8–30) compared to baseline (November 1–7). The contribution of childbirth-related admissions was large Tables  and 2. SThe results from our study show that there was an overall decrease in the number of admissions in the two weeks after Haiyan. We noted a decrease in admissions for females vs. males in the post-typhoon period. With regard to age groups, the very young and the older populations were more likely to be hospitalised than those between 5–49 years of age after the typhoon. Obstetrics and surgical admissions decreased, in contrast to orthopaedic admissions and hospitalisations for infections and respiratory diseases. The proportion of deaths among admitted patients was low and was not significantly affected by the typhoon.Typically, acute events such as tropical cyclones and earthquakes do present peaks in the number of admissions , 15, 16,We noticed an overall decrease in the absolute number of patients admitted in the Obstetrics ward and for reasons related to ‘Pregnancy, childbirth and the puerperium’, of which 94% consists of deliveries, after Haiyan compared to baseline Tables  and 2. TApart from deliveries, Haiyan also affected other types of admissions. In EVRMC, a relative reduction in admissions in the Surgery ward was observed, although this was not seen in ODH . This reThe relationship between lack of roofing and pneumonia has been shown in a study in urban settings in Dhaka, Bangladesh . An incrWe observed some differences in the sex and age patterns between the two hospitals. The absolute decrease in female admissions in ODH after Haiyan compared to the week before Haiyan, and the relative decrease compared to male admissions, were not observed in EVRMC. It may correspond with the decrease in admissions in the ODH Obstetrics ward, although this was not confirmed by our sensitivity analysis without cases admitted to the Obstetrics ward and new-borns. People aged ≥50 years had the highest relative risk of admission in EVRMC after Haiyan compared to baseline, while this was the case for children aged 0–4 years in ODH. Both these age groups are generally observed to be also at risk for increased mortality after tropical cyclones .Our study had some limitations. First, in EVRMC, data on individual diagnoses was missing for a large part of the admissions. We used ward as a proxy for diagnosis, although some wards provide very little information on the type of admissions, e.g. the Medicine ward. Second, due to a high level of destruction in the study area during and after Haiyan, it is not possible to say with certainty how some of the patterns observed in our study can be explained, e.g. direct impact of the typhoon, damage and accessibility to the hospitals, closure of other hospitals, availability of field hospitals or casual seasonal changes. To gain more insight into these underlying patterns, we conducted a qualitative study with hospital personnel, which will be published separately.Our study identified several priorities for hospitals in zones at high risk of tropical cyclones. First, because of the observed reduction in patients after the event, accessibility to the hospital should be protected by measures such as removing debris in the direct hospital vicinity and prioritising access for emergency transportation, in order to ensure access for both staff and patients in case of mass emergencies. Second, deliveries will remain a constant through the emergency period and constitute a significant proportion of all hospital care in countries such as the Philippines, where fertility is high. The decrease of admissions in the Obstetrics ward suggests that not all deliveries took place in the hospital setting. Therefore, the capacity to respond to urgent obstetric needs should be foreseen, e.g. by ensuring skilled birth attendants in reach-out activities if needed. Third, the most common conditions for admission after Haiyan were gastroenteritis and pneumonia, confirmed as well by studies elsewhere. Hospitals in high risk zones should therefore be prepared to treat large numbers of patients with these conditions, and this should be incorporated in their disaster plans. Finally, our study brings further evidence to the higher risk of admission faced by children and elderly following an acute event. These findings and recommendations are of particular importance for operational activities after a tropical cyclone.


With growing concerns for the sustainability of the financial burden that health care—and especially cancer services—poses on the national budgets, the role of health economic analyses in coverage decisions is likely to grow. One of the strategies for the biomedical research field—also in oncology research—to foster coverage and health system implementation, is to anticipate this new role and to involve health technology assessment techniques earlier in various stages of translational research.In this article, we elaborate on the early involvement of health technology assessment in translational research and the concept of Coverage with Evidence Development in The Netherlands Cancer Institute and give two case examples that are currently ongoing: (1) tumour infiltrating lymphocytes therapy for metastatic melanoma; and (2) high-dose chemotherapy for BRCA1-like subgroup in triple-negative breast cancer.We conclude with recommendations for institutional policy. When innovations resulting from research reach the patient in routine clinical practice, the full cycle of translational biomedical research is completed. In the case of innovative procedures, inclusion in guidelines by professional agencies and coverage decisions by policy makers are essential to complete the process and present themselves often as last hurdles, before wider implementation in the clinic and diffusion in the health system is possible.www.nice.org.uk). Decisions are mostly taken based on a mix of data, primarily on clinical effectiveness and clinical utility, sometimes in combination with health economic criteria such as cost-effectiveness analyses. The regulations for the latter are often stipulated by those health insurance agencies/boards mentioned earlier and clinicians often have little involvement. Particularly, in the field of drug research, pharmaco-economics has developed into a plethora of techniques under the umbrella of health technology assessment, such as budget impact analysis, cost utility analysis, cost-effectiveness analysis and value of information analysis, with which clinicians often have little affinity. Inclusion of innovative technology in professional guidelines is another essential condition that is depending on factors like strength of evidence, the voice of key opinion leaders and barriers and facilitators related to practical implementation in the clinic. Increasingly, professionals are aware of this aspect and cost-effectiveness or value related aspects are included in their decision process towards adaptation of guidelines. The focus of this paper will be on coverage and system acceptance issues.Coverage decisions are usually made by medical boards within Ministries of Health or within health insurance agencies or health insurance governance and/or advisory boards, such as National Institute for Health and Care Excellence (NICE) in the United Kingdom  tumour infiltrating lymphocytes therapy for metastatic melanoma; and (2) high-dose chemotherapy for BRCA1-like subgroup in triple-negative breast cancer. We conclude with recommendations for institutional policy.The Netherlands Cancer Institute is the only accredited, freestanding Comprehensive Cancer Center in The Netherlands, with a large research laboratory, hosting a number of core facilities, and a cancer hospital providing all relevant diagnostic, intervention, and radiotherapy treatment facilities.In early stages of technology development, there is usually high levels of uncertainty around various aspects of the procedures or the interventions that are being developed. It is often not exactly known what indications will be relevant, how the technique interferes with the existing methods, what the exact domain or market share (in terms of diffusion), will be.By verifying a broad range of assessment aspects, such as organisational, ethical, legal, and patient-related factors, it is possible to identify the potentially relevant issues and improve the chances of actual clinical acceptance in an early stage of the process. Examples of this method can be found in studies on nanotechnology and gene array testing in breast cancer treatment , 3. ThisThere are various techniques to anticipate on uncertainties related to those aspects. Scenario analysis is an example in which experts are involved to give their best estimate of possible future development of a future technology , 5 and ra priori investments versus societal returns [Modelling techniques in which a decision algorithm of treating the decease is adapted by the data on the new technology characteristics can be used to estimate health economic values. This can be either used to stepwise improve the model when additional data become available , but als returns . ApplyinIf there is wide consensus among key opinion leaders on the clinical effectiveness and clinical utility of a new technology, cost-effectiveness analyses usually provide straight forward answers. In those cases, it is merely up to the decision boards to finalise the coverage decision process according to established criteria.Increasingly, countries realise that there are often flaws in the data on new technologies, which—when promising in terms of health-added value—pose a dilemma for the regulators in that a promising technology may be withheld from the population when a coverage decision is delayed due to a late start of cost-effectiveness analysis and/or missing information.Many governments are experimenting with coverage evidence development (CED) or comparable schemes . The arrIn The Netherlands, the government has experimented with an early schedule of CED in which initially a few procedures were included combined with rather large funding of research programs on those technologies. Establishing the prognostic value using a 70-gene microarray technique (MammaPrint) for node-negative breast cancer was included as a pilotCED; a prospective feasibility trial including data management, diagnostic testing and evaluation, and an early technology assessment (constructive technology assessment) was funded. It lead to positive decisions of various individual health care insurances. A lack of data from a controlled randomized trial, however, hampered diffusion and a formal coverage decision was delayed until data from controlled studies would be available. In view of trials with personalized treatment on biologically plausible targets, we expect that prospective cohort based trials or mixed designs—as examples of innovative trial funding will gain ground, as the need for innovative trials with small sub groups of patients is expected to grow in the coming years, considering the rapid developments in Personalised Medicine.After this phase of experiments, a formal procedure to decide on CED was installed by law in The Netherlands as from 2012 for hospital based new technologies. The procedure to be followed means that in year 0, a call will be posted with a deadline of 1st September for possible procedures to be included in the CED programme. This will require information on (A) the current state-of-the-art regarding usual care and the new technology, clinical effectiveness, and clinical utility, a first estimation of the cost price of the new technology, and on the position and (preferably) support from the relevant scientific medical societies and data on the health economic status and (B) a full-research proposal including a randomised controlled trial and a health technology assessment, with a clearly formulated research question regarding the (cost)effectiveness of the new intervention. This should be conducted and finalised in a period of around 4 years in order to finalise the files for a final coverage decision. In year 1, a preliminary decision is taken on the innovative treatments/procedures that may qualify for CED. First, the Dutch health care insurance board advises based on feasibility and societal relevance, second, the trial funding agency advises based on the quality of the proposals, and finally, the ministry of health makes a final selection for potential candidates for the CED programme. In the second half of year 1 and the first half of year 2, the design is further elaborated and approved and an agreement with all stakeholders various aspects of service delivery are negotiated (such as an exit strategy in case of inferior results). Finally, after final approval of the ministry of health, the CED trial can start usually in year 2. Throughout the study period, every 6 months, there is a progress meeting including all involved stakeholders, to closely monitor the process. After finalising the trial , a certain period (~6 months) is allowed to further cover the procedures awaiting the finalization of the research and presenting the final dossier to the insurance board and the ministry. At that moment, if the new intervention meets the criteria of ‘the state of science and practice’, a final decision on coverage can be taken. In the application stage, the view of professional medical societies is involved as well as in the ultimate decision on the consequences of the project’s findings; in this way, swift acceptance in updating guidelines with the new technology is assured both in the CED and in the following national implementation phases.Box 1.Tumour-infiltrating lymphocytes (TIL) therapy for metastatic melanoma , 17.Within melanoma metastases lymphocytes can be found. These tumour-infiltrating lymphocytes (TIL) have become less effective due to immunosuppressive functions from the tumour, or the tumour microenvironment. It is possible to excise a metastasis from a patient and extract TIL from it. The TIL can then be cultured and multiplied to large numbers. After a cycle of non-myeloablative chemotherapy, the TIL are given back to the immunosuppressed patient, followed by infusion of high-dose bolus interleukin-2. In around 50% of patients treated with TIL, a partial response, or even complete response can be seen. TIL is highly personalised and complex therapy. It requests substantial upfront investments from the hospital in expensive laboratory equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, a randomised controlled trial including an early health economic modelling study, as part of a coverage with evidence development (CED) program, is currently ongoing.In The Netherlands Cancer Institute (NKI), we have decided to involve health economic and technology assessment knowledge in the early stages of biomedical research in order to improve the chances of the development of innovations to be actually covered by insurance and reach the patient earlier. This started with various publications and involvement in early CED experiments on the70-gene signature, which resulted in a number of publications and on various data on the cost-effectiveness of this technology , 11–15. In 2015, again two procedures suggested by, and based on research from the NKI, were selected by the Dutch government to be elaborated in a final proposal for CED, being high dose chemotherapy for BRCA-like triple negative breast cancer .Box 2.High-dose chemotherapy for BRCA1-like subgroup in triple-negative breast cancer.In the late nineties, high-dose alkylating chemotherapy (HDAC) was provided to triple-negative breast cancer patients with little firm evidence; the high impact of the treatment on patients and fear of serious side effects lead to fierce debate within the oncology community on the appropriateness of prescribing this treatment. An RCT coordinated by the NKI showed no overall benefits  and afteSubgroup analysis in follow-up studies and research on genomic profiling showed that there might, however, be a group within the triple-negative population showing a BRCA1-like genetic pattern that was responding highly to HDAC. Proof of principle of first series showed promising results –21 and hIntra-operative hyperthermic intraperitoneal chemotherapy (gastric HIPEC) for locally metastasised gastric carcinoma  and/or tumour positive peritoneal cytology (C+)) was another example that was recently awarded to the NKI as leader of a CED project.For both treatments (HDCT and gastric HIPEC), the same procedure was followed as earlier with the TILCED trial proposal. Leadership ensured that there was an annual central call within the NKI and a procedure for selection of promising innovations by senior clinical management within the institution. Only after careful selection a maximum of three proposals was allowed for submission. Further, it was ensured that, apart from specific cancer-related content, health economic and coverage knowledge was included in the submission of the proposals. The health economic input consisted of close involvement through literature reviews, (early stage) health economic modelling and screening on aspects of technology assessment that may be involved apart from specific economic features . FurtheInvolving health economics and health technology expertise in the early stages of research and in preparation for ‘coverage with evidence development’ (CED) experiments can be very successful in ensuring innovative technologies to reach the patient in an efficient way.Conditions for this approach are the availability and presence of HTA and health economic expertise and knowledge on coverage procedures within (or closely available for) the institution. Oncologists have to be aware and appreciate this while drawing the project proposals for CED. Professional societies need to be involved to ensure acceptance in practice guidelines both during the CED project as well as after receiving the conclusions.It is not absolutely necessary to have own groups or expertise on HTA, but close cooperation and scientific ‘presence’ on the site are essential. Otherwise, clinicians may not be aware of the essential and useful technicalities. When HTA experts are involved early in the translational research process, the chance of a traditional role—performing a cost-effectiveness analysis in a late stage, just before coverage is decided upon—is reduced. More innovative early stage HTA schemes are likely to evolve, which are also better fitting to the development stage of the technology. This also requires an open mind for agencies deciding on coverage, as these still tend to rely on more traditional HTA approaches.As financial constraints are expected to become even more pressing in the future on a global level, there’s a better chance of leading their findings to the patient when they are cost effective. Early-stage involvement of ‘understanding’ HTA experts is likely to help them achieve this goal.


Gastric cancer is a neoplasm with a high incidence and mortality rate in Chile where more than 3000 people die every year from this type of cancer. This study shows the clinical and epidemiological considerations of this disease, information about translational research on this pathology in Chile, the contribution of Chilean doctors to the development of gastric cancer management awareness and the general situation of gastric cancer in Chile. Its incidence and mortality estimated by the IARC is 15.6 and 13.8 per 100,000 inhabitants, respectively . AccordiHelicobacter pylori (H. pylori). This subtype has experienced an important decrease in recent years, which explains a decrease in the worldwide incidence [The majority of malignant stomach tumours correspond to the histological type of adenocarcinoma (90% approximately), with a lower percentage of MALT lymphomas, leiomyosarcomas and other rarer tumours . The adencidence . On the ncidence .In Chile, an increase has been reported of the cardia location of gastric cancer but with reports of incidence rates that range between 12% and 45% of the total , 8. RegiCardial tumours have worse survival rates and higher operative mortality , as wellH. pylori [H. pylori in adults and children  [H. pylori, increases the risk of developing gastric cancer [Research into gastric adenocarcinoma etiopathogenesis has enabled us to understand the development of gastric cancer as a step-by-step process in the intestinal subtype, which progresses through stages from a chronic superficial gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia and finally cancer formation . This pr. pylori , 14 and . pylori . In Chileported) , and a heported) , which ic cancer . Anotherc cancer .The Epstein-Barr virus (EBV) has received special interest in recent years. The presence of this virus is found in approximately 8.7% of all gastric cancers. It has been possible to research the presence of monoclonal EBV in neoplastic cells, and it has been suggested that there is an epigenetic alteration mechanism involved in carcinogenesis . Within As has already been mentioned, cancer located in the cardia has increased its incidence in recent years, which has awoken the interest of national researchers. It has been possible to identify the presence of EBV in 16.8% in a Chilean cohort of gastric cancer patients, which represents one of the highest rates worldwide, with a prevailing cardial location (26.9%) and without significant differences according to histological subtypes . StrangeThere has been an increase in incidence and mortality in some indigenous populations worldwide, such as the Inuit, Maori and Mapuches . The MapScience has enabled us to understand that the etiopathogenesis of cancer is a complex, dynamic process that is still not fully understood. Current technology, progress in genomic sequences, and new molecular techniques have made the study of the complex quantity of genes and multiple pathways involved possible, making distinctions between genetic and epigenetic alterations involved in the tumorigenesis.We know that in the majority of cases of gastric cancer, a hereditary precedent cannot be found, and in the majority of family cases, which represent no more than 15% of the total number of patients with this pathology, it has not been possible to establish a germline mutation . NotwithOne of the most important epigenetic alterations described is microsatellite instability. Microsatellites are sequences of usually noncoding DNA that are highly repetitive and numerous. When the process of replication is produced, there can be sequence slippage, which generates mutations that are normally corrected by the DNA repair mechanism, formed by encoded protein from several genes, with the hMLH1 being especially important. If these genes are inactivated for different causes, for example due to hypermethylation in its promoter region, mutations in the sequences are accumulated, creating the phenomenon of microsatellite instability. This way the microsatellite instability reflects alterations in the machinery of cell repair that can produce determining alterations in the development of the neoplasm such as the inactivation of suppressor genes; hence, the identification of this could be used as a potential investigational test for this disease .H. pylori and gastric atrophy [Other epigenetic mechanisms associated with the methylation of DNA have been studied; in particular, the study of the Reprimo gene has opened an interesting line of investigation. The Reprimo gene located in the chromosome 2q23.3 codes a highly glycosylated p53-mediated protein, being able to cause abnormal cells to stop at G2 phase. It is believed that it regulates the activity of the complex cdc2/cyclin B1 and prevents the uncontrolled proliferation of the cell , its ina atrophy . Several atrophy .Despite the fact that advances in the understanding of gastric cancer in our country promise to be the first step towards improved quality in the treatment of these patients, there are still problems left to resolve. Even though the genetic differences in etiopathogenesis and the evolutionary theory depending on the histological subtype source are known, so far, there are no substantial differences in the management of these different groups of patients. Notwithstanding the above, for more than a decade, important scientific studies have been carried out in Chile that have contributed to global knowledge and have served to improve the management of patients with gastric cancer. It is important to emphasise the contributions of Csendes in the surgical area of patients with gastric cancer  and of BIn recent years, more efforts have been made in the interest of improving access and treatment opportunities for different health problems, and this is why in 2004 Law Nr 19.966 was passed. This establishes a health-care guarantee scheme GES-AUGE , and sinA low educational level has been established as one of the determining social factors associated with gastric cancer in our country , 40. It H. pylori and EBV, high salt consumption and racial factors such as Mapuche descent.The present epidemiological changes both worldwide and in Chile have encouraged researchers to look for answers that enable us to understand the new observable phenomena regarding gastric cancer. As Chile is a highly endemic country for this disease, the study of the determining factors for gastric cancer in our population enables us to recognise findings present in other populations, like the relationship between infectious factors such as In reference to this last point, given the extensive multiethnic character of our population, and thanks to the new tools that provide genome sequencing and molecular techniques, these make the genetic and molecular model of the gastric cancer in the Chilean population an attractive topic to research. This is how translational medicine gains an important value, enabling the identification of epigenetic mechanisms such as the methylation of the hMLH1 and Reprimo genes, opening up an important line of research as it generates knowledge that could identify the presence of gastric cancer in early stages and predict the response to existing therapies. Given the lack of systematic screening in our country and the high rate of diagnosis in advanced stages of the disease, the basic science and clinical research that has been carried out in recent years in Chile has become even more relevant. Despite efforts made by the state in pursuit of improving diagnosis and appropriate treatment, there are still evident gaps to bridge, which not only need economic resources but also multidisciplinary efforts between the different parties dedicated to the research and treatment of this disease, in order to reach the ultimate goal, which is to improve the health of our population, provide better quality of life and meet the health demands of our patients.


In the rapidly developing specialty of palliative care, literature reviews have become increasingly important to inform and improve the field. When applying widely used methods for literature reviews developed for intervention studies onto palliative care, challenges are encountered such as the heterogeneity of palliative care in practice , the explorative character of review questions, and the poorly defined keywords and concepts. To overcome the challenges and to provide guidance for researchers to conduct a literature search for a review in palliative care, Palliative cAre Literature rEview iTeraTive mEthod (PALLETE), a pragmatic framework, was developed. We assessed PALETTE with a detailed description.PALETTE consists of four phases; developing the review question, building the search strategy, validating the search strategy and performing the search. The framework incorporates different information retrieval techniques: contacting experts, pearl growing, citation tracking and Boolean searching in a transparent way to maximize the retrieval of literature relevant to the topic of interest. The different components and techniques are repeated until no new articles are qualified for inclusion. The phases within PALETTE are interconnected by a recurrent process of validation on ‘golden bullets’ (articles that undoubtedly should be part of the review), citation tracking and concept terminology reflecting the review question.To give insight in the value of PALETTE, we compared PALETTE with the recommended search method for reviews of intervention studies.By using PALETTE on two palliative care literature reviews, we were able to improve our review questions and search strategies. Moreover, in comparison with the recommended search for intervention reviews, the number of articles needed to be screened was decreased whereas more relevant articles were retrieved. Overall, PALETTE helped us in gaining a thorough understanding of the topic of interest and made us confident that the included studies comprehensively represented the topic.PALETTE is a coherent and transparent pragmatic framework to overcome the challenges of performing a literature review in palliative care. The method enables researchers to improve question development and to maximise both sensitivity and precision in their search process. Palliative care (PC), a relatively young specialty, is growing rapidly and will continue to do so over the next decades , 2. The Widely used methods for literature reviews are developed primarily for intervention studies and have been applied to other fields, including PC. However, there is a need for literature reviews in PC beyond those that seek to pool evidence from intervention studies. The methods used for reviews concerning evaluation of interventions may not be transferable to literature reviews on less clearly defined topics that involve different challenges . One of After formulating a review question, the next stage of study identification has its own challenges. A young discipline such as PC often suffers from concepts and terms that are heterogeneous, poorly defined, indexed, or standardised, making term-based searching difficult. This is not unique for PC, as similar problems have been encountered in social sciences , 12, 17.Although the Boolean search query is most widely used in literature reviews, it is not the only way of retrieving studies or finding information. Other retrieval methods, including berry picking Table , pearl gTo address the aforementioned issues, there is a need to combine several of the existing retrieval methods in a logical way to ensure transparency and provide guidance for researchers. To reflect the more iterative nature of searching for PC studies, we developed a pragmatic framework, Palliative cAre Literature rEview iTeraTive mEthod (PALETTE), to guide the fine-tuning of the review question, performing a literature search, and applying screening eligibility criteria. By introducing intermediate validation steps, the reasoning for going from one phase to the next within the framework becomes visible which increases the transparency. It is the combination of these iterative steps, the use of multiple retrieval methods, and the validation on evaluated suitable studies that will boost confidence by the researchers that all relevant studies are captured. The structured iterative manner also facilitates a better ability to trace-back decisions for re-evaluation in light of new discoveries and adjust when or where necessary.In this paper, we assess the usability and performance of PALETTE on two literature reviews in PC. Furthermore, with a detailed description, we provide guidance on how to apply PALETTE for literature reviews in PC.In this section, we describe the phases of PALETTE and present the criteria for observation to provide insight into our initial experiences with the framework.The iterative literature search, PALETTE, consists of four phases: 1) developing the review question, (2) building the search strategy, (3) validating the search strategy, and (4) performing the search. Each subsequent phase consists of sub-phases and is informed by what is previously learnt. Results from one phase could require the researcher to return to the previous phase. A detailed description of the phases, moments of decision-making, and techniques used is presented below and visualised in Fig.  developiAt the beginning of a PC review, the researchers first explore the key elements of the question carefully by performing an initial literature search. This search will be explorative, covering (a combination of) various topics from the initial review question supplemented with searches for reviews and overview articles to enhance the understanding of the overall perception within the field. In addition to the initial search, experts in the domain of interest are contacted to provide valuable articles. When experts cannot be contacted, it can be helpful to scan publications by key authors within a field to identify key papers and find relevant phraseology. Moreover, to overcome bias in the article set and to increase the body of knowledge, the key articles from the initial search and experts are expanded by adapted pearl growing Table  and by bAfter having collected all the references from the initial search, experts, and expansion, the researchers discuss the found body of evidence and map it to the initial review question whereby all related concepts are envisioned. When necessary, they refine, based on the added knowledge about the topic of interest, the review question, or concepts and thus the search strategy. This fine-tuning of the review question helps to address the most important viewpoints on the topic and, therefore, ensures a rich evidence-base. Furthermore, clear eligibility criteria are developed. Based on the final review question and the eligibility criteria, the researchers, preferably two researchers to minimise subjectivity, will select those articles from the retrieved articles that are relevant to the review question and fit into the eligibility criteria. These articles are the so-called ‘golden bullets’ and will be used for both fine-tuning the search query as well as the validation of the searches Table .This iterative process of screening the articles, fine-tuning the review question, modifying and developing the search strategy, and defining the eligibility criteria for answering the review question should be carefully explored by the researchers. It is of utmost importance that this process is well documented so that decisions leading to the final review question, the eligibility criteria, and the ‘golden bullets’ are transparent for the reader.The ‘golden bullets’ are analysed using PubMed PubReMiner . The second review concerned patients’ experiences with Advance Care Planning (ACP) (LR2).Firstly, we share user experiences to elicit relevant aspects of the process of PALETTE: use of experts, development of the review question, and understanding of the topic of interest. Secondly, the value of PALETTE was evaluated by comparing the PALETTE results for both LR1 and LR2 with results retrieved from a recommended search method for reviews of intervention studies (PICO). Criteria were number and value of identified ‘golden bullets’, NNS, and comprehensiveness of the search.The input of experts in the phase of developing the review question was only applied in LR2 , the NNS when applying PALETTE decreased in both LRs, whereas the number of relevant articles increased Table . In LR1,Constructing relevant, focussed review questions in PC is a daunting task and requires an intricate knowledge of this field and all its actors. The same applies to the terminology used and the ability to identify all relevant studies. To address these issues and the shortcomings of the current literature review methodology, mainly developed for intervention studies, we present PALETTE as a pragmatic framework, which encompasses multiple retrieval methods applied in an iterative transparent way. Although the different techniques used within PALETTE have been around for some time, we provide a framework to use these in a transparent and coherent way with a clear decisional tree. As such, we provide guidance for researchers in the field of PC as well as in other specialties challenged by explorative questions, heterogeneity, and poorly defined keywords and concepts when conducting a review. Not every single technique will lead to a proportional number of relevant articles in every review; however, using PALETTE ensures a high likelihood of retrieving relevant articles with confidence.The introduced iterative method results in four main positive aspects. Firstly, because of the more qualitative nature and the poorly defined concepts, review questions in PC need preliminary exploration. If not, researchers run the risk of missing a related concept not envisioned at the beginning. When applying the more iterative approaches such as berry picking and pearl growing solely, , 25 it iSecondly, as compared with the search building methods in intervention studies, PALETTE enables the research team to provide input on opinions and views, which in-turn enables them to explain what works for whom, in what contexts, and why in a transparent manner , 28. ThiThirdly, the total body of evidence in an article on PC is not well captured in terms. Therefore, validation is required on an article level. By checking the ‘golden bullets’, PALETTE grants this opportunity and validates the literature search on content and not just on the presence of keywords. This technique within PALETTE results in a representative set of articles.Lastly, PALETTE might offer greater proportionality between the efforts of the researchers and the results of the literature search. When using a Boolean logic search query based on the initial review question and using every conceivable terminology on its own, some of which are quite ambiguous, huge amounts of results (10s of thousands) have to be screened manually and highly relevant citations are still missed . The litFour limitations of PALETTE should be considered when applying PALETTE. Firstly, regular feedback within the research team is necessary to fine-tune the review question and to keep focussed on the aim of the review. Secondly, care should be taken when compiling the ‘golden bullets’. The ‘golden bullets’ should reflect the topic well from multiple angles so as to not introduce a skewed data set. By combining wisely chosen experts with the initial literature search and the expansion of articles, the risk of a skewed data set can be avoided. Thirdly, the benefit of the involvement of experts was limited in our examples. In the literature, different opinions regarding the involvement of experts are evident , 29. We Some strengths and limitations should be taken into account. PALETTE is a new approach that can be helpful in performing literature reviews in PC. However, we still have limited experience with the application of PALETTE and compared minimal results between PALETTE and the recommended search method. We, for instance, did not measure the costs in terms of time needed for each phase of PALETTE. Regarding the time needed, we know from previous research that an experienced reviewer can screen an average of two abstracts per minute, but abstracts for complex topics may take several minutes each to evaluate . Given tWe presented PALETTE, a transparent and coherent pragmatic framework to overcome the challenges of conducting a literature search for a review in PC. This guidance enables the researchers in a relatively young and developing specialty to maximise both sensitivity and precision in their search process. PALETTE helps to improve question development and increase the understanding of the topic of interest and the development of a literature search. Compared with the recommended search method, PALETTE provided greater balance between the NNS and identified relevant articles. Whilst our initial results with PALETTE are promising, more research would provide valuable data about the applicability of PALETTE within the field of PC.


Mycoplasma pneumoniae is a major human pathogen that causes both upper and lower respiratory infections, and is one of the leading causes of community-acquired pneumonia (CAP), accounting for 11–15% of CAP throughout the world . M. pneumoniae is also one of the smallest free-living human pathogens, with a genome size of less than 700 genes . In this volume of Frontiers we have explored few of many aspects related to this major human pathogen. The purpose of this topic was to thoroughly review and to create a body of knowledge encompassing both medical and biological information gathered in both the western world and Asia.Saraya contributed a nice historical perspective on the discovery of M. pneumoniae and a few authors contributed an updated and fresh look on the clinical manifestations of M. pneumoniae . The unique epidemiological challenges presented by this pathogen include both outbreaks and the “Olympic” (3–5 years) intervals between epidemics, which reported here in both Japan and the UK . Since its discovery, the main challenge for diagnostic labs and clinicians was its fastidious growth that led to a reliance on serology, and later on, amplification techniques for diagnosis. Two reviews cover diagnostics here . An additional review combines the antibody response to epidemiological aspects as a means to explain the epidemiology (Dumke and Jacobs). Pathogenesis is covered by 2 topics: One on the bacterial aspect and the other on the host inflammatory response to M. pneumoniae infection . Additionally, Spuesens et al. explored the possible role of genomics in elucidating the differentiation between sick and carrier patients. Obviously, for each infectious agent, treatment and cure is the goal, if prevention is not possible (yet). However, since M. pneumoniae is lacking a cell wall, antibiotic choices are limited to the use of macrolides and related antibiotics, tetracyclines and quinolones, and some of those classes have limited use in the pediatric populations . Pereyre et al. summarized the emerging macrolide resistance and Balish and Distelhorst explored the possible use of new agents in the future.Obviously, not everything can be covered in depth and many of the topics explored here raise many new questions that remains to be answered, by the scientific community.RN wrote the first draft; TSa, TSh, AV, and CB reviewed commented and edited the manuscript. All authors have approved the manuscript.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.