Starters outperformed non-starters in most capacities among U13, but only in FS_RAG among U15 . Multiple regression calculations indicated nonsignificant association between independent and dependent variables in U13 , but independent variables explained significant proportion of both dependent variables in U15 . The study confirmed the applicability of newly developed tests in distinguishing studied age categories of players. Results indicate that superiority in all studied fitness capacities is translated into performance level in U13. Meanwhile, FS_RAG seems to be important determinant of quality in U15.Reactive agility (RAG) and change of direction speed (CODS) are important determinants of success in football (soccer), but there is an evident lack of information on reliable and valid football-specific testing procedures which will be applicable in defining sport-specific RAG and CODS in youth players. This study evaluated reliability and construct validity of newly developed tests of football-specific RAG (FS_RAG) and CODS (FS_CODS), which involved the ball kicking football technique. Additionally, factors associated with FS_RAG and FS_CODS were evaluated. The participants were youth football players  divided according to their age into U13 , and U15  categories. Additionally, performance levels (starters [first-team] vs. non-starters [substitutes]) were observed in each age category. The dependent variables were newly developed FS_RAG and FS_CODS tests. The independent variables were sprinting capacities over 10 and 20 meters , countermovement jump (CMJ), the reactive strength index (RSI), and a generic CODS test of 20 yards (20Y). The newly developed FS_CODS and FS_RAG were observed as dependent variables. Results showed appropriate intra-testing and inter-testing reliability of the FS_RAG and FS_CODS, with somewhat better reliability of the FS_CODS . Additionally, better reliability was evidenced in U15 than in U13 . Independent samples t-test indicated significant differences between U13 and U15 in S10 ( Agility is defined as a rapid change of speed and direction of movement as a reaction to an external stimulus . This quFootball (soccer) is an intermittent team sport characterized by frequent transitions in activity patterns, from high-intensity movements such as sprinting, jumping, shooting, accelerating, and decelerating to low-to-moderate intensity activities such as jogging, walking and even standing still ,9. DemanThere area largenumber of tests and testing protocols used to measure agility performance in team sports, including football ,13. HoweBecause of the known importance of agility for long-term sport development, studies frequently elaborated the reliability and validity of the tests aimed at evaluation of agility in young athletes,18. HoweWith regard to agility in football, it is also important to note that performance in this sport often involve dribbling, passing, and kicking movements, indicating the importance of ball-handling even in CODS and RAG. As a reThe aims of this study were: (i) to evaluate the reliability and construct validity of the football specific test of RAG (FS_RAG) and football specific test of CODS (FS_CODS), and (ii) to identify associations between specific conditioning capacities with FS_RAG and FS_CODS in youth football players. The leading hypotheses of the research were: (i) the newly developed tests will have proper reliability and validity in distinguishing age groups and performance levels of studied players, and (ii) the fitness capacities will be significantly correlated to FS_RAG and FS_CODS in studied players. This study combined test–retest (repeated measurement) and cross-sectional approaches, and consisted of several phases. Initially, the design of the newly developed tests of football-specific RAG and CODS (FS_RAG and FS_CODS), which are applicable in youth players, was determined through consultations with three experts in football, who were informed about the main idea, previously applied test designs in football and other team sports, technical requirements, boundaries, etc. Finally, the testing design and scenarios proposed previously for older football players  were simplified and applied herein (see “Variables” for details) . The repeated measurement(separated by 7–9 days), was applied in order to define the reliability of the developed RAG and CODS tests, which was additionally broadened in further cross-sectional measurements of independent variables, consisting of basic anthropometrics, sprinting, generic-CODS, and jumping capacities. Specifically, groups of participants (age groups and performance levels) were compared on all applied variables in order to identify the construct validity of the tests. Finally, independent variables were correlated to dependent variables in order to identify predictors of football-specific CODS and RAG.2) from two football academieslocated in Split-Dalmatia county in southern Croatia. Football academies included in this study were selected on the basis of following criteria: (i) having football teams in all age categories starting from U11 to seniors (+18 years), (ii) having at disposal courts with artificial-plastic turf (see later for details about testing), and (iii) licensed  coaches working with U13 and U15 teams (see later for details).The total sample of players was divided into two subsamples according to their age: (i) players who were 11–12 years of age  and players who were 14–15 years of age at the moment of testing . For the purpose of this study, players in each age group (U13 and U15) were additionally grouped, according to their performance level, into starters  and non-starters. The grouping into starters and non-starters was done by coaches, and investigators had no influence on coaches’ decision. Specifically, starters were players who regularly “start the game” , and non-starters were actually their “substitutes”. In this study, we observed only field players, meaning that goalkeepers were not observed. All participants had at least 3 years of experience in systematic football training, and at the moment of testing participated in 3-4 training sessions weekly, plus one game. Most of their trainings (more than 80%) was oriented toward specific technical and tactical skills, but two of 10 training sessions are oriented toward development of physical and conditioning capacities. Players from both football academies were equally represented in each age group. For all participants, pubertal timing was estimated according to the biological age of maturity (maturity offset), as described by Moore et al. (Maturity offset = −7.999994 + (0.0036124 × age (yrs.) × height (cm)[Participants in this study were young football players  were included in cross-sectional measurement (see previous text for details), in the repeated measurement (test–retest procedure) we observed 14 players to define the inter-testing reliability. Test and retest were separated by 7–9 days. Prior to the study, participants and their parents/responsible adults were informed about the purpose, design, benefits, and risks of the study, and parents provided informed consent for the study participation of their children. The study was approved by ethical board of the University of Split, Faculty of Kinesiology . The testing was done during March 2019, and all to avoid diurnal variations, all tests were performed in the morning hours between 10:00 and 12:00.Independent variables consisted of anthropometrics , one generic CODS test, two tests of sprinting performance, and two tests of jumping performances. Dependent variables were two newly designed tests of football-specific CODS (FS_CODS) and football-specific RAG (FS_RAG). Participants were familiarized with dependent variables a day before testing, and performed several testing trials at submaximal intensity and 1–2 at maximum. The familiarization trials were not included in further analyses. Since participants were already tested on independent variables, the familiarization was not necessary. Anthropometrics were measured by an experienced technician using standardized equipment. Body mass (BM) was measured in 0.1 kg, and body height in cm (extrapolated at 0.5 cm). The countermovement jump test (CMJ) was conducted with an athlete starting from an upright position with hands on the hips, performing fast downward movement to approximately 90° of knee flexion followed by a maximum-force upward vertical motion. The height and the contact time of the jump were measured by the Optojump system . Test waThe reactive strength index (RSI) was calculated from the height jumped, and from the contact time with the ground while performing the double-leg drop (depth) jump. For the start of the drop jump, athletes were standing on a 40 cm high box and were instructed to step off forward between two photoelectric beams (Optojump system) and to jump upwards maximally while minimizing the contact time. The tesFor the purpose of this study, we included a twenty yards test (20Y) in the test of generic CODS capacity. The tesSprinting was assessed by a sprint test of 10 m (S10M) and 20 m (S20M). One photoelectronic timing gate (Powertimer) was placed at the start line, a second gate was placed at 10 m from the marked starting line, and a third at 20 m, with reflectors placed at a 1 m height. From the standing start, the athletes had their preferred foot placed forward on the marked line 1 m before the start line  and were instructed to run at maximum speed along the 25 m field. The time was recorded at 10 m (S10M) and 20 m (S20M). Athletes performed three testing trials, with 2–3 minutes of rest between the trials, and the best achievements were used for the analyses.The FS_CODS and FS_RAG were measured using a hardware device system based on an ATMEL micro-controller , which has been previously used in similar studies in handball, basketball, futsal, and football ,23,26,27The FS_RAG test started with the player running at maximal intensity through gate where the IR signal was placed . At thatFor the FS_CODS test, players were tested on the same testing field , but witAll data were log-transformed to reduce the non-uniformity of error, and all statistical analyses were done on transformed data. Distributions of the variables was checked by Kolmogorv Smirnov’s test , and resThe inter-testing reliability of the FS_CODS and FS_RAG was analyzed by the intraclass correlation coefficient  as a measure or relative reliability, and by the coefficient of variation (CV) as a measure of absolute reliability ,29,30. TAdditionally, all variables were checked for intra-testing reliability, with testing items treated as repeated measures for each variable. First, a repeated measures ANOVA with a corresponding Tukey post hoc test was calculated for each variable to assess systematic error  among trials, and the intra-testing ICCs and CVs were then calculated for all variables ,32. The construct validity of the tests was assessed by comparing (i) age groups  and (ii) performance levels (starters vs. nonstarters) in each age group. For such purposes, a 2-sided t-test for independent samples was calculated. Additionally, Cohen’s d effect sizes (ES) for differences in studied variables between corresponding groups  were calculated, and they were interpreted using the following qualitative descriptors: <0.2 = trivial, 0.21–0.49 = small, 0.50–0.79 = medium, >0.79 = strong . To establish the univariate associations between variables, Pearson’s product moment correlation (r) was calculated. The standard multiple regressions were calculated to identify the multivariate relationships between independent variables (predictors) and dependent variables . For the purpose of the interpretation of explained variance, the coefficient of multiple correlation, and the coefficient of determination (percentage of explained variance) were calculated. In order to identify partial contribution of each predictor to overall multiple regression calculation, the standardized- and non-standardized-regression-coefficients were reported. Before multiple regressions’ calculation, the predictors were checked for multicollinearity by calculating the variance inflation factor (VIF), and those variables with a VIF larger than 10 were not included as predictors in the specific multiple regression calculation ,35,36,37p-level of 95% was applied, and Statistica v.13.0  was used for all statistical analyses. The The inter-testing reliability of FS_CODS and FS_RAG was appropriate , with better reliability of FS_CODS than of FS_RAG . This wap < 0.001; large ES differences), S20M, 20Y , FS_RAG , and FS_CODS   . p> 0.05), with a large ES for maturity offset, S10M, S20M, 20Y, FS_RAG, and moderate ES for CMJ and FS_CODS. The differences between performance levels (starters vs. nonstarters) in the tested variables for each age category are presented in p < 0.05; moderate ES differences), with a better performance in starters than in nonstarters. Pearson’s product moment correlation coefficients did not reach statistical significance when correlations were calculated between independent and dependent variables in U13.The only variable that significantly differentiated performance groups in the older group (U15) was FS_RAG , achievement in 20Y (r = 0.63 and 0.50), and CMJ results  . p> 0.05)  . When mup> 0.05) .There are several important findings of this study. First, the reliability of the newly developed tests of football-specific CODS and RAG is appropriate, with better reliability of FS_CODS in both age groups. Next, the discriminative validity  of the newly developed tests differs across the studied age groups. Additionally, conditioning capacities are significantly correlated to FS_CODS and FS_RAG in U15 but not in U13. Collectively, we may accept our first study hypothesis . Because of the week correlations between studied conditioning capacities with FS_CODS and FS_RAG, the second study hypothesis is denied.Inter-testing and intra-testing reliability of the FS_RAG and FS_CODS is comparable to tests of similar capacities in other sports, and football-specific RAG and CODS in older male and female players ,23,27. ISpecifically, Benvenuti et al. observed Italian female players and reported ICC of 0.80 for specific football RAG test, while Pojskic et al. recently presented results of the study with U17 and U19 male players from Sweden and reported 0.70–0.90 for inter- and intra-testing reliability ,23. It mThe fact that the reliability of the FS_CODS is better than the reliability of the FS_RAG is consistent with previous reports where authors simultaneously observed different types of CODS and RAG tests ,38. In bThe newly developed FS_CODS and FS_RAG are found to be applicable in defining the differences between U13 and U15. Therefore, we may accentuate the construct validity of the tests in defining performance levels in youth age football players. However, age groups significantly differed in sprinting, and generic CODS as well  and consequently is directly translated to their performance level, our results highlight that skill level becomes more important in the older age group (14–15 years of age). The RAG performance is generally considered as being more influenced by the level of expertise in specific motor skills than the corresponding CODS . The facThe FS_RAG and FS_CODS shared 16% of the common variance in younger players and 35% of the common variance in older players, and we may highlight the relative independence of these qualities in youth football players. This is supportive of previous studies where authors have confirmed similar correlations between corresponding CODS and RAG tests in college-level athletes (up to 36% of the common variance) ,45, handThe implicit goal of the CODS and RAG tasks is to redirect total body momentum in a new direction as quickly as possible, so it is expected that, despite the purported importance of decision making, the physical actions constitute a great proportion of time necessary to complete CODS and RAG tasks . HoweverTo the best of our knowledge, only one study so far has examined the factors associated with RAG in football players. Specifically, Lloyd et al. observed young football players and examined the relationships between functional movement screen (FMS) scores, maturation, and various physical performances (including reactive agility) in young football players . Since iIndeed, the observed predictors explained a larger percentage of variance of criteria (FS_RAG and FS_CODS) in the older group than in the younger group, and this is consistent with the recent report of Hammami et al., where authors investigated predictors of CODS performances in youth handball players . Most liThe previous discussion can be translated into strength and conditioning processes in youth football. In short, the stronger association between the studied conditioning qualities and FS_RAG and FS_CODS in older boys indicates that the training process in younger players should be mostly focused on the development of specific motor skills, techniques, and corresponding neural parameters. While this is important for the long-term development of young players, it will probably also facilitate an improvement in technical competency and assist in coping with anthropometric changes that occur in this period of life . For thiThe main limitation of this study is its cross-sectional design. Therefore, in order to clearly identify the cause–effect relationships between studied variables, intervention studies are needed. Further, participants were selected from two football teams; therefore, we cannot ignore the possibility that differential training program influenced our findings to some extent. However, in both groups (older and younger) we included a similar number of participants from two teams, which probably reduced the possibility of a previously noted bias. Also, all tests were performed on artificial turf , and since players perform on natural turf, there is a certain possibility that they did not perform at maximal level due to non-familiarity. However, usage of the artificial turf was necessary to assure standardized  testing conditions for all participants. Finally, players were not observed according to playing position, which will almost certainly contribute to better applicability of the results. However, U13 players were not strictly defined with regard to their playing-position in football game, which consequently did not allow us to apply such grouping into experimental design. This is likely one of the first studies to examine the reliability and validity of football-specific tests of RAG and CODS, specifically in youth age, and likely the first in which two age categories were separately observed. A very narrow age span in each of the studied groups is also a substantial strength of this research. Finally, tests were based on previous research in the field and on experiences in the development of similar tests for other sports and for other age groups in football. Therefore, we believe that, although this investigation is not the final word on the problem, it will improve the knowledge in the field and that further research will be initiated. The football-specific tests applied in this study showed appropriate reliability and therefore may be used as appropriate and consistent testing procedures in evaluation of RAG and CODS in youth football players. However, it must be stressed that the study consisted of familiarization and testing trials, so we may accentuate the necessity of familiarization with the testing sequence before testing both capacities. When it comes to the validity of the tests in distinguishing the age groups studied herein (U13 vs. U15), the validity of the FS_RAG and FS_CODS is comparable to the validity of the tests evaluating sprinting, jumping, and generic CODS. However, the high validity and consequent applicability of the FS_RAG is evidenced in distinguishing performance levels in U15. Therefore, it can be concluded that, while physical and maturity-related variables are more important determinants of success in younger age, with the advancement of the maturity process, the importance of skill-related variables increases. From the practical aspect it is important to note that that our results point that improvement in sprint and jumping could be theoretically beneficial in improvement of sport-specific RAG and CODS in U15 players. Meanwhile, the RAG and CODS in U13 players are more influenced by various neurological factors, including technique and quality of the execution of the specific movement templates that occur in the applied testing sequence. As a result, training programs aimed at the improvement of RAG and CODS in early pubescent football players should be more oriented toward achieving an accurate and effective movement technique, and not toward the development of conditioning capacities, which  contribute to RAG and CODS due to physiological background .


Cutaneous leishmaniasis (CL) is the most frequent form of leishmaniasis, with 0.7 to 1.2 million cases per year globally. However, the burden of CL is poorly documented in some regions. We carried out this review to synthesize knowledge on the epidemiological burden of CL in sub-Saharan Africa.We systematically searched PubMed, CABI Global health, Africa Index Medicus databases for publications on CL and its burden. There were no restrictions on language/publication date. Case series with less than ten patients, species identification studies, reviews, non-human, and non-CL focused studies were excluded. Findings were extracted and described. The review was conducted following PRISMA guidelines; the protocol was registered in PROSPERO (42016036272).From 289 identified records, 54 met eligibility criteria and were included in the synthesis. CL was reported from 13 of the 48 sub-Saharan African countries . More than half of the records  were from western Africa, notably Senegal, Burkina Faso and Mali. All studies were observational: 29 were descriptive case series , and 24 followed a cross-sectional design. The majority (78%) of the studies were carried out before the year 2000. Forty-two studies mentioned the parasite species, but was either assumed or attributed on the historical account. Regional differences in clinical manifestations were reported. We found high variability across methodologies, leading to difficulties to compare or combine data. The prevalence in hospital settings among suspected cases ranged between 0.1 and 14.2%. At the community level, CL prevalence varied widely between studies. Outbreaks of thousands of cases occurred in Ethiopia, Ghana, and Sudan. Polymorphism of CL in HIV-infected people is a concern. Key information gaps in CL burden here include population-based CL prevalence/incidence, risk factors, and its socio-economic burden.The evidence on CL epidemiology in sub-Saharan Africa is scanty. The CL frequency and severity are poorly identified. There is a need for population-based studies to define the CL burden better. Endemic countries should consider research and action to improve burden estimation and essential control measures including diagnosis and treatment capacity. Cutaneous leishmaniasis (CL) is the most common form of this group of parasitic diseases, transmitted by sandflies. In sub-Saharan Africa, its extent of the problem is unknown, while elsewhere its disfigurement and stigma may cause a severe impact. This study systematically searched the literature to find evidence on the epidemiological data on human CL in this part of the world. Historically, CL has been present for decades in both western and eastern Africa, but unfortunately, in the last decades, the data are irregular and patchy. The estimated burden, relying on detected cases, may only capture part of the true number of cases. This article shows that there is insufficient evidence to have accurate figures; the diversity of the disease, along with poor surveillance have resulted in unprecedented CL outbreaks in the past. Many knowledge gaps remain, and we highlight the importance of improving the current fragmented knowledge by increasing commitments to tackle CL and conduct better population studies. CL in sub-Saharan Africa appears to be a blind spot and should not remain so. Leishmania species and transmitted by the bite of Phlebotomine sand flies, the clinical presentations of CL include localized skin nodules , diffuse non-ulcerated papules, dry or wet ulcers, and, in the mucocutaneous form, extensive mucosal destruction of nose, mouth, and throat. Transmission of CL may involve animal reservoir hosts  in zoonotic foci, while anthroponotic CL (where humans are the main parasite reservoir) occurs in urban or periurban settings [Cutaneous leishmaniasis (CL) is the most common clinical manifestation of leishmaniasis, a parasitic neglected tropical disease (NTD) . Caused settings . Environsettings ,4, in reL. major, L. aethiopica, L. tropica, and, rarely, the viscerotropic L. donovani (in Sudan), resembling similar a phenomenon more known for L. infantum [Globally, the World Health Organization (WHO) considers CL as endemic in 20 countries in the New World  and in 67 countries in the Old World  . Betweeninfantum . Though infantum .Due to the clinical and epidemiological diversity in CL, its geographic clustering and lack of reliable surveillance data, estimating the CL burden are challenging . The mosMoreover, in sub-Saharan Africa (SSA), not only the disability but also the number of CL cases is largely underestimated. A recent global burden analysis listed 19 countries in SSA in the top 50 high burden countries . The pasWhereas attention has been given to CL in Northern Africa  and the Middle East –24, dataWe searched the following electronic databases: National Library of Medicine through Pubmed, Cochrane Register, Web of Science, CABGlobal Health, African Index Medicus and Google Scholar. We did an initial keyword search and subsequent searches based on Medical Subject Headings (MeSH) with various combinations of search terms “cutaneous leishman*” AND “Africa, South of the Sahara”  OR “Leishmaniasis, cutaneous” OR “Leishmaniasis, diffuse cutaneous” OR “Leishmaniasis, mucocutaneous” AND each individual sub-Saharan countries. The World Bank classification was used to define sub-Saharan African countries and to group them according to the region  Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sirra Leone, Somalia, South Africa, South Sudan, Sudan, Swaziland, Tanzania, Togo, Uganda, Zambia, ZimbabweLeishmania species only, studies on diagnostic tests or treatment for CL and cases of Post Kala Azar Dermal Leishmaniasis (PKDL)–skin sequelae of VL. Case reports and case series of fewer than ten patients were also excluded. Sub-Saharan Africa as the main geographical interest refers to the settings where the studies were performed/conducted. Reviews about CL in a specific country or region without original data were excluded.We included studies if they are reporting primary data that help to determine the burden of CL in countries in SSA. The burden is defined as elements of 1) severity of the problem  in human patients; 2) frequency  and 3) economic cost . We excluded animals or vector studies, studies on pathogenesis, immunology, histopathology, or on The systematic review was conducted in line with PRISMA guidelines ,26. The We selected the articles in a two-step process. In a first stage, titles and abstracts of all retrieved records were independently reviewed by two investigators (TS and KV). In a second stage, the selected full-text articles were again reviewed  for eligibility. When full-text articles were excluded, the reason for exclusion was registered and reported. Any discordances were resolved through discussion or seeking consensus with a third investigator (MB).The data were extracted in parallel by two independent readers, using a specific data form, including information on the published record , setting (country), aim, study design, and main outcomes. We sought data on prevalence or incidence of CL among patients in health facilities and the community; demographic and clinical characteristics of CL patients, and the association between CL and other morbidities, notably Human Immunodeficiency Virus (HIV). We attempted to use the STROBE checklist  to assess the ‘risk of bias,’ but could not continue due to a large number of historical studies that are not in line with current reporting standards. The data analysis thus resulted in a narrative, qualitative synthesis of the included studies.Supporting Information 1 for all the included studies and the key information).The flow diagram in The studies were published between 1955 and 2016; with only 12 (22%) after 2010. The studies were conducted in 13 out of the 48 countries in Sub-Saharan Africa: in eastern Africa , western Africa  and southern Africa (pre-independent Namibia). More than half of the studies were from western Africa (30/54), notably Senegal (6), Burkina Faso (5) and Mali (5). Twenty-three studies studied CL in the community (including three among school-children), and 28 used data collected in health facilities . The remaining three studies were mixed. All 54 studies were observational: 29 (54%) were descriptive case series , and 25 (46%) followed a cross-sectional design, usually survey with various tools employed such as clinical screening or questionnaires.L. aethiopica as a distinct taxonomic entity was published in 1978 [L. tropica was later reported from certain areas in Kenya during the 1990s, and since then considered to have a more restricted distribution than L. major [In eastern Africa, CL has been known for more than a century, with the first indigenous CL case recorded in 1911 in Sudan . In Ethi in 1978 ,31, and  in 1978 . L. tropL. major ,34.L. major has been thought to circulate in this region. The oldest case reports of CL come from Niger in 1911 [th century, the colonial medical officers documented sporadic case reports from an area that later became recognized as the ‘CL belt’ [In western Africa, only  in 1911 , then fr in 1911 . Later m in 1911 ,38. DuriCL belt’ –42, MaliCL belt’ . CurrentCL belt’ , but theCL belt’ .Leishmania antigens, the induration is being read 48–72 hours later as a demonstration of a delayed type hypersensitivity reaction, much like a tuberculin skin test [Twelve studies  reportedkin test . LST doekin test .Leishmania infection in Kemena was 45%, with the incidence of 19% and 17%; higher than Sougoula with 20%, 6% and 6% for the same years [These studies were conducted at the community level in CL foci, and have shown fluctuation over time . Changesme years . Reasonsme years .L. major as the causative agent. LST positivity was also shown to be correlated to higher levels of antibodies to sand fly salivary proteins [A 2014 study from Mali complemented LST surveys with PCR and finger prick blood sample to measure antibody levels to sand fly saliva in endemic districts . The resproteins .Leishmania parasite [Across the studies, a consistent finding is that the proportion of positive LST increased with age and areas where CL transmission is active, at least a third of the population have had exposure to the parasite –51,54–56Twenty-one studies reported estimates of CL prevalence or incidence; five were using medical records from hospitals, and the remaining were population estimates obtained through active screening for CL lesions and scars at the community level. All diagnosis was based on clinical examination. Though additional confirmatory methods  were mentioned in all studies but two, it is unclear whether these were used in some or all or none of the patients. Among the five studies that were hospital-based, two used the number of dermatology consultations as the denominator, and the CL cases proportion found is 2% in Ouagadougou, Burkina Faso  and 14% In most of the studies in the community, the prevalence of active CL was less than 5%. In endemic areas, the frequency of CL scars usually exceeds that of CL active lesions, except in a few special settings . In UtutTo complement the findings from published studies, we also examined the data from the country official reporting system to WHO. The system record data from 1996 onwards, but clearly there are missing data . The absThe majority (n = 28) of the included records are clinical case series based on medical files from dermatology clinics or hospitals as the main data source. These studies describe a cohort of CL patients over a certain period, ranging from two to nine years. Chronologically, 10 studies reported CL cases in periods before 1980 ,74,76–80Hospitals reported that CL patients mainly came from surrounding areas or outside the cities or capital, such as Dakar, Senegal ,88,93 orL. major LON-1 [Sayda el-Safi, personal communication). In Ethiopia, a CL outbreak occurred in 2005 in a district 150 km south of Addis. A survey then established an overall prevalence of 4.8% (92/1907), and 1 in 5 cases had mucocutaneous lesions [Three countries have published studies on CL outbreaks: Sudan, Ethiopia, and Ghana. The first ever epidemics in Sudan were reported in 1976–1977 along the Nile, in Shendi-Atbara north of Khartoum , while tor LON-1  and the  lesions .Leishmania enriettii complex, a possible new subgenus of pathogenic human Leishmania parasites [In Ghana, an outbreak of localized skin lesion consistent with CL occurred in Ho municipality, Volta region in 2003 . The usuarasites .Thirty-two studies described the clinical presentations of CL lesions. The most commonly used categories of the lesions are as followed: the localized CL or LCL, otherwise known as the classic oriental sore, refers to the lesion at the site of sand fly bites that may get ulcerated. LCL may appear as dry, papular forms with crust, or the wet, ulcerative forms with indurated edges. LCL can be singular or multifocal. When the nodules are multiple and nonulcerative, this is typically called a diffuse CL or DCL. In Sudan, mucosal leishmaniasis is described as lesion(s) that involves destructive mucosal inflammation which does not always start with a cutaneous lesion. This differs from New World mucocutaneous leishmaniasis (MCL), which refers to a metastatic dissemination to the mucosal tissues starting from a distal cutaneous lesion ,100. BacThe diagnosis documented in the medical files are often missing. A dermatology hospital in Addis, Ethiopia reported that among 234 confirmed CL cases, only 22% were categorized—consisting of 9% DCL, 10% MCL and 3% LCL . The higL. major heals within approximately 2 to 12 months and L. tropica within 15 months, with a terminal scar appearing after about 24 months [L. aethiopica suggests that it presents initially with nodules which do not heal or ulcerate but can metastasize widely [In the majority of the studies, the natural history of the lesions is only briefly described (n = 51). The duration between the first bite to lesion formation for LCL varied between 3–12 weeks ,90. Alth4 months . The dese widely  and are e widely ,80,100. With regard to the locations of CL lesions, there appears to be a regional difference. CL lesions from eastern Africa are mostly found on the head  and less on the arms, legs or trunk, while from western Africa the highest proportion of lesions are on the upper and lower extremities.Amongst the 42 studies reporting the sex ratio of the patients , only 12CL and HIV co-morbidities has been described in Burkina Faso ,60,103, The consistent finding is that the clinical forms of CL are more diverse and complex in HIV co-infected patients, posing significant challenges in diagnosis and treatment. The lesions tend to be more severe: there are reports of infiltrative, leprosy-like, diffuse, psoriasis-like, verrucous, sporotrichoid, and angiomatous or Kaposi-like. Patients are more likely to have more than one lesion and more than one clinical forms . Also, tth century, but the published literature on CL can best be described as irregular and patchy. There is a lack of population-based or longitudinal studies to measure prevalence and incidence. The current CL burden is difficult to estimate accurately as primary data are scarce and CL cases often clusters in pocket areas. The prevalence in western Africa appears to be low, yet unprecedented outbreaks have occurred, such as in Burkina Faso and Ghana. Several CL outbreaks probably never get reported [Our review shows that CL is reported in at least 13 countries in SSA but the true burden remains unknown. Several foci in Mali, Guinea, and Senegal have been studied intensively in the last half of the 20reported ,106. In The findings from this review provide further insights vis-à-vis the official data reported to the WHO’s global surveillance system. Based on reported cases in 2002–2009, WHO estimated a global CL incidence of 214,036 in 2012 with 35,300–90,500 cases from eastern Africa and a mere 790–1500 cases from the rest of SSA, albeit with 5–10 fold underestimation . From thThe quality of evidence found in our review is inadequate to establish a more accurate CL burden in this region. Case series provide a snapshot of a specific situation in a certain time and place, yet are hard to extrapolate. A considerable part of the data we reviewed originated from specialized dermatology services which only represent a small proportion of all CL cases. The patchwork distribution of CL within a country further hampers surveillance. The CL belt in SSA from West Africa to the Horn of Africa , confirmVarious factors have been attributed to the poor CL data from SSA ,12,109: Our review identified the fragmented knowledge on burden as one of the key challenges for CL control in SSA. Being a largely zoonotic disease, the control efforts for CL remains limited to care provision, while vector control or environmental measures are not feasible. The risk of outbreaks, however, should not be undermined. Co-infection with HIV, already a concern for VL, might pose further challenges in CL management. What can be done in the face of all these adversities?In lights of the scanty data, steps should be taken to improve existing surveillance systems or establish one where it is non-existent. Each country could undertake a thorough review of CL epidemiological situation, using standardized methods, enabling compilation and comparison. The future actions must be adjusted to the country context. An integrated paradigm should be adopted: either in setting up rapid epidemiological assessments for CL alone or in taking opportunities to include CL with other skin-NTDs ,114. RecThe strengths of this review are the systematic search of the literature and the stringent process and reporting following a published protocol in PROSPERO. Furthermore, standardized reporting according to PRISMA guidelines is adhered to. The exclusion criteria for case series of fewer than ten patients have been chosen as the aim is to provide an idea on disease burden though we might risk missing individual case report(s) and may exclude countries which only has case report publications. By systematically assessing all published articles we aimed to draw attention to the importance of the disease and identify research priorities.The major limitations of our study are first, the publication bias. Sub-national studies that are not published nor listed in the international electronic databases might be missed. Secondly, the weakness of passive detection and clinical case reporting. We could not provide a meta-analysis nor compare the results between studies, due to the high variability across individual studies . We could not systematically assess the risk of bias in the individual records and apply the current standard of as many studies pre-dated this era. The quality of the data in the studies is relatively poor. However, with the limited data we had to rely on, we understand better the state of the evidence in regards to CL in SSA: still an uncharted territory.Based on the gaps identified in this review, there are some research priorities to be addressed see . ImproviThe epidemiological burden of cutaneous leishmaniasis in sub-Saharan Africa appears to be poorly documented. There is a paucity of robust evidence on prevalence and incidence on CL in this region. The diversity of CL epidemiological characteristics in endemic countries is not yet fully investigated. Nevertheless, the burden of CL morbidity remains important and most likely to be underestimated. Surveillance and mapping should be improved to mitigate outbreak risk and address dual co-infection with HIV. The current fragmented knowledge should be approached regionally, and awareness must be raised. In addition to population-based studies that better define the CL burden in sub-Saharan Africa, health systems should consider studies and action to improve CL essential diagnosis and care.S1 Diagram(DOC)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Patients with chronic mental illness are highly vulnerable to chronic respiratory problems. We examined the influence of mental disability on respiratory infection-related utilization risk in individuals with and without mental disabilities (MDs). A population-based, retrospective cohort design and two-part model were used to analyze respiratory infection-related utilization in individuals with MDs (MD group) and a matched reference group. The respiratory infection-related utilization rate in one year was lower in the MD group (53.8%) than in the reference group (56.6%). The odds ratios (ORs) were significantly higher among individuals with profound MDs  and those with a history of dental cavities  or periodontal disease  after controlling for covariables. The average number of visits was higher in the MD group (5.3) than in the reference group (4.0). The respiratory infection-related utilization rate and average number of visits were significantly higher in the mild, moderate and severe disabled groups with a history of periodontal disease, respectively, than that of the reference group. In conclusion, healthcare authorities must develop an incentive program to prevent respiratory infections among individuals with MDs.  Although lower respiratory tract infections (LRTIs) are largely preventable , respiraTaiwan’s NHI program currently includes >99.7% of the population of Taiwan and provides universal, compulsory, and low copayment health services that minimize the economic barrier to medical care for inpatient, outpatient, prescription, and various other healthcare services. The NHI database (NHID) contains detailed records of outpatient visits, hospital admissions and emergency department visits, including diagnosis, procedures, medication, provider information, and expenditure. These databases are encrypted for de-identification and have been monitored for completeness and accuracy by Taiwan’s Ministry of Health and Welfare. A population-based, retrospective cohort design was used to analyze the digital claim data between 2013 and 2015 of the NHID, and information relating to disabled individuals (Disabled Population Profile) in the 2014 Taiwan’s Ministry of Health and Welfare Database. All data are stored in the Health and Welfare Data Science Center and only analyzed results can be obtained. This secondary data analysis study was performed following the rules of the Declaration of Helsinki of 1975. This study was approved by the Institutional Review Board of National Yang-Ming University in Taiwan .n = 1580) and those with missing data (n = 1050). Following exclusion, a total of 117,874 cases were included in the analysis. The reference group was randomly selected from the non-MD group  using a 1:2 match with the MD group based on age and sex. Following matching, the MD group  and reference group  were included in the analysis. All study participants were followed up for one year after enrollment. Both groups were followed for one year to investigate healthcare utilization related to respiratory infections.The two study groups involved in the present study were selected from the Disabled Population Profile and NHID, comprising an MD group and a reference group. The study participants encompassed disabled individuals with chronic mental disability of all ages between 1 January 2014, and 31 December 2014, from the Disabled Population Profile. A total of 120,504 individuals in the MD group were eligible for inclusion. Exclusion criteria for the MD group were individuals who died between 1 January 2015, and 31 December 2015 . The independent variable was mental disability. The severity of the mental disability was categorized into mild, moderate, severe, and profound by physician according to ICF  criteria. The relevant covariates included the following: (1) demographic characteristics, such as gender and age; (2) economic status, such as premium-based monthly salary, and community resources, such as the degree of urbanization in the subject’s area of residence ; (3) health condition, such as dental diseases and chronic disease comorbidity. The history of dental diseases comprised of a history of no dental disease or dental disease  during the previous year. In this study, only patients who had at least two ambulatory visits or one hospitalization prior to the index date (31 December 2014) with a diagnosis of dental cavities (ICD9-CM codes 521.0) or periodontitis (ICD9-CM codes 523.3–5) were identified as patients with a history of dental cavities or periodontitis. The chronic disease comorbidity was based on the disease score calculated by the D-M Charlson comorbidity index (CCI) definition [p < 0.05. Multicollinearity was also analyzed via the variance inflation factor (VIF) using regression analysis. As the VIF of each coefficient was <5, it was considered that the effect of correlation among the independent variables was not sufficient to distort the estimation. Programming and data analyses were performed using SAS statistical software, version 9.4 . Descriptive statistics are represented by the numbers of cases, percentages, and means with standard deviation. The frequency and percentage of respiratory infection-related utilization were then analyzed. The Chi-square test and t-test were used to compare the proportions and means between the two study groups. A two-part model was used to analyze respiratory infection-related utilization. The first part was a binary equation to model the probability of any respiratory infection-related utilization; for the second part, a generalized linear model was used to explain the number of respiratory infection-related healthcare utilizations in cases with at least one physician visit or hospitalization in one year. Conditional logistic regression and generalized linear models were used to analyze related influential factors associated with respiratory infection-related healthcare utilization in patients with MDs, and the significance level was p < 0.0001). Out of the study participants of the MD group, 12.7% had a history of dental cavities. A total of 117,031 individuals with MDs and 234,062 individuals without MDs were recruited for the study. The matched data showed that there was no significant difference in gender, age group or history of periodontal disease between the MD and reference groups . The levp < 0.001). The probability increased with the level of urbanization of residential location. The probability in individuals with profound MDs was 59.8% for those residing in locations with a low level of urbanization and 61.1% for those residing in locations with high-level urbanization. The probability increased with an increase in the CCI and was highest in the severe (CCI ≥ 2) group (p < 0.001). The utilization was significantly higher for those in the MD group with a history of dental cavities (62.8%) compared with that in those without such a history (52.5%). Similarly, among those in the MD group, the probability was significantly higher for those with history of periodontal disease (63.6%) compared with that in those without such a history (51.6%). .  p < 0.001) (p < 0.001)  higher in the profoundly MD group, but 0.66 to 0.80 times lower in the mild, moderate and severe MD group than the reference group (< 0.001) . The pro< 0.001) .p < 0.001), <20-years-old (p < 0.001), high month salary (p < 0.001), lower urbanization area (p < 0.001), low CCI (p < 0.001), no history of dental cavities (p < 0.001), and no history of periodontal disease (p < 0.001), respectively. We analyzed the number of visits for respiratory infection disease only in those with utilization. As shown in p < 0.001) (p < 0.001). Additionally, the average number of visits in the high-income group and low level of urbanization area were 0.22 and 0.24 significantly lower than that in the lowest income group (p < 0.001) and high urbanization area (p < 0.001), respectively. The average number of visits in those with mild (CCI = 1) and severe (CCI ≥ 2) CCI were 0.98 and 1.52 significantly higher than the people without CCI = 0 (p < 0.001). The average number of visits in people with a history of dental cavities and periodontal disease were 0.22 and 0.14 significantly higher than those without such a history (p < 0.001), respectively. The average number of visits were 0.59 and 0.34 significantly higher in the mild, moderate, and severely disabled groups with a history of periodontal disease, respectively than that in the reference group without such a history (p < 0.001). After controlling for potential confounding covariates, the generalized linear regression model showed that the average number of visits related to respiratory infection in the MD group was significantly higher than the reference group (< 0.001) . The aveThis study yielded three noteworthy results. Firstly, we identified significant differences between individuals with and without MDs regarding respiratory infection-related healthcare utilization. The main results of the study indicate that, compared with the general population, individuals with MDs were less likely to receive medical care due to respiratory infections within one year. However, the utilization of respiratory infections among individuals with profound MDs was significantly higher than that in the reference group . Universal coverage of healthcare aims to secure access to appropriate healthcare for all at an affordable cost. Since 1995, Taiwan’s NHI system has provided an equal package of benefits, including outpatient, inpatient, dental and pharmaceutical services for all. Reduced copayment and other welfare programs are available to the elderly and vulnerable groups. Access to primary healthcare (PHC) is a fundamental human right and central to the performance of healthcare systems, however, persons with disabilities (PWDs) generally experience greater barriers in accessing PHC than those in the general population. According to one previous study, individuals with psychotic disorders  and bipolar disorder  had significantly reduced odds of having access to a primary healthcare physician compared with individuals without mental disability. Individuals with psychotic disorders, bipolar disorder or major depressive disorder have higher odds of reporting difficulties in accessing care (OR = 2.5–7.0) . Secondly, after controlling for potential confounding covariates, the average respiratory infection-related healthcare utilization visits in individuals with MDs was significantly higher compared with that in the reference group and increased with increased disability severity. Previous studies have demonstrated a higher prevalence of respiratory disease , respiraFinally, this study revealed a higher association between dental diseases and respiratory infection-related healthcare utilization. The respiratory infection-related healthcare utilization rates and the average number of visits were significantly higher in the mild, moderate, and severely disabled groups with a history of periodontal disease, respectively, than in the reference group. Oral bacteria, poor oral hygiene, and periodontitis influence the incidence of pulmonary infections. The oral colonization by potential respiratory pathogens, possibly fostered by periodontitis, and possibly by bacteria specific to the oral cavity or to periodontal diseases contribute to pulmonary infections . The amoThis study has several strengths. Firstly, using a nationwide population-based dataset, the number of subjects provides ample statistical power to detect differences between groups after adjusting for confounding variables. A comparison of respiratory infection-related healthcare utilization outcomes with the general population was also possible. Secondly, the study participants encompassed different severities of mental disability for chronic mental disability. The severity of the MDs was credible through professional diagnosis and identification by physicians. The resulting outcomes show a statistically significant dose-response relationship between the severity of the mental disability and respiratory infection-related healthcare utilization. Finally, the dental diseases in question comprised the presence or absence of a history of dental cavities and periodontal disease in the previous year. A regression analysis model with an interaction term between mental disability and periodontal disease history variables was used to examine the effect of mental disability and dental diseases on respiratory infection-related healthcare utilization. The presence of interactions can have important implications for the interpretation of statistical models.n= 21,853,264). Therefore, the non-excluded cases of mental disability in the reference group might be very limited and not influence the study result. Second, compared to the reference group, people with mental disabilities are often excluded as candidates for organ transplantation in clinical practice. Therefore, respiratory infection-related utilization rate and average number of visits may influence the reference group more than the mental disability group. The results of a significant higher respiratory infection-related utilization rate and average number of visits in mental disability group might not be changed. Third, we were unable to obtain a history of alcohol intake and smoking data for all subjects to discuss those effect of respiratory infection. Fourth, we were able to count the number of respiratory infection utilization only in patients who were treated. For patients with respiratory tract infections who do not receive medical treatment, it is impossible to calculate utilization. Because of access to affordable low health insurance copayment and health care providers in Taiwan, the economic barrier of mental disability people is limited. Therefore, the underestimation of the association between mental disability and respiratory may be limited. Fifth, we were unable to record the oral health behavior of all subjects or dental care utilization data for individuals who did not receive care due to dental diseases. The oral health status among individuals with MDs was poorer than that of the general population. As patients with severe mental illness visit dentists less frequently than those in the general population in Taiwan [Given the nature of secondary data analysis, our study has some limitations. First, we could not exclude the patients with mental disorders in the reference group if physicians did not make the diagnosis codes of mental disability in their claim form. However, physicians try hard to record all the diagnosis of their patients in claim form in order to reimburse payment from NHI. On the other hand, the reference group  was coming from non-MD group (In summary, there were significant differences between individuals with and without MDs in respiratory infection-related healthcare utilization. Individuals with MDs received less medical care than those in the general population in Taiwan. Once they had received medical care, individuals with MDs used services more frequently than those without MDs. The respiratory infection-related utilization rate and average number of visits were significantly higher in the mild, moderate and severe disabled groups with a history of periodontal disease, respectively, than in the reference group. Changing the care-seeking behavior of individuals with MDs in the short-term would be difficult; therefore, healthcare authorities should organize health systems to facilitate meeting the medical needs of individuals with MDs. Healthcare providers, including psychiatrists, dentists, nursing staff in institutions, and caregivers, should encourage those with MDs to regularly visit the dentist and strengthen their oral health literacy, so as to improve the oral health of these vulnerable groups. There must be greater investment in early intervention and the development of service plans that will deliver accessible provision over time, which may reduce the risk of respiratory infections for the mentally disabled. Appropriate, quality healthcare should be equitably and accessibly delivered across the country and to all groups of individuals with mental disabilities.


In the present study we investigated the efficacy of the differential outcomes procedure (DOP) to improve visuospatial working memory in patients with Alzheimer’s disease and mild cognitive impairment (MCI). The DOP associates correct responses to the to-be-remember stimulus with unique outcomes. Eleven patients diagnosed with Alzheimer’s disease, 11 participants with MCI, and 17 healthy matched controls performed a spatial delayed memory task under the DOP and a control condition . We found that performance  was significantly better in the DOP condition relative to the NOP condition in all three groups of participants. AD patients performed worse, and took longer to benefit from the DOP. In line with previous animal and human research, we propose that the DOP activates brain structures and cognitive mechanisms that are less affected by healthy and pathological aging, optimizing in this way the function of the cognitive system. According to the WHO, 47.5 million of people lived with dementia in 2015 and this number is expected to increase by 59%(75.6 millions) until 2030 . DementiSince there is currently no accepted pharmacological treatment for MCI , and simA different approach to enhance cognitive performance is to activate processes that are less affected by aging and dementia by applying, for example, basic principles of learning and reinforcement that were discovered early on in animals e.g., , insteadthe two-memory systems model, which is based on work conducted by Savage and colleagues in rats  theoretical framework proposed to explain the effects observed with the DOP is ts v.g., . Accordinetworks , which anetworks . Althougnetworks . Thus, tTo sum up, evidence so far suggests that the DOP can be effective in improving memory for faces in healthy older adults and in patients with AD. In the present study, we further test this hypothesis by investigating the effectiveness of the DOP in improving spatial working memory in a group of individuals with MCI, a group of patients with AD and a group of matched healthy controls. Neuropsychological research on AD has mostly investigated verbal mediated memory (episodic memory and semantic memory), which has long been considered as the most characteristic and earliest cognitive sign of the disease. Comparatively, very little attention has been paid to visuospatial memory, while more recent evidence suggests that spatial memory deficits are present in early stages of AD and may actually constitute early predictors of the disease see , we expelate MCI has recently been coined in the literature to refer to a subtype of MCI, which shows a greater cognitive impairment and is more likely to progress to AD (Eleven patients with Alzheimer disease (AD group), 11 patients with mild cognitive impairment (MCI group) and 17 healthy controls (HC group) participated in the study. Nine of the MCI participants were diagnosed with multi-domain amnestic MCI (aMCImd) and the remaining two with single domain aMCI. Patients were recruited from the Greek Association of Alzheimer’s Disease and Related Disorders (Alzheimer’s Hellas) in Thessaloniki, and diagnosed by a neurologist. Diagnosis of dementia was made according to the criteria of NINCDS-ADRDA . AD patiss to AD .Cognitively healthy older adults  were recruited from Seniors Day Care centres in Neapoli, Thessaloniki. The exclusion criteria for healthy older adults included; (i) any mental health condition that could affect performance on the task , (ii) intake of psychotropic drugs such as anti-depressants and anxiolytics; and (iii) a score in the MMSE below 24 . The stuThe task was designed and run by E-prime v2.0 . There wEach participant was assessed individually in a quiet room. At the beginning of the first session, each participant was randomly assigned to one of the two outcomes conditions (DOP or NOP). Then, the researcher explained the task orally while a sample trial was shown on the screen, and participants run a practice block of 4 trials. In the DOP condition, each target location was always paired with a specific outcome . In the NOP condition, a landscape picture-phrase (the outcome) was randomly presented after correct responses to target locations. That is, in this condition each target location was equally often paired with each of the four landscape pictures-phrases. In each version of the task, although the shape could be presented in all eight possible locations across the trials, four locations were never used as targets, and so responses to any of these non-target locations were never reinforced.Each trial sequence  as the between-subject factor and Outcomes (DOP and NOP) and Delay (2 and 15 s) as the within-subject factors. Bonferroni F = 11.56, p = 0.002, F = 13.40, p < 0.001, post hoc pair-wise comparisons showed also significant differences between the AD group (49%) and the MCI and HC groups . That is, healthy control and MCI patients were both more accurate than AD patients. Finally, a significant effect of Outcomes was observed [F = 22.23, p < 0.001, ps > 0.05).Results from the accuracy data . Thus, it appeared that AD patients needed more training with the procedure in order to observe improvements in performance. To test this ad hoc hypothesis, we grouped the data from these participants in three blocks of sixteen trials each  = 15.78, p = 0.003, F = 4.56, p = 0.023, F = 4.16, p = 0.031, df = 1; p = 0.072 for Block 2 and Chi-square = 9.0, df = 1; p = 0.003 for Block 3). However, in the NOP condition performance never reached above chance levels.Although participants in the three groups appeared to show a better spatial delayed recognition memory in the DOP than in the NOP condition , it is worth noting that overall AD patients’ performance was at chance in the DOP condition , the performance of AD patients was significantly worse, relative to the group of MCI and HC, and at chance level. This finding is in agreement with evidence suggesting that spatial memory deficits are significant in AD see . Given ttwo memory system model, we propose that the beneficial effects of the DOP observed in all three groups result from the activation of neural systems and cognitive processes that are less affected by healthy and pathological aging. Future studies should test this hypothesis by additionally investigating how brain reserve and neuroplasticity in MCI and AD . Since the present study employed a typical experimental-cognitive task, future studies may investigate the effectiveness of the DOP in training spatial skills using more ecological contexts and tasks.AV contributed to the original idea, design of the study, data analysis, and drafted the manuscript. AE contributed to the original idea, design of the study, data analysis, and writing. AY recruited and tested the healthy controls and MCI participants, contributed to data analysis and writing. AL tested Alzheimer’s disease patients and contributed to the writing. FK and MT were responsible for recruitment and testing of AD and MCI patients, for their diagnosis and neuropsychological assessment, and approved the final version to be submitted.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.


Supplemental Digital Content is available in the text Increasing studies were performed to explore the prognostic value of snail in lung cancer (LC), however, with inconsistent results. Hence, this systematic review is aimed to evaluate the prognostic role of snail in patients with LC.A comprehensive literature search in the PubMed, Embase, the Cochrane Library, and Web of Science databases will be conducted to identify eligible studies. Language is limited as English. We will employ hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the correlations between snail expression and overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), disease-free survival (DFS), and clinicopathological features. Meta-analysis will be performed using STATA 14.0 software.This study will provide a high-quality synthesis of current evidence of the correlations between snail expression and OS, PFS/RFS/DFS, and clinicopathological features.The study will provide updated evidence to assess whether the expression of snail is in association with poor prognosis in patients with LC.It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference.This systematic review protocol has been registered in the PROSPERO network (No. CRD42018095191). Advances for LC have been slow, for which the 5-year relative survival is currently 18%. While more than one-half of cases are diagnosed at a distant stage, leading to an extremely poor 5-year survival rate of 4% among patients with stage IV LC. The high recurrence and metastasis largely contribute to the poor overall prognosis. Therefore, it is crucial to identify reliable therapeutic and prognosis biomarkers for LC.Lung cancer (LC) is currently a leading cause of cancer-related mortality. The epithelial to mesenchymal transition (EMT) seems to play a crucial role. It is a complicated progress, during which, epithelial cells lose their epithelial features and gain mesenchymal phenotypes, and epithelial cells become migratory and invasive.,7 As one of transcription factors, snail homolog 1 (Snai1) is considered as one of the primary drivers of EMT and has been implicated in the EMT associated with tumor progression.,9 The expression of snail has been disclosed to associate with invasion and metastasis as well as poor prognosis of many malignancies, such as gastric cancer, breast cancer, hepatocellular carcinoma, colorectal cancer and lung cancer. In recent years, a number of studies analyze the relationship between the snail expression and prognosis of patients with LC, but due to differences in research method, sample size and the study population, the findings of a single study are difficult to extend to the entire population and the obtained conclusions are inconsistent. The study conducted by Merikallio et al supported that the expression of snail was strongest in small cell lung cancer. Whereas, the prognostic role of snail is contradictory in NSCLC. Yanagawa et al indicated that lung adenocarcinoma patients with elevated snail expression had a significant reduction of survival time, while the high expression of snail was not a prognostic biomarker in lung squamous cell carcinoma. However, the study conducted by Sun et al indicated that snail was not a prognostic factor in lung adenocarcinoma. Given that the clinical results are controversial, we aim to systematically evaluate the prognostic role of snail in lung cancer patients.The prognosis is highly associated with the metastatic behavior of the tumor.22.1The protocol for this systematic review was registered on PROSPERO with registration number: CRD42018095191. This protocol follows the guidelines according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines.2.1.1This study will perform a complete computer-based search of the PubMed, Embase, Web of Science, and the Cochrane Library databases for clinical trials up to the date of April 28, 2018. The strategy is created based on a discussion among all reviewers according to the Cochrane handbook guidelines. The following search terms will be used: lung neoplasm(s), lung cancer(s), lung tumor(s), lung carcinoma(s), pulmonary cancer(s), snail family transcription factors, snail, snail 1, prognosis, outcome, prognostic value, survival, and prognostic biomarker(s). The example search strategy in Table 2.2The main inclusion criteria are as follows: Retrospective or prospective studies evaluating the prognostic relationship between the expression of snail and LC; the expression of snail in tissues detected by immunohistochemistry analysis; providing sufficient data to estimate the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS)/relapse-free survival (RFS)/disease-free survival (DFS), along with their 95% confidence intervals (CIs) or p values; published in English.The main exclusion criteria are as follows: Reviews, case reports, conference abstracts, specialist experience, comments and cell or animal studies. studies without enough data to pool the HRs; studies not focusing on the role of the snail expression on the clinicopathological features or prognoses in LC; not published in English.2.32.3.1http://www.prisma-statement.org), the screening and selection process of this study will be documented and summarized. The primary selection process is shown in a PRISMA flowchart  independently. Initially, we will screen the titles, abstracts, and keywords of all retrieved records. The articles meeting inclusion criteria will be reviewed comprehensively by reading the full text. A table named “Reasons for excluded studies” will be used for recording excluded studies. We will resolve disagreements by consensus between the 2 reviews or by involving a third review author (ML). Using the PRISMA-compliant flowchart .Data extraction of the included studies will be performed by 2 independent authors (MS and GD). We will use a data extraction form (Excel) designed by all the authors in consensus to conduct the data extraction. The following information are extracted: name of the first author, publication time, country, number of patients, recruitment time, follow-up duration, analysis method, tumor type, clinicopathological features, antibody epitope, antibody company, method and score for its evaluation, cut-off value of snail overexpression, positive expression rate, HRs, and their 95% CIs. If HRs and their 95% CIs are not reported, we will extract them from Kaplan–Meier curves using the methods proposed by Tierney et al.2.3.3 A study with a score of at least 5 will be considered of high quality. Two independent authors (MS and DL) will use the criteria outlined in the NOS. Any disagreement will be resolved by discussion or by involving an arbiter (ML).The Newcastle–Ottawa Quality Assessment Scale (NOS) is employed to assess the quality of the selected studies. The NOS included 3 main aspects: selection, comparability, and outcome.2.3.4For prognostic outcomes including OS, PFS, RFS, DFS, data will be expressed as the HRs along with their 95% CIs or p values.2.3.5In several studies which some data are missing, we will consider why the data are missing (missing at random or not). We will try to contact the authors to request any inadequate and missing data of the included studies. If the data are still incomplete, available case analysis will be performed. And we will address the potential impact of missing data on the findings of the review in Section 3.2.3.6Q test and Higgins I2 method. When the result of a Q-test (I2 ≥ 50% or P < .05) indicating substantial heterogeneity, while I2<50% will be taken as evidence of no heterogeneity. In cases of substantial heterogeneity, we will explore the possible causes by sensitivity analysis and subgroup analyses.The heterogeneity was assessed across all studies by Cochran's 2.3.7 are used to evaluate publication bias .We will assess the publication bias with a funnel plot if the number of included studies is more than 10. Visual inspection of funnel plot, Egger's test, Begger's test2.3.8I2≥50%, the random-effect model will be used for data analysis, otherwise a fixed-effect model will be used for data analysis. Besides, the sensitivity analysis and subgroup analysis will be employed for exploring the causes of heterogeneity. All the p values are 2-side and P < .05 is considered statistically significant.Meta-analysis will be performed using STATA software . The prognosis outcomes are explored using the HRs and the corresponding 95% CIs. If 2.3.91.Different nationalities2.Histology type of LC3.Different statistical analyses.The prognosis outcomes mainly contain the OS and PFS/DFS/RFS. In cases of high heterogeneity, we will perform subgroup meta-analyses to determine the possible factors that may influence the results. The following subgroup analyses will be considered:2.3.10The sensitivity analysis will conduct using the “metaninf” STATA command  to examine the robustness of the pooled results.3 EMT is considered to be one of the major molecular mechanisms inducing tumor invasion, metastasis, and postoperative recurrence.,24 It is an important cellular process, which occurs during cancer development and progression and has a crucial role in metastasis by enhancing the motility of tumor cells. The first step of EMT process is that epithelial cells lose cell–cell junctions and the epithelial marker E-cadherin. E-cadherin acts as a tumor suppressor inhibiting invasion and metastasis. While, downregulation of E-cadherin expression increases tumor cell motility and promotes invasion. The snail, which is zinc finger transcription factors, is overexpressed in epithelial cell lines and mainly repress expression of E-cadherin to reduce cell adhesion during the EMT.,28 Therefore, snail is an important factor in regulating EMT and its high expression is related to the enhancement of LC invasion, metastasis, and progression.Cancer metastasis is the major cause for the poor survival of LC patients. The metastasis of LC is extremely complex processes, where multiple steps are involved.Several studies were conducted to explore the prognostic significance of snail in LC. Unfortunately, the results of these researches were controversial. A number of studies have shown that EMT transcription factor snail is closely related to the prognosis of patients with LC, but some individual studies show that there is no clear relationship between snail and the prognosis of patients with LC. Hence, we hope this review will provide more accurate and objective evidences of the relationship between the snail and the prognosis of patients with LC.While, there are several limitations that need to be addressed in this review. Firstly, only studies published in English will be included, which may increase the bias of our study. Secondly, different nationalities, histology type of LC and different statistical analyses may run risk of heterogeneity. In addition, the methods and cut-off definitions for evaluating snail expression may be different.The PRISMA-P checklist of the protocol is supplied in PRISMA-P checklist.Data curation: Meiling Shi, Guangtong Dong, Daorui Li.Supervision: Peitong Zhang, Kaiwen Hu.Writing – original draft: Meng Li, Xing Zhang.Writing – review & editing: Meng Li.


TM (FFP) program, established in 2004, is a peer volunteer-led collaboration between state and local public health organizations. The goal is to bring sustainable physical activity programs to underserved populations, including those in rural and frontier communities. FFP program is designed to help older adults maintain independence by improving mobility and function and providing opportunities for social engagement. The aim of this study was to evaluate the impact of participation in the program. A 6-month longitudinal study evaluated physical, social, and emotional outcomes among participants. The FES-I, SF-36v2, and Timed Up and Go (TUG) were collected. A convenience sample of new participants  representing rural and urban communities were recruited. FFP produced results similar to programs using physiotherapists or athletic trainers. Significant improvements were seen in TUG and SF-36v2 measures of physical, social, and emotional health. Participants completing at least one 10-week session (66%) demonstrated sustained improvements on these measures. While the average change in TUG between baseline and 10 weeks was statistically significant (p = 0.003), improvement in TUG was dependent on age and attendance. For participants <75 years, all attendance levels resulted in similar improvements in TUG. However, for those ≥75, improvements were strongly associated with the number of classes attended. Both the raw data and the model-based estimates of TUG times demonstrated that as age and attendance increase, greater improvements in TUG times were observed. The FFP program promotes health equity by reaching community-dwelling, underserved senior populations. The FFP program is in its 15th year and serves as an example of a sustainable collaboration between state and local public health organizations that is translatable to both urban and rural settings.Fit and Fall Proof The population of older adults is growing at an unprecedented rate, outpacing the growth of the total US population . This deThe Centers for Disease Control and Prevention's (CDC) Healthy People 2020 recognizes fall prevention and increasing physical activity for older adults as public health priorities. Fall injuries are among the top 20 most expensive medical conditions, with costs to Medicare reaching $31 billion in 2015 –6.Indirect and quality of life costs of falling are high as well, including lost wages and travel expenses for fallers and their family caregivers. Quality of life costs include loss of independence, increased anxiety and fear of falling, social isolation, inability to perform daily tasks, and pain and suffering caused by falls –9.There are numerous, interacting factors that influence a person's risk of falling, including age, medical conditions, and loss of balance and strength , 10, 11.The tracking of falls in a community-setting is difficult without access to medical records because self-reporting of falls is often underreported by older adults. One commonly used tool for assessing and identifying fall risks in clinical and community settings is the Timed Up-and-Go (TUG) , 16. It The CDC and National Council on Aging (NCOA) recognize a number of evidence-based programs designed to reduce falls while generating positive return on investment (ROI) , 18. SomA review of the literature revealed a “research-to-practice” gap with little information about the impact and sustainability of fall prevention programs outside the controls of a research model which allows for the direct tracking of falls –27. Li eTwo recent studies, a case study by Harnish et al.  and Li eFit and Fall Proof™ (FFP), the focus of this study, is a theory-based, peer-led physical activity program for older adults designed to reduce risk of falling by improving function and mobility. The program is a collaboration between public health organizations and the private sector . The goal is to bring sustainable physical activity programs to underserved populations, including those in rural and frontier communities. Established in 2004, FFP is based on principles of adult learning and the Social Cognitive Theory constructs of social support, normative beliefs ; modeling, observational learning (peer leaders and classmates); and behavioral capacity and reinforcement . A pre- and post-assessment of strength and mobility using the eight-foot Timed Up-and-Go (TUG) provides a personal measure of change (outcome expectation) as individuals develop behavioral capacity and increased self-efficacy .The 10-week program delivered 2–3 times per week was developed and updated based on best practices to improve physical function and balance in older adults –34. The The program is funded through a CDC block grant and state resources, and administered by FFP Coordinators located within Idaho's seven local health districts with oversight from the Idaho Department of Health and Welfare. It was designed specifically to reach the rural/frontier Idaho populations where access to exercise facilities, physiotherapists, or certified personal trainers is limited.Core Master Trainers have doctoral or graduate degrees in kinesiology and physical education and extensive knowledge and experience in physical activity for older adults. Master Trainers must meet specific qualifications including demonstrated knowledge of anatomy and physiology, experience with providing instruction to older adults, and familiarity with the FFP program. The Master Trainers work closely with the local health district FFP coordinators to ensure consistency in instruction and program fidelity across the state. Health districts, through agreements with the state, are required to maintain appropriate class sites, purchase class materials and supplies, provide oversight of class leaders and Master Trainers. District FFP Coordinators and Master Trainers are required to attend an annual 1-day Refresher Workshop lead by the Core Master Trainers. Master Trainers teach the volunteer class leaders using the Manual as their textbook. Volunteers practice the exercises and lead segments of a FFP class during the training to develop their skills as a class leader.Coordinators conduct quarterly site visits to ensure program fidelity and to manage process and outcome evaluation measures. Data collection at each site includes location, participant names, attendance records, and pre- and post- TUG scores. Class leaders collect TUG scores for all new participants and at least twice annually for ongoing participants. Records are reviewed by the coordinators, submitted to the state FFP coordinator, and analyzed quarterly and annually to monitor impact and guide program improvements.The objective of this study was to evaluate the impact of the Idaho FFP program among new participants. The primary measurement tools were the TUG test and the SF-36v2. Secondary tools included the Falls Efficacy Scale International (FES-I) and a brief, opened-ended survey collected from participants at the end of a 10-week session.All research procedures were approved by the Boise State University Institutional Review Board. The Transparent Reporting of Evaluation with Non-randomized Designs (TREND) framework was used to guide study design and reporting ; see FigTo minimize disruption by the researchers, class leaders conducted the sessions without researcher involvement. Researchers obtained informed consent from interested individuals and distributed surveys in the first week and made follow-up visits at the completion of each of two 10-week sessions.Study participants in this longitudinal cohort study were identified from FFP classes in rural and urban settings in two waves and visited during the first week of the 10-week sessions conducted between September 3, 2014 and March 27, 2015. Individuals who were new to or returning after a >3-month hiatus from the program were recruited. No individual was excluded due to presence (or number) of chronic health conditions or because they used an assistive device for personal mobility.Participants completed three baseline surveys; a demographic survey , self-perceived health, use of assistive devices for walking), the Falls Efficacy Scale International  and theThe SF-36v2 instrument  uses 36 The eight-foot TUG test is a frequently used functional fitness assessment for community residing older adults. The TUG score represents the time (in seconds) it takes to stand up from a chair, walk eight-feet around a cone, and return to the chair. The test has a published test-retest reliability of 0.95 , 39, 40.For the 11 outcomes studied , we validated that missing data did not create apparent bias by fitting a logistic regression on the presence of data as a function of the predictors to be used. To determine whether participants demonstrated improvements in the outcomes, we used a hierarchical linear model to account for repeated measures of participants, and correlation among participants within locations, using a compound symmetric structure for both variance components.C) , age, attendance (number of classes per session), and interactions for age by test, and age by attendance. This was the fullest model that allowed estimation of outcomes at all test times, was appropriate based on residual plots and Akaike's Information Criterion adjusted for small sample size (AICC) , and addPedersen .These models were used to estimate and compare outcomes at the three testing times; for each outcome, we adjusted the comparisons using a Hochberg adjustment . We usedC, we addressed whether better models resulted, and whether the interaction was an added improvement. We considered models within two AICC units to be comparable, and highlighted results with AICC better than two less than the base model and when the overall p-value of the effect was <0.15 . Using AICas <0.15 .We compared the baseline responses of the 12 outcomes studied, plus disease burden and general health between those who did and did not complete a 10-week session using a t-test, and a chi-square test for use of assistive devices. No statistically significant differences were identified.TM Scoring Software 4.5 to obtain age and gender-based results for the eight domains and the two composite scores. Statistical significance was set at p < 0.05.Statistical analysis was completed with IBM SPSS Statistics, Version 22.0 , SAS 9.4The open-ended survey responses were entered into a Microsoft Excel (2013) database. We conducted frequency counts and used the Key Word In Context method to identify themes and develop codes , 50. An n = 120) were recruited from 10 sites in southwestern Idaho. Two of the sites were rural with 64 participants (53.0%) and the remaining eight were urban with 56 participants (47.0%). Of the 120 participants, 66 (55%) completed two 10-week sessions (20 weeks), and 37 (30.8%) completed one 10-week session. Seventeen (14.2%) withdrew from the study due to scheduling conflicts and lack of interest in continuing in the study. The baseline population included 95 women (79.2%) and 25 men (20.8%). There were 63 participants aged 75 (52.5%) and over. Of the 57 (47.9%) participants aged ≤74, over half (63.2%) were from rural locations. Participants . The baseline average FES-I score for participants was 23.3 (±7.1) indicating a moderate concern about falling based on cut-points identified by Delbaere et al.  classes, or 62.5% of available classes. For the second 10-week session, average attendance was 15.5 (±5.7), or 64.5% of the available classes.From the modeling results, outcomes with statistically significant test effects were TUG, PF, VT, RE, SF, MH, and MCS . Age wasModel-based estimates and changes in outcomes from baseline to the first and second 10-week sessions, calculated at the average age (76 years) and attendance  are reported in After controlling for the test, age, and attendance, each additional chronic condition significantly decreased SF-36 scores for all physical health outcomes . Chronic conditions also decreased scores in the mental health outcomes SF and RE. Those using assistive devices had lower scores on all physical health domains and on the social health domains SF and VT see . The phyMH also had a statistically significant decrease with each added chronic condition, but this drop was nearly erased by the second 10-week assessment. Those using devices had lower scores on all physical health domains, and for two of those (BP and PCS), the scores declined with each additional test. This was also true for the social health domains SF and VT. Women scored significantly higher than men on the SF domain. Rural residents scored statistically higher than urban participants on the social health domains MCS, MH, SF, and VT, and on the physical health domain RP, on at least one of the assessments .There was no association between number of chronic diseases and TUG baseline time, and change over the testing period . TUG timp = 0.003), improvement in TUG was dependent on age and attendance. For participants <75 years, all attendance levels resulted in similar improvements in TUG. However, for those ≥75, improvements were strongly associated with the number of classes attended. Both the raw data  was the opportunity for social engagement as evidenced by the following comments:“Getting to be around positive people.”“Visiting with friends while getting to exercise.”“The people, laughter and friendships we share.”“I look forward to seeing everyone each week and socializing.”Some participants provided suggestion for program improvement, with the most common being a request that instructors add more variety in exercise routines (28%) and for more classes each week (12%).The aim of this study was to determine whether the FFP program achieves its goals of increasing mobility, function, and social engagement for participants. Based on our primary outcomes, FFP demonstrated results consistent with other community-based fall prevention programs using physiotherapists and other certified, and often paid, trainers , 27, 51.Findings indicate that the FFP program provides functional benefits, based on improved TUG times, as well as improved Physical Functioning (PF) and PCS scores. The MCS, MH, VT, and SF also demonstrated significant improvements in social/emotional health over time when controlling for assistive devices or chronic conditions. Although norms for TUG have been established , 53, we Evidence that TUG improvements gained over the first 10-week session were sustained during the second session reinforces that these changes can be attributed to participation in the FFP program. The benefits of participating in the FFP program were particularly evident among those who were older, reported a higher number of chronic conditions, or slower on their baseline TUG . ProgramIndividuals with chronic disease experience significantly higher rates of falling than those without a chronic condition , 55. AltThe results of this study must be interpreted with caution due to the lack of a control or comparison group. This limitation is mitigated somewhat by the use of a longitudinal cohort study design which allowed us to draw inferences by monitoring change over time and demonstrating baseline equivalencies .The use of the SF-36v2 survey in this population may also be a limitation due to a lack of consistency noted across domains for individuals. For example, an individual who said that they had “A lot” of limitations climbing stairs also selected “No limitations” in vigorous activities such as running. We also found that some SF-36v2 questions were not applicable to our population. e.g., RP , asks about health affecting employment, which did not apply to most of our participants.In addition, the community-based nature of the intervention, budget, and privacy considerations limited our ability to collect information on falls among FFP participants. Based on a recent review, we can assume a reduction in fall risk because FFP includes functional exercises and balance training at each class .Current studies of fall prevention/physical activity programs and validated tools are developed for use with generally healthy older adults. Future research is needed to establish the effectiveness of these programs involving diverse populations, i.e., those with limited mobility  and high disease burden.There are numerous studies examining the effects of fall prevention strategies. But there are few evaluations of long-term, community-based programs using the train-the-trainer model with older adults as class leaders. This study provides triangulated evidence that participants, regardless of age, gender, disease burden, or physical limitations receive significant physical and psychological benefits from participation in the FFP program. The 15-year history of the delivery of FFP addresses the research-to-practice gaps identified in the literature , 26. SpeThis program also aligns with the recommendations from a meta-analysis by Sherrington et al.  that phyThe FFP program promotes health equity by reaching underserved populations. Older Idahoans who are low-income or reside in rural areas often lack access to gyms, athletic trainers, and fee-based exercise programs. Bridging this gap provides needed social interaction and exercise opportunities for many seniors. By actively engaging in community partnerships with senior centers, churches, and other organizations that offer facilities for FFP classes, and by mobilizing and training volunteer peer instructors to lead the classes, FFP provides a supervised, evidence-based curriculum at no cost to participants.Participation in the program promotes healthy aging, allowing many Idahoans to age in place and avoid or delay institutionalization, regardless of income or location. This partnership between the private and public health sectors demonstrates the ability to bring sustainable, critical physical activity programming to rural and frontier communities.The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.This study was carried out in accordance with the recommendations of the U.S. Department of Health and Human Services (HHS) Office for Human Research Protections with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Boise State University Institutional Review Board.MA: lead author, study conception and design, manuscript writing, and data collection and final approval of version being published. ST: study conception and design, manuscript writing, and final approval of version being published. LB: data analysis, manuscript writing, and final approval of version being published. EH: study conception and design.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.