Regular/frequent dental visits, at least annually, can aid in reducing the public health burden of head and neck cancers (HNCs) by facilitating earlier detection of the disease. The aim of this study was to conduct a quantitative assessment of any independent association between past dental visits/check-ups and incidence of cancers of HN/upper aerodigestive tract (UADT) and oral cavity worldwide.PubMed, CINAHL, and Cochrane databases were searched for all observational studies published until August 2017 in any language that assessed an association of past dental visits/dental check-ups among the incident cases of HNC/UADT cancers. Screening and quality assessment of the articles was performed by two independent reviewers. Three different meta-analyses were conducted: two based on the incident cancer reported in the studies ; another included all studies irrespective of the type of cancer reported with the frequency of past dental visits as subgroups.Searches retrieved 3164 titles: after removing duplicates, 1377 remained. Of these, 62 were reviewed in full, but only 38 were eligible for inclusion. Under the random effects model, odds of past never/irregular/not frequent dental visits were greater in HNC cases and oral cancer cases as compared to the hospital-based/population-based controls [HNCs-unadjusted odds ratio (OR) 2.24; 95% confidence interval (CI) 1.89 to 2.65) and . Meta-regression findings indicate that none of the subgroup influenced the effect estimates for incidence of cancers. There was no publication bias in our study.This systematic review and meta-analysis indicates that individuals with never/irregular/not frequent dental visits are more likely to be incident cases of HNCs/UADT cancers. Routine/frequent dental visits can aid in detection of head and neck cancers (HNCs) at an early stage –4. More In high-risk populations, some OCs may be preventable through identification of oral potentially malignant disorders by general dental practitioners facilitating diagnosis at an early stage, thus initiating the first line of treatment, enabling better treatment outcomes, and lowering the cost of care . DiagnosThe present systematic review and meta-analysis aims to critically appraise data from comparable observational studies published in any part of the world, leading to a quantitative summary of the scientific evidence of past dental visits versus never dental visits and its association with the incidence of cancers of HN/UADT and oral cavity worldwide. To the best of our knowledge, there is no previously published systematic review and meta-analysis on this topic.https://casp-uk.net/). Case-control, prospective and retrospective cohort, cross-sectional, and screening studies that assessed an association between past dental visits/dental check-ups among the incident cases of HNC and UADT cancers were considered for inclusion. This meta-analysis is based on MOOSE guidelines: Meta-analysis of Observational Studies in Epidemiology [We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) strategy . We haveemiology .We identified all the published studies using an extensive search of the PubMed, CINAHL, and the Cochrane database from the inception of relevant database until August 2017. The following search terms were used with Boolean operators to combine searches:  with no limitations on year of publication and language (Table 1). A health librarian reviewed and provided input on the search strategy. Additional search strategies included (i) a hand search of the reference lists of included studies, (ii) the use of the “related citations” feature in PubMed, (iii) an ongoing surveillance of the literature while updating the manuscript, and (iv) authors were contacted for the articles for which full text was not available. EndNote software was used to remove the duplicates for the same type of article in more than one database. Alerts with search strategies were created in the databases to maintain an ongoing surveillance of the literature.To be eligible for inclusion, the paper had to report a primary study with any population, one or both genders specified, participants of any age, incidence of any cancer subsite of HN, and UADT reported as the health outcome, frequency of dental visits/check-ups prior to the diagnosis of one of these cancers (assessed as the exposure), and availability of sufficient data to estimate the measure of association, i.e., unadjusted odds ratio (OR) along with its corresponding 95% confidence interval (CI). Where a single study was described in several publications, the study which reported the incidence data most comprehensively was included in the analysis. Gray literature, such as unindexed or unpublished conference proceedings, pre-prints, and state of art reports, were not included due to limited resources to access the same.Two reviewers (B.G. and N.K.) independently screened the title and abstract of the identified citations. Full texts of citations judged as potentially eligible were acquired by at least one of the two reviewers. Thereafter, both the reviewers used a standardized and pilot-tested form to independently screen every full text for eligibility. Disagreements were resolved by consensus among the authors. Data extraction from individual studies included information on first author’s last name, year of publication, region of study, study design, number of cases and controls (or number of participants and events), population characteristics (gender and age), exposure definition , definition of cancer site, its subsite and its diagnostic/confirmation criteria, method of selection of controls , adjusted covariates in the regression model, and risk measure in each reviewed article.Studies were assessed for methodological quality using the quality assessment tool for quantitative studies developed by the Effective Public Health Practice Project (EPHPP) . This toQ statistic (measure of weighted square deviations), with N-1 degrees of freedom (where N is the number of studies), results of statistical test based on Q statistic, between studies variance (T2), and ratio of the true heterogeneity to total observed variation (I2). We conducted sensitivity analysis by dropping one study at a time and examining its influence on the summary effect estimates. To investigate publication bias, funnel plots were constructed, plotting the logarithmically transformed ORs against the standard error of the associated log OR. The distribution of study risk estimates across the funnel plot was examined visually and Egger’s test for small study effects was performed to assess the degree of asymmetry. Comprehensive meta-analysis software was used for all analyses [A random effects model was employed in all meta-analysis procedures which produces results that generalize to a range of populations and to different study designs in addition to accounting for heterogeneity between studies. Forest-plots were used to demonstrate the effect of each study and the summary effect size. For effect size estimates, standard errors of its logarithm were calculated from the reported or estimated CIs, assuming that the effect size was log-normally distributed. The logarithms of the effect sizes and their corresponding standard errors formed the data points for random effects meta-analysis. For each analysis, heterogeneity was assessed using by Cochran’s analyses . Unadjusanalyses , 19.The classification of exposure variable  differed between studies, with few studies reporting more than two categories. In the second situation, a single effect estimate was computed by comparing the frequency of dental visits in highest category versus the pooled data from the other categories.Studies that evaluated cancers of the HN/UADT and oral cavity were pooled in two separate evaluations. Some studies presented data on both HNCs as well as OCs and were included in both evaluations. Two different meta-analyses were conducted based on the health outcome as reported by the authors in the articles: one for HNCs/UADTCs and the other meta-analysis was conducted based on OCs exclusively. To report the pooled effect of frequency of dental visits on incidence of cancers, the exposure variable was categorized as yes/regular/frequent  and never/irregular/not frequent . A third meta-analysis was executed by pooling the data from all the studies irrespective of the cancers with the frequency of dental visits as subgroup. Three studies could not be included in any of the other subgroups and shared individual identity for subgroups.n = 2970), CINAHL (n = 185), and Cochrane Library (n = 9). A total of 1377 articles remained after excluding 1793 duplicate records. A further 1315 articles were excluded after study of the abstracts, leaving 62 for which the full texts were assessed for eligibility. The systematic review finally included 38 articles after excluding 24 articles due to unrelated outcome, frequency of dental visits not given for cases and controls to estimate the effect size, study design other than case-control, review articles, letter to editor or comments, similar data from same study population presented in another manuscript, and sample size less than 50. Finally, a total of 26 case-control studies were included in the meta-analysis. The summary and the characteristics of these articles are presented in Tables 2 and 3.The detailed process of the literature search and article screening is described in Fig. Overall, this systematic review includes 32 case-control and 6 other design studies not limited to cross-sectional, observational, case-series, and screening. Fourteen of these studies were conducted in Europe –33. TherAmong the studies included in the meta-analysis, 11 were based on HNCs and 13 studies included OCs as the health outcome (details of same available in Tables 2 and 3). Only two studies included both HNCs and cancers of the esophagus , 24. TheMajority of the studies (29) were of strong quality. Moderate quality was assessed for seven studies and three studies were assessed as weak (Table 4).P < 0.001). The test for heterogeneity produced Tau square of 0.00, Q = 38.25, I2 = 34.63%, test for overall effect z = 8.81, (P < 0.001). The highest risk estimates observed were  in a study conducted in Poland from 1997 to 2000. However, the wide CIs indicate the small sample size of the study. We did not find any statistically significant results for three studies . The test for heterogeneity produced Tau square of 0.00, Q = 15.96, I2 = 24.83%, test for overall effect z = 4.76, (P < 0.001). Highest risk was found in a study conducted in Taiwan on 287 cases and 296 controls  , data not shown.The odds of never/irregular/not frequent dental visits as compared to yes/regular/frequent dental visits were higher among the cases as compared to controls indicating a statistically significant increase in the cancer. Under the random effects model, the overall pooled estimate risk was . The test for heterogeneity produced Tau square of 0.00, Q = 36.33, I2 = 31.76%, test for overall effect z = 9.24, (P < 0.001).The studies were divided into various subgroups according to reported frequency of dental visits in respective studies as follows: ; ; ; ; ; . Figure t = 1.16, df = 24, and P = 0.2558. Publication bias for studies conducted on OCs shows Egger’s regression intercept = − 1.3239, standard error = 1.7850, 95% CI − 5.25 to 2.60, t = 0.7416, df = 11, and P = 0.474. For all the studies included in meta-analysis and grouped by the frequency of dental visits: the Egger’s regression intercept was − 0.889, standard error = 0.8946, 95% CI − 2.73 to 0.9941, t = 0.9940, df = 24, and P = 0.330. Results of meta-regression analysis indicate that none of the included subgroups for history of dental visits influenced the effect estimate (Table 5).The symmetrical funnel plot in Fig. In this meta-analysis, we aimed to quantify the effect of frequency of dental visits on incidence of HNCs/UADTCs and OCs. To the best of our knowledge, this is the first systematic review and meta-analysis on this topic. All the included 26 studies in meta-analysis were hospital- or population-based case-control studies, which included history of dental visits among incident cancer cases. Our meta-analysis irrespective of the frequency of past dental visits indicates a significant association between lack of dental visits (never/irregular/not frequent) and incidence of HNCs, particularly so for OCs. This may be partly attributed to the hypothesis that individuals not visiting the dentists for oral check-ups are ignorant of their oral hygiene and any potentially malignant changes in their oral cavity. Other reasons could be perceived lack of need, affordability, limited resources, and limited availability of oral health care providers and populations with low gross national income per capita.Lack of dental visits on regular or frequent basis has been posited to contribute to the incidence of, and outcomes for HNCs, as a synergistic and independent variable , 40, 53.Results of a case-series on 441 incident cases of oral and oropharyngeal cancer in the Greater Boston area reports that never or rarely going to the dentist was associated with being diagnosed at higher stage  compared to those going to the dentist at least annually .Pooled analysis of 8925 incident cases of HNCs and 12,527 controls of 13 INHANCE case-control studies found 26% reduction in incidence of OCs among the patients who made one or more than one annual visits for dental check-ups . This reN > 50) so that the statistical power and precision of analysis in this paper are strong, and ensure generalizability of our results. Furthermore, majority of the studies we have chosen are of sufficiently good quality.We have made every effort to include all case-control studies with adequate sample size  via other databases, web resources, and gray literature. There is also a possibility of having excluded some studies which reported/published insufficient data to meet the inclusion criteria of this review when these studies may have had adequate unpublished data. However, it was beyond the scope of this review to trace this data.Though most of the studies were of strong quality, they differed in nature of population, study setting, cancer case definition, method of diagnosis of cancer, selection and type of controls, history of frequency of dental visits, method of data collection, and its analysis. Also, the positive association between never/irregular dental visits and incidence of cancer could be understated in our pooled estimate as this meta-analysis is conducted on case-control studies where recall and selection bias remains a concern. Another potential limitation is the varied distribution of frequency of dental visits among the studies. Unfortunately, not all dentists consider it mandatory to undertake a comprehensive examination of the oral and oropharyngeal soft tissues at the time of visits made for issues involving strictly dental problems, such as toothache or the need for dental restorations.Oral health is a part of general health and quality of life. Targeted education to alert those at risk about OCs and other HNCs, and the warning signs, and better training coupled with opportunistic oral cavity examinations by dentists could reduce the burden of this disease. According to The American Cancer Society, a cancer-related check-up annually for all individuals aged 40 and older, and every 3 years for those between the ages of 20 and 39, should include health counseling and examinations for cancers of the oral cavity . DespitePlease refer to Table 6.


The meta-analysis revealed a prevalence of 49% : 35–64%) of any type of human papillomavirus in men and 35% (95% CI: 26–45%) of high-risk human papillomavirus in men. The included studies showed that stable sexual habits, circumcision and condom use are protective factors against HPV. In addition, there is a certain positive association with tobacco use and the early initiation of sexual intercourse. In conclusion, the prevalence of HPV in men is high. The risk factors for HPV infection are sexual promiscuity, early sexual debut, absence of circumcision, lack of condom use and smoking. Further study in this field about the effectiveness of the vaccine and health education should be conducted.Human papillomavirus (HPV) is one of the most prevalent sexually transmitted infections. Although the research focus has been on women, men are also affected. Thus, the aim was to estimate the prevalence of HPV in men and to analyse its risk factors. A systematic review with meta-analysis was performed. The main health science databases were consulted. The search terms were was: “papilloma virus AND  AND men”. The final sample of studies was  Human genital papillomavirus (HPV) is a common sexually transmitted infection (STI) which has become a major source of morbidity and mortality worldwide . More thAmong the low-risk subtypes, the most common serotypes include HPV-6 and HPV-11, which usually cause benign warts and are occasionally associated with non-invasive lesions. In contrast, serotypes HPV-16 and HPV-18 are considered high-risk subtypes, due to their high carcinogenic potential. HPV-16 appears primarily in invasive tumours and in those lesions with a high degree of malignancy, while HPV-18 is associated with poorly differentiated carcinomas and with increased lymph node involvement ,7.Most studies of HPV have analysed diagnosis, treatment and prevention in women. Moreover, strategies in sexual and reproductive health programmes in many countries have focused on epidemiological control in women, but they have tended to overlook the role of men in this infection, despite its high prevalence. In fact, it has been suggested that men may constitute a reservoir for inadvertently transmitting infection to women, due to its asymptomatic nature, thus contributing to the persistence of infection and cancer . A furthSeveral of the risk factors for HPV in men are associated with deficits in hygiene and prevention ,10. In fIn view of the above considerations, this study was undertaken to perform a meta-analysis of HPV prevalence in men and to analyse the corresponding risk factors. The question that guided this study was: what is the prevalence of HPV in men and which are its risk factors?A systematic review and meta-analysis of the literature was conducted, following the PRISMA  recommenThe analysis included quantitative studies on HPV in men published in English or Spanish, unrestricted by year. Studies lacking quantitative statistical information were excluded, as were studies with mixed samples without independent data on HPV in men, studies that associated HPV with other diseases, and studies focused on the genetics of the virus.A data collection notebook was used. For longitudinal studies with more than one HPV evaluation, the first measure obtained in the study population was recorded. The following variables were collected on the characteristics of the sample: year of publication, country of study, type of publication  and study design .Once the preliminary results obtained from each database, the title and abstract were read. The full text was then read. After this, a forward and reverse search was carried out within the studies included to locate as many documents as possible. Finally, the studies were read critically before the inclusion. The methodological quality was assessed with the checklist proposed by Ciaponni. The levels of evidence and degree of recommendation used were those proposed by the Oxford Centre for Evidence-based Medicine .2 index.Data analysis was performed with the StatsDirect meta-analysis package . The first step was to perform a sensitivity analysis to ensure that none of the studies included produced significant changes in outcomes when excluded. Publication bias were then assessed using Egger’s linear regression test. Prevalence and confidence intervals were calculated by random-effects meta-analysis, one for each burnout dimension. The heterogeneity of the sample was analysed by Cochran’s Q test and the In = 568 records were excluded because they were not related to the study topic, the sample also included women, the study design was not appropriate for this review, or due to the language of publication. After reading the full texts, the final sample was n = 16 after eliminating duplicates and applying the inclusion and exclusion criteria. The search and selection process is described in In total, 945 relevant studies were located. After reading the titles and abstracts, The meta-analytical estimation of the prevalence of any HPV in males was 49% with a 95% confidence interval of 35–62%. The forest plot is shown in p < 0.001) and the I2 index was 99.7%. For the high-risk HPV meta-analysis the Cochran Q-value was 1118.93 (p < 0.001) and the I2 index 99.1%.In the heterogeneity analyses of the any HPV meta-analysis, the Cochran Q-value was 3555.24 .A significantly higher risk of HPV detection was associated with an increased number of lifetime female sexual partners; OR 6.96–9.01 for non-oncogenic HPV (any type) and for oncogenic HPV among men with ≥50 partners versus only one partner . AccordiIngles et al.  reportedVarious studies have shown that circumcision is a protective factor against HPV infection ,19,20,24According to Tarnaud et al. , the mecMale circumcision is strongly associated with a lower probability of flat penile lesions. Backes et al.  reportedCondom use is considered a protective factor against HPV infection ,28,30. ASeveral studies have concluded that tobacco use aggravates the risk of HPV infection ,26. CurrA stronger association was observed between smoking 10 or more cigarettes per day (compared to smoking 0–9 cigarettes per day) and each of the following outcomes: detection of any HPV (OR 3.0 (95% CI: 1.4–6.4); oncogenic HPV (OR 3.7 (95% CI: 1.6–8.5); and non-oncogenic HPV (OR 2.4 (95% CI: 1.1–5.6]) .According to King et al. , based oEducation is considered to be a factor related to HPV infection . UniversAccording to Ingles et al. , genitalAkogbe et al.  conducteDue to the association between cervical cancer and HPV, men have not been the focus of HPV research . NotwithSexual promiscuity, related to the number of sexual partners, in men is an important risk factor due to multiple sexual contacts facilitate contamination by HPV, which is then transmitted to sexual partners . When seSome authors argue that the prevalence of HPV infection is associated with age, and hence with the pattern of sexual behaviour in the community. Thus, HPV prevalence is greater at earlier ages (15–25 years) with the initiation of sexual intercourse; later, between 25–40 years of age, there is a marked decrease, after which the prevalence stabilises . HoweverRegarding prevention, penile circumcision appears to be a protective factor against high-risk HPV infection. Circumcised men show a lower risk of HPV infection . In unciCondoms present an impermeable barrier to particles the size of the pathogenic microorganisms of STIs, preventing their transmission and acquisition by avoiding contact between the penis and genital secretions, the mucous membrane and the skin of the sexual partner. Therefore, condoms are considered to be a protective factor against HPV infection ,39.The tetravalent HPV vaccine provides effective prevention, as shown by the significant decrease in the rate of immune infection . HoweverSmoking is considered to induce added negative effects to HPV infection because cigarette smoke contains chemicals that damage the genetic structure of the human cells. As a result of this damage to the DNA, cells turn into oncogenic cells, which accelerates the appearance of genital lesions and evolution towards cancer .This study has some limitations. First, the number of studies is low because not all the studies did inform about the prevalence of HPV in men or its risk factors without mixing the data with female populations or using other diseases as main subjects of the study. Second, the analysis of the risk factors has been done individually, lacking multivariable analysis. Some variables may influence the other HPV risk factors, e.g., the educational level has been identified by some authors as a predictor of condom use, HPV awareness and HPV vaccination in males ,43. FinaTo our best knowledge, this is the first meta-analysis addressing the prevalence of HPV in the male population and associated risk factors. We have observed a prevalence of 49% in any HPV and of 36% in high risk HPV. Stable relationships, circumcision, condom use and non-smoking are potentially beneficial factors in preventing the development of HPV infection and thus, they should be given serious consideration. The issue of HPV infection in men warrants further research, particularly studies aimed at promoting the provision of a vaccine for this population group and educational campaigns aimed to change sexual behaviour, especially among young men.


The implementation of the United Nations (UN) Millennium Development Goals (MDGs) and Sustainable Development Goals (SDGs) has resulted in an increased focus on developing innovative, sustainable sanitation techniques to address the demand for adequate and equitable sanitation in low-income areas. We examined the background, current situation, challenges, and perspectives of global sanitation. We used bibliometric analysis and word cluster analysis to evaluate sanitation research from 1992 to 2016 based on the Science Citation Index EXPANDED (SCI-EXPANDED) and Social Sciences Citation Index (SSCI) databases. Our results show that sanitation is a comprehensive field connected with multiple categories, and the increasing number of publications reflects a strong interest in this research area. Most of the research took place in developed countries, especially the USA, although sanitation problems are more serious in developing countries. Innovations in sanitation techniques may keep susceptible populations from contracting diseases caused by various kinds of contaminants and microorganisms. Hence, the hygienization of human excreta, resource recovery, and removal of micro-pollutants from excreta can serve as effective sustainable solutions. Commercialized technologies, like composting, anaerobic digestion, and storage, are reliable but still face challenges in addressing the links between the political, social, institutional, cultural, and educational aspects of sanitation. Innovative technologies, such as Microbial Fuel Cells (MFCs), Microbial Electrolysis Cells (MECs), and struvite precipitation, are at the TRL (Technology readiness levels) 8 level, meaning that they qualify as “actual systems completed and qualified through test and demonstration.” Solutions that take into consideration economic feasibility and all the different aspects of sanitation are required. There is an urgent demand for holistic solutions considering government support, social acceptability, as well as technological reliability that can be effectively adapted to local conditions.  •Data for sanitation research from year of 1900 to 2016 have been collected and analyzed.•Hotspots for sanitation research have been discussed for future work based on the keywords data.•The constraints for global sanitation have been identified.•Promising technologies have been evaluated and proposed. In the 1990s, 192 UN member states and at least 23 international organizations agreed to the Millennium Development Goals (MDGs) at the World Summits. MDG 6 (Target 10) was intended to halve the proportion of people without sustainable access to safe drinking water and basic sanitation by 2015. In September 2015, the 2030 Agenda for Sustainable Development Goals (SDGs) was adopted by world leaders at the UN, which calls on countries to begin new efforts to achieve 17 SDGs over the next 15 years, including the goal to “ensure the availability and sustainable management of water and sanitation for all”. To inspire action to tackle the global sanitation crisis, “World Toilet Day”, which was established by the World Toilet Organization in 2001, was declared an official UN holiday in 2013. Every November 19th since then, UN-Water, local civil society organizations, and volunteers have planned events all over the world with themes such as “Toilets and Nutrition”, “Toilets and Jobs”, and “Wastewater”. Narendra Modi, the prime minister of India who launched projects like the Swachh Bharat Mission (Clean India Mission) in 2014, forged ahead to eliminate open defecation with the goal of constructing toilets in every household in the country by 2019. India is making impressive headway with its comprehensive planning for achieving this goal . PresideHowever, although the percentage of people gaining access to improved sanitation increased from 54% to 68% and the percentage for open defecation has fallen from 24% to 13%, the world still missed the MDG target . CurrentHere we present a statistical analysis based on published research that appeared in journals between 1992 and 2016 intended to identify trends in publication, explore research patterns and hotspots, isolate the specific issues with global sanitation as well as the assessments of those issues. The results offer a comprehensive overview of current issues and perceptions in sanitation research. This work can also help researchers develop ideas concerning future research areas and make more informed decisions.22.1Information about scientific output was extracted from the Science Citation Index EXPANDED (SCI-EXPANDED), Social Sciences Citation Index (SSCI), and the 2017 Journal Citation Reports (JCR), Science Edition, from Clarivate Analytics on August 17, 2017. The 2017 JCR covers 11,459 journals across 236 scientific disciplines spanning 81 countries. In this study, we searched for the keywords “sanitation” or “sanitary” in the period from 1900 to 2016.2.2h-index. It has to be mentioned that h-index was regarded as the h of Np articles were cited no less than h times each and the other (Np-h) articles were cited no more than h times each . These names all appeared on the article “Global, regional, and national comparative risk assessment of 79 behavioral, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013” , indicating that there were many opportunities for prevention. The three most cited publications showed that sanitation is closely linked to health conditions for humans; poor sanitation and bad hygiene result in the spread of disease. Thus, improving sanitation is key to creating a better quality of life for millions of people.The dy 2010”  had 207 dy 2010”  with 216dy 2013”  was also3.1.2h-index, and journal's country of origin. The top 20 most productive journals were extremely influential. The number of their published articles comprised about 15.8% of the works we investigated. The Journal of Water Sanitation and Hygiene for Development, with an h-index of 8, published the most articles , followed by the Journal of Food Protection , Water Science and Technology , PLOS ONE , and American Journal of Tropical Medicine and Hygiene . There were some unusual results in our analysis. For example, Water Research had the highest JIF value (6.942) and h-index (33); this journal was the top publication for water resources (Q1: 1/88). However, it came in eighth place in our results for its output. The Journal of Water Sanitation and Hygiene for Development is a journal of the International Water Association (IWA), which emphasizes issues of concern in developing and middle-income countries, as well as in disadvantaged communities worldwide. The journal articles address themes that explore the water supply, sanitation, and hygiene, which potentially explains why this is the most productive journal. There were various trends exposed by the relationship between the h-index, JIF, and the rank order of the 20 most productive journals. We found that Water Science and Technology ranked third among the most productive journals. However, this journal's JIF (1.197) came in 16th place among the top 20 publications. In addition, its h-index (12) only ranked 17th. We found that the 14th-ranked journal  had a JIF of 6.198, which placed it second among the other journals. Its h-index was 27, which then moved it to third place. This interesting pattern may be partly due to the fact that the highest impact journals are not as specialized as those with less impact. In addition, with their stronger impact, they may target higher quality studies or more often consider research that offers an original approach to a problem or idea. There was a clear supremacy of publications that came from developed nations: the UK published nine influential journals, and seven publications were from the USA. Brazil had a mere two journals, which was mirrored by the Netherlands (2). There was a strong dominance of five journals. These publications were responsible for 677 (5.6%) of the articles studied. The 11,956 articles we utilized for our analyses came from a wide range of journals. They appeared in 2714 publications that dealt with sanitation issues. These articles addressed a broad range of topics, including 143 subject categories in the SCI-Expanded and SSCI databases. We found that 1306, or almost half (48.1%), of the journals investigated had only one article that appeared in our results. Other journals had more articles . Of the remaining journals, 443 (16.3%) had two articles and 286 (10.5%) journals had three articles. About 5% of the journals (141 publications) had 4 articles, while 227 (8.4%) journals published 10 or more. Since journals could be assigned to multiple subject categories in this research, sanitation research actually encompassed 143 subject categories. 3.1.3h-index for each area. The top 20 countries included three Asian countries/regions, ten European countries, five American countries, one Oceanic country, and one South African country. The 20 most productive countries generated the vast majority of published articles (94.5%). Almost four-fifths (78.6%) of the sanitation articles examined in this analysis were from Canada, France, Germany, Italy, Japan, the UK, and the USA. These developed countries have superior economic capabilities and higher academic levels than those of developing nations  independent articles and 2803 (23.8%) internationally-collaborative articles. Our analysis addressed the 20 most prolific countries. We examined the total number of works from a single country as well as internationally-collaborative research.  nations . Of the  nations . Russia h-index of 87 and published 1032 corresponding author articles. Sixteen nations partnered with researchers from the USA, and these collaborator data are shown in The USA appeared at or near the top in our results, indicating that it is a global leader in sanitation studies and publications. The USA had the highest number of total articles published (2680). It was also first for its independent articles (1648) and first authored articles (2195). The USA had an The most productive countries are the USA and UK. They both have outsized and complex groups; 28 belong to the USA cluster and 22 groups belong to the UK cluster. Switzerland, France, and Belgium come next, but they have significantly lower numbers of articles and cooperation. The USA-UK collaborations ranked first, with 187 cooperative articles, followed by USA-Switzerland (95), USA-Canada (69), USA-India (66), USA-Brazil (63), and China-USA (54) collaborations. These articles covered several aspects, including social, political, environmental, public health, technical aspects and so on, which were mainly related to the context of developing countries. The descriptions of these articles expressed three phases for sanitation development, the first phase is the baseline study, to investigate the main sanitation related issues, e.g. technologies for disinfection and hygiene, which could be effective to prevent the transmission of disease; the second phase is the realization of MDG, global estimation of the indicators according to MDGs; the third phase is the development of new technology for sanitation with the concept of closing the loop in order to reach the SDGs.For the techniques developed by the USA, during the MDGs period, the target was to get improved sanitation, intended for safe separation of humans from excreta by employing flushing toilets, septic tanks, latrines, composting toilets etc., but not a goal of hygienization or source recovery. Thus, the main technologies were composting and storage processes. Recently, because of the implementation of SDGs and encouragement by the Bill and Melinda Gates Foundation, some non-sewer and source oriented toilet systems have been developed, as mentioned in the Reinvent the Toilet Challenge manuscript. From the year 2011 to 2013, 15 Grants have been awarded for innovated toilet developers, and 6 of them are from USA, further supporting the statements. Of the 11,956 articles spanning 11,781 institutes in 182 countries, 6890 (58.5%) were inter-institutionally collaborative publications and 4891 (41.5%) were independent publications. The collaboration between institutes was 34.7% higher than that between countries. The top 20 research facilities included 9 in the USA, 5 in Brazil, 3 in Switzerland, 2 in the UK, and 1 each in France and Spain; 8 of the 9 institutes in the USA were universities. These data are shown in Center for Disease Control and Prevention, U.S. Department of Health & Human Services’, ‘WHO’ and the ‘University of North Carolina’ are the top three institutions in h-index with high values of 34, 28, and 27, respectively, which further emphasizes the importance of sanitation for hygiene and disease control. Over half of the 20 institutes were universities, demonstrating that the universities are the core drivers of sanitation research.The ‘3.23.2.1The statistical analysis of the author keywords, article title, article abstract, and “Keywords Plus” could be used to identify directions in science; keyword analysis is efficient for comprehending the progress of new frontiers in science . The anaE. coli” and “Salmonella” ranked 12th and 21st, respectively, in the most frequently used keywords, which indicate that these bacterial species have been extensively used as indicator pathogens for hygienization. E. coli had an apparent upward movement in the ranks, from 65th in 1992–1996 to 10th in 2012–2016, which could be attributed to the fact that E. coli is commonly observed in the gut of humans and warm-blooded animals. This trend also reflects the awareness of the public's health. The names of developing countries  ranked 15th in the top 30 most frequently-used substantives in author keywords; they were initially ranked 15th in 1992–1996, then moved to 22nd in 1997–2001, 7th in 2002–2006, and finally to 6th place in 2007–2011. However, they decreased to 24th in 2012–2016. This trend could be explained by the continuing attention given to a specific area and country, especially low-income districts. Hence, “India”  and “Africa”  ranked 16th and 27th, respectively, in the top 30 most frequently-used keywords, and both of these keywords had a significant increase over the past 25 years. “India” and “Africa” ranked 158th and 174th, respectively, in 1997–2001 and 8th and 27th, respectively, in 2012–2016. “Child”  ranked 17th in the top 30 keywords, but it was ranked 65th from 1992 to 1996 and then it moved to 10th place in 2012–2016. This trend occurred because children are the most sensitive to poor sanitation. “Sustainability” has become increasingly popular in recent years, moving up in the rankings from “not available” in 1992–1996 to 158th in 1997–2001, 38th in 2002–2006, 19th in 2007–2011, and 15th in 2012–2016. From 1992 to 1996, improved sanitation was a primary focus of research. It was important to ensure the hygienic separation of human excreta from human contact and the suggested facilities that could reach the targets included flush/pour-flush-to-piped-sewer systems or septic tanks/pit latrines, ventilated improved pit (VIP) latrines, pit latrines with slabs, and composting toilets. This explains why sustainability was barely mentioned during the first 5 years in our study. Since the awareness of protecting human health and the environment has increased, the concept of sustainable sanitation has been promoted, and sustainability has garnered increasing attention.Because the terms “sanitation” and “sanitary” were the subject words in this study, the most frequently-used keyword (“sanitation”) was ignored. 3.2.2Baskerville (1904) showed that patterns and ideas in research can be identified via author keywords and the title of articles. We therefore used an algorithm to generate “KeyWords Plus”. These terms were drawn from the titles of works that appeared in the articles .We also th Five-year Plan”. The majority of those without improved sanitation are people who live in rural areas, thus, rural areas are characterized by the great disparity in sanitation improvements. However, UNICEF noted that clean water, basic toilets, and good hygiene practices are essential for the survival and development of children. (i)Hygienization of excreta: The hygienization of human excreta is essential for reducing the transmission of diseases by pathogenic microorganisms. Human urine contains very few, if any, pathogens, but the amount increases due to cross-contamination with feces. Nevertheless, the health risk can be eliminated through natural attenuation . It is followed by Salmonella and Listeria monocytogenes.enuation  or existenuation . For safenuation . In ordeperature . The rapperature and nitriperature . Similarperature . Alkalinperature . Thermalperature . Fig. 8f(ii)Resource recovery from excreta: Urine accounts for only ∼1% of the total volume of domestic wastewater, but it contains >80% of the nitrogen (N) and 50% of the phosphorus (P) load in domestic wastewater , which is the chemical precipitation that occurs at an alkaline pH with a suitable ratio of ammonium, phosphorus, and magnesium. This process converts nutrients from liquid to solid form, and its products can be used as a slow-release fertilizer  can be harvested from hydrolyzed urine in 28 h at 40 °C and in 32 h at 30 °C  crystallization was developed to simultaneously recover phosphorus as well as potassium (3+) has also been used for phosphorus recovery ((iii)Micro-pollutant control of excreta: Sustainable sanitation takes into consideration both the reuse and safe disposal of waste after treatment, and forming a cycle (from reuse to agriculture to humans) is an ideal solution. The nutrients in excreta can return to the table through agriculture and food production. Hence, with the increasing attention on food security, the investigation of unwanted antibiotics and heavy metals is as important as obtaining the nutrients from human excreta. The control of heavy metal concentrations in human-excreta-related fertilizer is important since heavy metals can accumulate in crops and throughout the food chain, creating a health risk for humans. Heavy metals  have been detected in solid waste from human excreta  should be established, such as subsidies, ISO/National standards, regulations, in order to form a healthy market for new sanitation systems, so that everyone could play a specific and positive role in it. Social acceptability is closely linked to private behavior; thus, the developed toilet should adapt to religious belief, ethnic culture, and economic level as well, which would be conducive to governmental motivation. Technological reliability is the driver for sanitation development and practical application. The developed technologies should meet the requirements for safe local discharge, efficient nutrient/energy recovery, limited air emission, non-noise, operability following non-usage/short term/long term shutdown, overload protection, expected lifetime, flexibility in ambient change, etc.4.1Sanitation issues vary from location to location, season to season, and community to community. People who lack sanitation facilities are often living in the most challenging geographies and climates, so there is no one-fits-all solution that is best for all situations. Different approaches are required for each unique situation . Hence, 4.2A survey of the sanitation initiatives in Monkey Bay, a port town on the southern part of Lake Malawi, showed that only 26.6% of the NGO-donated sanitation interventions were in use after two years. This low sustainability was primarily influenced by the lack of consideration of the institutional, technical, educational, operational, social, and cultural factors . A studyGovernment should play a strong leadership role and take responsibility for legislation and the coordination and definition of roles, regulations, and policy. The state should lay a foundation and enforce health standards and regulations. Regulations should create conditions that will be of advantage to innovation both in terms of financing mechanisms and technology support. Products, such as fertilizer, electricity, reclaimed water, biochar, and biodiesel, should be harvested using the most appropriate technology where the operating models, municipal administration, industry, and business model are in demand . In addi5In this study, bibliometric and word cluster analyses were used to evaluate sanitation research using the Science Citation Index-EXPANDED (SCI-EXPANDED) and the Social Sciences Citation Index (SSCI) from 1992 to 2016. A systematic analysis of global sanitation using the background, current situations, challenges, and perspectives was performed on the results. We demonstrated that researchers are focusing more on sanitation in recent years, which is supported by the increased quantities of publications. Developing countries are facing more serious sanitation problems, but the USA plays a leading role in researching and developing sanitation techniques, ranking first in the quantities of articles and 6 US- innovated toilet systems have been selected from a global pool by BMGF. There are challenges for the adoption of newer technologies in the form of the actual requirements of the people who need them as well as technical development issues. Currently, sanitation encompasses water, solid waste, air pollution, human health, and food security. Hence, a closed-loop analysis of the energy and substance of the internal circulation, transformation, and process control is essential but still lacking in published works. Moreover, although innovative solutions have been developed in terms of the hygienization of human excreta, resource recovery, and removal of micro-pollutants, gaps in the technological development and commercialization of products, as well as issues with integrated solutions that address political, social, institutional, cultural, and educational factors, all still exist. There is no one-size-fits-all approach for achieving the successful implementation of adequate global sanitation. Efforts should be made from view of government support, social acceptability, as well as technological reliability to realize a holistic solution.


To compare methods to assess visual field (VF) progression in glaucoma.4,950 VFs of 253 primary open angle-glaucoma patients were evaluated for progression with the following methods: clinical evaluation, guided progression analysis (GPA), mean deviation (MD), and visual field index (VFI) rates, Advanced Glaucoma Intervention Study (AGIS) and Collaborative Initial Glaucoma Treatment Study (CIGTS) scores, pointwise linear regression (PLR), permutation of PLR (PoPLR), and glaucoma rate index (GRI). A separate simulated series of longitudinal VFs was assessed with all methods except for GPA and clinical evaluation.The average (±SD) age of the patients at baseline was 65.4 (±11.5) years. The average (±SD) follow-up was 11.8 (±4.6) years, and the mean (±SD) number of VFs was 16.8 (±7.0). Proportion of series detected as progressing was 65% for PoPLR, 58% for GRI, 41% for GPA, 40% for PLR, 36% for CIGTS, 35% for clinicians, 31% for MD rate, 29% for AGIS, and 22% for VFI rate. Median times to detection of progression were 7.3 years for PoPLR, 7.5 years for GRI, 11 years for clinicians, 14 years for GPA, 16 years for PLR, 17 years for CIGTS, 19 years for AGIS, and more than 20 years for MD and VFI rates. In simulated VF series, GRI had the highest partial area under the receiver operator characteristic curve (0.040) to distinguish between glaucoma progression and aging/cataract decay, followed by VFI rate (0.028), MD rate (0.024), and PoPLR (0.006).GRI and PoPLR showed the highest proportion of series detected as progressing and shortest times to progression detection. GRI exhibited the best ability to detect progression in the simulated VF series.Knowledge of the properties of every method would allow tailoring application in both clinical and research settings. Glaucoma is a progressive optic neuropathy characterized by characteristic alterations of the optic nerve head, retinal nerve fiber layer, and visual field (VF). Standard achromatic perimetry is the gold standard for VF assessment, which remains a fundamental test for the diagnosis and care of glaucoma patients. Recognition of longitudinal VF changes allows the timely application of therapeutic measures to preserve visual function and prevent visual disability.25Detection of true progression and VF rates of change are confounded by intertest variability, often referred to as long-term fluctuation. This fluctuation is higher in glaucoma patients than in healthy subjects.19We compare here nine published algorithms to detect VF progression, including expert evaluation, GPA, MD and VFI rates, AGIS and CIGTS scores, pointwise linear regression (PLR), PoPLR, and GRI in a cohort of patients and in computer-simulated VF sequences with predetermined rates and patterns of progression.A total of 4950 VF exams from 253 patients from the Glaucoma Division of the Stein Eye Institute, University of California, Los Angeles (UCLA) were included in this retrospective, longitudinal, observational study. This study adhered to the tenets of the Declaration of Helsinki, was approved by the UCLA Human Research Protection Program, and conformed to the Health Insurance Portability and Accountability Act (HIPAA) policies. Inclusion criteria were as follows: diagnosis of primary open-angle glaucoma with six or more VFs and minimum follow-up of 3 years. All tests were performed with Humphrey Field Analyzer's (HFA) Swedish Interactive Thresholding Algorithm (SITA) Standard 24-2 strategy and size III white stimulus. Reliable exams were defined as those with false-positive rates 15% or less, and false-negative and fixation loss rates 30% or less.Based on models proposed by Spry et al.The user specifies the baseline threshold sensitivities, length of follow-up, annual pointwise rates of progression, and number of VF examinations. Tests are equally spaced over the follow-up period, and their frequency is derived as the ratio between the number of VFs and length of simulation;Linear regression analysis is applied at every test location. Independently from the determined rate of progression, an additional decay of 0.1 dB/y is added to simulate age-related decline22:For each location, the noise-free value is replaced by a Monte-Carlo value randomly computed from a Gaussian distribution. The mean of the distribution is equal to the estimated noise-free threshold sensitivity. The standard deviation (SD) is calculated with the function proposed by Gardiner and Crabbi and j being the coordinates of a 10 × 10 grid. According to this model, the variability is proportional to the diminution of threshold sensitivity and the point eccentricity. Values generated below 0 dB or above 36 dB are truncated at 0 or 36 dB, respectively.To account for higher variability in peripheral test locations, an eccentricity-weighting factor is added to the SD as described by Spry et al.The “VisualFields R” package was employed to generate MD, VFI, the total deviation numeric map, and the total deviation probability map for each simulated examination.24A total of 267,840 VFs belonging to 13,392 simulated eyes were generated, with a ratio of 1:1 between progressing and nonprogressing sequences, in accordance with previous simulation studies.Focal decay, wherein four , eight (medium scotoma), or 16 (large scotoma) locations significantly deteriorate. Simulated defects of small dimensions were represented by a nasal scotoma and a paracentral scotoma. Medium-sized defects were represented by a nasal step and an arcuate scotoma extending to 5° from fixation. Large defects consisted of two broad, inferior and superior, arcuate scotomas. Pattern of focal deterioration were selected by a glaucoma specialist author from VFs of actual glaucoma patients. Three different rates of progression, −0.5, −1, and −2 dB/y, were applied to deteriorating locations in addition to normal age-related decay. The hemifield involved was randomly assigned. Based on the baseline exams, rates, and patterns of progression, 18 scenarios were simulated and each of them was run 372 times, to match the number of eyes in the cohort of patients. All eyes with deterioration of simulated scotomata were considered progressing.Diffuse decay, wherein every location undergoes the same rate of progression. In one model, we applied only age-related decay (0.1 dB/y).Nine methods were employed to identify perimetric progression as follows: (1) qualitative clinical evaluation, (2) GPA based on Early Manifest Glaucoma Trial (EMGT) criteria, (3) MD rates of change, (4) VFI rates of change, (5) the AGIS scoring system, (6) the CIGTS scoring system, (7) PLR, (8) PoPLR, and (9) GRI.All metrics were computed in a sequential fashion, starting at the fifth VF of the series and adding the next examination at every cycle. For the simulated VF examinations, GPA and expert evaluation were not applied. The former is proprietary software and cannot be exactly replicated outside the STATPAC 2 environment . The latter is based on SITA printouts, which were not available as output for the simulations. For actual patient data, all modalities were available. Methods to evaluate VFs are explained below, and The grading protocol was previously described and is summarized here.P < 0.05, it is marked with an open triangle. If the worsening of that point is confirmed on two or three consecutive examinations, it is flagged as a half-filled or filled triangle, respectively. VF progression was defined as the deterioration of three or more locations sustained on three or more consecutive examinations, in accordance with the criteria adopted by the EMGT.3GPA is proprietary software of the HFA . GPA is based on similar principles as its earlier version, the Glaucoma Change Probability Analysis.P < 0.05) rate of change of −0.5 dB/y or less and −1.8%/y or less, respectively. The value of 1.8% for VFI was chosen because it corresponds approximately to the 0.5 dB/y value used for MD.29Rates of change for MD and VFI were calculated with linear regression, and progression was defined as a significant  of −1 dB/y or less was defined as progression.Ordinary least squares of the raw threshold sensitivities over time was performed for each of the 52 VF pointwise series. The slope of the regression line, expressed in decibels per year, was defined as the pointwise linear rate of change. The presence of three pointwise series having a significant regression slope , a is the constant, b is the slope (regression coefficient), and x is the time (years). For locations with a positive trend, the following formula was used: Y−y = ea+bx), a is the constant, b is the slope, x is the time (years). Outliers were removed with the sequential application of Cook's distance and the Studentized residual tests. After carrying out PER, two values were obtained, pointwise rate of change (PRC) and the 90% confidence interval (CI) of the slopes. The former indicates the rate of change of each pointwise sequence, expressed as the percentage of the entire perimetric range corrected for age and location. A GRI score is generated by summing the PRC values from locations with significant negative (decaying) and positive (improving) rates across the VF series in an individual eye. The summed value is then normalized from a maximum rate of decay (−100) to a maximum rate of improvement (+100). A GRI value of less than −6 was defined as progression.17The GRI algorithm has been extensively described elsewhere.The proportion of series determined as progressing was defined as the percentage of progressing eyes defined by each algorithm. Eyes meeting progression criteria according to a given method at any follow-up visit were defined as progressing. Because there is no gold standard to define perimetric progression in a cohort of glaucomatous patients, the proportion of series detected as progressing is used as a surrogate measure of sensitivity. Summary results were expressed as a mean ± SD, unless specified otherwise. As an alternative to a very complicated Venn diagram, the UpSet technique was used to graphically demonstrate progression detected by each method alone and their intersections.32Pairwise agreements among the methods were measured with Cohen's kappa statistic. Values of k between 0.00 and 0.20 indicate slight agreement, fair agreement between 0.21 and 0.40, moderate agreement between 0.41 and 0.60, substantial agreement between 0.61 and 0.80, and almost perfect agreement 0.81 or more.33Internal consistency was evaluated by counting the number of flips from one state to the other  for each method, as the VF series proceeded over time. For each method, the flips analysis was carried out only on those eyes progressing according to that method, and “stable” eyes were excluded to prevent the influence of the detection rate of each technique on the consistency estimate. The number of flips for the various methods was compared with the Friedman test, and pairwise comparisons were performed with Dunn's multiple comparisons as a post hoc test.35n = 32) were excluded from this particular analysis.We calculated the agreement with Cohen's kappa statistic between status at the last visit with the entire and the half-time VF sequences for each technique as a measure of prediction ability. Because data on progression were available starting at visit five, those eyes with nine VFs or less (Receiver operator characteristic (ROC) curves were generated for the trend-based methods with the known simulated model as the reference. ROC curves were calculated with the continuous values of the trend-based methods at the last visit of the simulated series. Two different ROCs curves were made. Both curves had simulated focal decay as the progressing reference eyes. One ROC curve defined nonprogressing as the age-related decay group only, while the second ROC curve defined nonprogressing as the cataract decay group in addition to the age-related decay group. Partial areas under the curves (AUROCs) were calculated to determine the average sensitivity between 90% and 100% specificity. The sensitivity and 1-specificity values for AGIS, CIGTS, and PLR at the last visit were calculated and plotted as points on the plot.The sensitivity and specificity in simulated series with the progression criteria used in the clinical cohort of patients were also calculated for trend-based methods. Computer-simulated series, which met the clinical criteria for progression at any simulated time point, were labeled as progressing, while the remaining ones were considered stable.For comparison of detection of fast progressing eyes, ROC curves were generated with simulated eyes having a focal decay of −2 dB/y as the progressing group and all the other simulated sequences as nonprogressing. Partial AUROCs were calculated to determine the average sensitivity between 90% and 100% specificities. The sensitivity and 1-specificity values of AGIS, CIGTS, and PLR at the last visit were calculated and plotted as points on the plot.The partial AUROCs values were reported in the uncorrected form. Partial AUROCs were compared in pairs with a stratified bootstrap test,32All statistical analyses were performed with R software and GraphPad Prism software 6.0 . The R package “pROC” was used to build the ROC curves on the simulated data and to compare partial AUROCs.36P < 0.001), whereas the difference between these two methods was not significant (P = 0.97). VFI rate and AGIS scores required significantly longer times to detect progression compared with all other methods (P < 0.01), and did not significantly differ from each other (P = 0.12). In addition, PLR detected progression significantly faster than MD rate (P = 0.04) and CIGTS (p = 0.04). None of the other pairwise comparisons were statistically significant.The cumulative proportion of progressing eyes according to each technique is illustrated in Pairwise agreement between methods for the patient cohort is given in The prediction ability of each method, defined as the agreement between results based on the half-time follow-up versus the entire follow-up, is shown in P = 0.17).Internal consistency , as evalP < 0.0001), except for the pairwise comparison between MD rate and PoPLR (P = 0.09). The introduction of eyes with simulated cataract .The ROC curves to distinguish fast-progressing from nonfast-progressing eyes showed a similar pattern both without and with the cataract group . SpecifiWe compared nine published methods to detect glaucomatous perimetric progression: qualitative clinical evaluation, GPA, MD rate, VFI rate, AGIS and CIGTS scoring systems, PLR, PoPLR, and a recently introduced index, GRI. We evaluated the proportion of series detected as progressing, time to progression detection, pairwise agreement of methods, prediction ability, and internal consistency in a cohort of primary open-angle glaucoma patients. Moreover, computer-simulated VFs with predetermined rates and patterns of progression were used as an external reference to test diagnostic performance and to estimate sensitivities and specificities of the tested methods. Agreement among the methods ranged from fair to moderate, except for the MD versus VFI rates, which expectedly displayed substantial concordance. GRI and PoPLR had the highest proportion of series detected as progressing and were the algorithms that detected perimetric progression the earliest. AGIS score, MD rate, and VFI rate had the lowest proportion of series detected as progressing. All methods showed good and similar internal consistency. We investigated the performance of the various trend-based approaches  to detect perimetric progression. All these methods discriminated “glaucomatous” focal decay from the age-related decline well, and the differences across the partial AUROCs were small. When we added a cataract-simulated decline in the nonprogressing reference group, the diagnostic properties of all the methods considerably diminished, with MD rate and, especially PoPLR, most severely affected. We also explored the performance of various approaches for identifying fast progressors in computer-simulated VFs. GRI had the best partial AUROC, followed by VFI rate, MD rate, and PoPLR. Inclusion of the cataract group in this setting had a negative impact only on PoPLR.In short, GRI and PoPLR had the highest proportion of series detected as progressing, and detected glaucomatous progression the earliest in the cohort of patients, but the latter performed poorly in the computer simulations, especially with the introduction of simulated cataract decay. AGIS, MD rate, and VFI rate showed the lowest proportion of series detected as progressing and were the slowest to detect progression.Although numerous approaches to detection of glaucoma deterioration have been proposed, timely determination of perimetric progression remains a challenging task for practitioners. None of the available techniques can be considered a gold standard. Subjective evaluation of VF series by the clinician is the most widely employed method, especially in the clinical setting, because it is fast, inexpensive, and independent of a digital environment.27Event-based analyses identify single events of statistically significant change relative to baseline tests. The proprietary GPA of the HFA is a commonly used event-based analysis and was used by EMGT for detection of glaucomatous progression. It is able to identify worsening test locations with as few as three tests after the two baseline exams. Its ability to detect progression depends on the magnitude of pointwise test–retest variability, which is known to be high at damaged test locations. GPA does not provide a robust estimate of pointwise VF rates of decay.38The AGIS and CIGTS scoring methods are two event-based analyses, which have been employed in large, randomized, controlled trials.Our results, both in the patient cohort and in the computer-simulated data, corroborate these previous findings. In our study, AGIS had one of the lowest proportion of series detected as progressing and required a long time to detect progression; conversely, it displayed high specificity and internal consistency. These results are not surprising, because the AGIS method applies stringent criteria, and a considerable, sustained amount of change is required to trigger progression. Mayama et al.Trend-based linear regression models are widely accepted as valuable tools for serial VF analysis because they are simple to calculate, can provide a global rate of change, and have a reasonably good ability to predict future outcomes.47Among the trend-based methods, those performing a regression of individual pointwise series over time have potential advantages over those based on global indices. By treating each test location individually, they allow the identification of small focal glaucomatous changes, which may be otherwise missed; as a consequence, pointwise methods have higher sensitivity (but lower specificity) than MD or VFI rates of change.41We recently described a novel trend-based model to assess glaucoma progression, called GRI.Because GRI and PoPLR exhibited high rates of progression detection, the cutoffs used in this study correspond to points of the ROC curve with high sensitivity and low specificity as shown in Chauhan et al.Several studies revealed a fair to moderate level of agreement among methods, including some of those employed in the present study.The present study has limitations. Its retrospective nature dictated that not all eyes had VFs performed at the same frequency, and this can affect the time to detect progression.In conclusion, we provide a comprehensive comparison of different approaches to assess perimetric glaucoma progression. PoPLR and GRI had the highest proportion of series detected as progressing, and detected glaucomatous progression the earliest; AGIS, MD rate, and VFI rate exhibited the lowest proportion of series detected as progressing and were the slowest to detect progression. Of all the methods tested, GRI had the best ability to detect glaucomatous progression and fast-progression in the simulated VF sequences. Knowledge of the properties, advantages, and limitations of every method would allow tailoring application in both clinical and research settings.


The discovery of this species adds to the list of deeply divergent and monotypic or depauperate lineages with narrow geographic ranges in the southern massifs of the WG. The southern regions of the WG have long been considered geographic and climatic refugia, and this new relict lineage underscores their evolutionary significance. The small range of this species exclusively outside protected areas highlights the significance of reserve forest tracts in the WG in housing evolutionary novelty. This reinforces the need for intensive sampling to uncover new lineages and advance our understanding of the historical biogeography of this ancient landmass.The Western Ghats (WG) is an escarpment on the west coast of Peninsular India, housing one of the richest assemblages of frogs in the world, with three endemic families. Here, we report the discovery of a new ancient lineage from a high-elevation massif in the Wayanad Plateau of the southern WG. Phylogenetic analysis reveals that the lineage belongs to Natatanura and clusters with Nyctibatrachidae, a family endemic to the WG/Sri Lanka biodiversity hotspot. Based on geographic distribution, unique morphological traits, deep genetic divergence, and phylogenetic position that distinguishes the lineage from the two nyctibatrachid subfamilies Nyctibatrachinae  Ancient lineages hold significant information for understanding the biogeographic past of different regions . A largeThis evolutionarily distinct and diverse assemblage of frogs has only been recently uncovered by studies highlighting the radiation of ancient lineages  and highsubfam. nov. and genus Astrobatrachusgen. nov., and describe a single new species Astrobatrachus kurichiyanasp. nov. The discovery adds to the list of ancient and monotypic lineages with narrow geographic ranges in the southern massifs of the WG.Here, we report the discovery of a hitherto unknown taxon; an ancient, monotypic, microendemic lineage forming a strongly supported clade with Nyctibatrachidae The taxon was discovered during an expedition to an isolated hill range  located on the western edge of Wayanad Plateau in the south-central region of the WG Escarpment . The expWe generated new DNA-sequence data from four specimens using existing primers. We sequenced 16S and RHOD (CESF 1566) and CYTB and RHOD (CESF 1567) . For CYTB and RHOD, there was no length variation, and thus the profiled alignments required no further refinement. For 16S, we realigned the regions overlapping with the new sequences using the MAFFT algorithm  in GeneiThe JP matrix had 4,062 terminals and 15,091 bp. Our final matrix had 4,063 terminals and 15,359 bp. As the samples of the new species did not overlap sufficiently in terms of sampled loci, we concatenated the 16S, CYTB, CXCR4, RAG1, and RHOD data from the three specimens, and included these data as a single composite terminal, for a total of 2,125 bp from five genes. This is justified as all three individuals were sampled from the same site and shared the unique morphological characteristics described below, and overlapping sequences were invariant.We used PartitionFinder 2  to estimDOI 10.5061/dryad.4q3d25m.PartitionFinder 2 identified 28 distinct model segments for the GTR-GAMMA model across the 41 possible partitions. We then used ExaML version 3.0  to inferThe following measurements were obtained from preserved specimens, measured to the nearest 0.1 mm using digital calipers: Snout to Vent Length—SVL, Head Length—HL, Snout Length—SL, Eye Length—EL, Inter Upper Eyelid Width—IUE, maximum Upper Eyelid Width—UEW, Inter-Narial distance—IN, distance between anterior corner of eyes—IFE, Tympanum Diameter—TYD, Fore-Limb Length—FLL, Hind-Limb Length—HAL, First Finger Length—FL1, Second Finger Length—FL2, Third Finger Length—FL3, Fourth Finger Length—FL4, Thigh Length—TL, Crus Length—CL, Foot Length—FOL, Tarsal Length—TAL, Fourth Toe Length—TL4, Inner Toe Length—ITL, Inner Metatarsal Tubercle Length—IMTL, Nostril to Eye Length—NE, Back of Mandible to Nostril Length—MN, Back of Mandible to front of Eye Length—MFE, Back of Mandible to back of Eye Length—MBE, Length between the Back of the Eyes—IBE, Length from Tympanum to the Back of the eye—TE.High resolution computed tomography (CT) scans were produced for two specimens of the new species, CESF 1565 and CESF 2898, at the GE India Industrial Pvt. Ltd. facility in Pune, India using a Phoenix v|tome|x M  with a 180 kV x-ray tube with a diamond-tungsten target and with the following settings: 60–80 kV, 300 mA, a one second detector time, averaging of three images per rotation and a voxel resolution of 3.0–4.9 µm. Additional CT-scans for comparisons were also generated at the Indian Institute of Science or were obtained from MorphoSource, having been generated separately as part of the oVert Thematic Collections Network at either the University of Florida Nanoscale or the University of Chicago PaleoCT lab. Raw x-ray data were processed using GE’s proprietary datos|x software v 2.3 to produce a series of tomogram images that were then viewed and analyzed using VG StudioMax 3.0.3 . For osteological terminology, we follow Theoretical and operational criteria for the diagnosis and delimitation of taxa at different ranks are crucial for a robust systematic revision. For diagnosis of species-level taxa, we follow the generalized lineage concept  and furtWe employed a comprehensive sampling strategy for all frogs, covering the topographic heterogeneity of the WG across latitudinal, elevational and rainfall gradients, ensuring that we detected sympatric relatives with confidence. The field diagnosis illustrates characters that could help diagnose the lineage in the field from syntopic and broadly sympatric species in the sister clades. For higher-level taxa above the species level, we assess whether or not the new lineage occupies a topological position within a currently recognized taxon , and whether or not it matches the diagnostic characters for that taxon .http://zoobank.org/. The LSID for this publication is: urn:lsid:zoobank.org:pub:5ADE399C-37CC-4821-BD81-15F420731BB7. The online version of this work is archived and available from the following digital repositories: PeerJ, PubMed Central and CLOCKSS.The electronic version of this article in Portable Document Format (PDF) will represent a published work according to the International Commission on Zoological Nomenclature (ICZN), and hence the new names contained in the electronic version are effectively published under that Code from the electronic edition alone. This published work and the nomenclatural acts it contains have been registered in ZooBank, the online registration system for the ICZN. The ZooBank LSIDs (Life Science Identifiers) can be resolved and the associated information viewed through any standard web browser by appending the LSID to the prefix Nyctibatrachus, Lankanectes, and the new lineage, the age of the MRCA of these three lineages fall within the range of the stem age of Nyctibatrachidae and the crown age of Natatanura, recently estimated to be in the Late Cretaceous or Paleocene (∼57–76 Ma)  .The full phylogeny  , and ZSI/WRC/A/2133 (CESF 2897) ; site same as holotype collection.Diagnosis.—This diagnosis applies to the subfamily, genus, and species. The following combination of characters can be used to diagnose this lineage from its close relatives Nyctibatrachus and Lankanectes: small to medium size (∼ 20–27 mm SVL); soft skin without ridged or wrinkled folds; fingers and toe tips with discs that are triangular in shape  with a squat, lean body see ; head leIn life, overall color on dorsum rufous brown, darker in anterior region of body and light in posterior part of body. Small pale bluish-white spots present all over body but larger and more concentrated on lateral, gular, anterior ventrum, and around tympanic region, jaws, and eyelid. In ventral region, arm, belly, thigh, and crus bright orange in color; gular region is dark gray with bluish white spots. Under surface of hand and foot dark gray. In preservative, color on dorsum dark brown with cream spots. Gular and anterior ventrum dark gray interspersed with cream spots, with melanocytes becoming widely spaced posteriorly; arm, posterior belly, thigh, and crus cream colored; hand and foot dark gray with pale gray skin under digit tips and subarticular tubercles.Based on micro-CT scan of ZSI/WRC/2132  and CESF 2898 and 2899   and 6. TThere are eight distinct, procoelous, non-imbricating presacral vertebrae that are not fused to one another and all of which have a large neural canal. The atlas lacks transverse processes and has widely separated cotyles. The transverse processes of Presacrals II are directly laterally, whereas those of Presacrals III–VII are directed posteriorly. Presacral VIII has weakly anteriorly directed transverse processes and a biconvex centrum, making the vertebral column displasiocoelous. The sacrum is procoelous with short transverse processes and has two condyles posteriorly. The urostyle bears two cotyles, which are not confluent, for articulation with the urostyle and a tall dorsal ridge that tapers posteriorly, ending approximately at the anteroposterior midpoint.The pectoral girdle is firmisternal and no elements are in direct articulation or synostosed. The scapula has a defined waist, expanding dorsally, and has an expanded and rounded acromial process. The clavicle is thin and nearly perfectly straight. The coracoid is widely expanded medially, with the medial extent approximately twice as wide as the lateral extent. A small omosternum is expanded posteriorly and tapers anteriorly. A stout and nearly rectangular bony xiphisternum projects distally from the coracoids.In CESF 2898, the three elements of the pelvic girdle—ilium, ischium, and pubis— are ossified and synostosed to one another. The shaft of the ilium is long and bears a weakly developed supraacetabular fossa, a well-defined dorsal protuberance, and a short dorsal crest for most of its length. The synostosis of the pelvic elements creates a broad sheet of bone posterior, ventral, and anterior to the acetabulum. In CESF 1565, the ventral acetabular expansion projects anteriorly, but not ventrally below the point at the margin of the acetabulum at which the ilium and pubis meet; the ischium and pubis are not fully ossified in this specimen.The humerus is thin and straight with a weakly developed ventral crest and entepicondyle. The forearm is approximately two-thirds the length of the humerus. The radiale and ulnare are large and elongate, and subequal in size. The distal carpals are fused into two groups: Element Y + distal carpal 2, and distal carpals 3+4+5. The phalangeal formula for the manus is 2–2–3–3 and there are two small ossified elements of the prepollex that are more ossified and discernable in the larger specimens (CESF 2898 and 2899). The terminal manual phalanges are blunt distally, and in some cases tapering. The tibiofibula and femur are similar in length. There is a tarsal sesamoid on the ventral surface at the articulation of the tibiofibula and the tibiale and fibulare. There are two distal tarsals, two small ossified elements in the prehallux, and a sesamoid on the plantar surface at the base of metatarsals IV and V. The phalangeal formula for the pes is 2–2–3–4–3. The terminal pedal phalanges taper and then expand into a small blunt tip.Astrobatrachus is clearly distinguishable from other members of the Nyctibatrachidae as well as other families endemic to the WG , has a second finger longer than the first finger, and indistinct subarticular tubercles.o the WG . No infohalanges  and 6. SAstrobatrachus differs from Nyctibatrachus in lacking rugose or wrinkled skin with longitudinal folds, having a distinct tympanum and canthus rostralis, lacking a subocular gland, having widely spaced nasals, having a long ridge of vomerine teeth, having separate anterior and posterior portions of the vomer with the latter fused to the neopalatine, lacking a forked omosternum, lacking femoral glands, lacking a prominent dorsal crest on the ilium, lacking both a tarsal fold and webbed pedal phalanges, lacking a rhomboidal pupil , lacks a lateral line system as an adult, and has a second finger longer than the first finger and indistinct subarticular tubercles.al pupil . SimilarAstrobatrachus is also distinguishable from genera of Micrixalidae  and Ranixalidae . Astrobatrachus differs from Micrixalus by having vomerine teeth and a posterior portion of the vomer, and lacking T- or Y-shaped terminal phalanges , a well-defined sternum, and lacking Y-shaped terminal phalanges, but is similar by having an unforked omosternum.The skeleton of halanges , but is A. kurichiyana from many species of Nyctibatrachus that are torrential frogs and prefer to live in water or next to perennial streams  are occasional litter-dwellers  which suggests either the failure of some lineages to diversify, incomplete sampling, or extinctions over time. At this juncture, our study and other extensive surveys exclude poor sampling as a cause. The peculiar mixture of hyperdiverse radiations such as Pseudophilautus Laurent 1943 and Raorchestes Biju, Shouche, Dubois, Dutta, and Bossuyt, 2010  and the family Nasikabatrachidae have narrow ranges and are restricted to different massifs in the southern and central latitudes of the Escarpment and Sri Lanka. The southern regions of the WG (and Sri Lanka) have long been considered ancient climatic refuges  of a small massif in the WG escarpment (carpment . Its dis10.7717/peerj.6457/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.6457/supp-2Supplemental Information 2Click here for additional data file.


Life expectancy increased in industrialized countries, but inequalities in health and mortality by socioeconomic position (SEP) still persist. Several studies have documented educational inequalities, yet the association between health and employment status remains unclear. However, this is an important issue considering the instability of the labour market and the fact that unemployment now also touches ‘non-traditional groups’ (e.g. the high-educated). This study will 1) probe into the association between unemployment and cause-specific mortality; 2) look into the possible protective effect of sociodemographic variables; 3) assess the association between unemployment, SEP, gender and cause-specific mortality.Individually linked data of the Belgian census (2001) and Register data on emigration and cause-specific mortality during 2001–2011 are used. The study population contains the Belgian population eligible for employment at census, based on age (25–59 years) and being in good health. Both absolute and relative measures of all-cause and cause-specific mortality by employment status have been calculated, stratified by gender and adjusted for sociodemographic and socioeconomic indicators.Unemployed men and women were at a higher risk for all-cause and cause-specific mortality compared with their employed counterparts. The excess mortality among unemployed Belgians was particularly high for endocrine and digestive diseases, mental disorders, and falls, and more pronounced among men than among women. Other indicators of SEP did only slightly decrease the mortality disadvantage of being unemployed.The findings stress the need for actions to ameliorate the health status of unemployed people, especially for the most vulnerable groups in society. Life expectancy has increased substantially in industrialized countries in the last decades . HoweverThis study aims to fill this gap by analysing inequalities in mortality by employment status. This is an important issue to address firstly because the likelihood of getting unemployed at a certain point in time has increased considerably due to the instability of the labour market; and secondly because unemployment now also touches ‘non-traditional groups’, such as the higher educated and the higher socio-professional groups . The assAs a result of the shifts in the global economic market and the economic recession, employment patterns have changed from stable and predictable to more flexible and uncertain . ConsequAs mentioned earlier, unemployment is now also increasingly affecting other groups than the ‘traditional ones’ , e.g. thThe literature on the link between unemployment and health is quite controversial, with a lot of debate on the causal direction of this relation ,14–17. SThe aim of this study is threefold: first, we want to assess whether unemployment is associated with higher mortality risks and if so for which specific causes of death (COD). Next, as single indicators of SEP do not maximally discriminate between social groups , we willst October 2001-31st December 2011. The dataset contained census-based information on socio-demographic and SE characteristics as well as cause-specific mortality figures for the total de jure Belgian population.Analyses were based on a population-wide dataset, consisting of a record linkage between the 2001 Belgian census and Register data on emigration and cause-specific mortality for the period 1The study population comprised the Belgian population aged 25 to 59 years at census 2001, eligible for employment and in good health . Limiting the analyses to the 25 to 59-year olds excludes those who may be still studying (<25 years) and those who are at the end-of-career periods (60 and older), which leads to a more homogenous study population. Moreover, to capture the population eligible for employment, students, retirees and people not working because of personal, social or health reasons as well as unemployed people not actively looking for a job were excluded from the study population. To exclude a health selection effect, people that claimed to be in ‘fair’, ‘poor’ or ‘very poor’ health at the moment of the 2001 census were also excluded from the analyses.The study population was classified by employment status at the time of the census 2001, contrasting employed and unemployed people who were actively looking for a job. Differences in cause-specific mortality by employment status were controlled for the following social characteristics: educational attainment, home ownership, living situation, and migration background. Educational attainment was categorized according to the International Standard Classification of Education : lower sCOD were classified according to the International Classification of Diseases and Health-related problems, tenth revision (ICD-10). The COD were grouped according to the chapters of ICD-10 ). In addition, major single COD such as diabetes, ischaemic heart disease and transport accidents were examined separately. To get the full picture of mortality inequalities by employment status, both absolute and relative measures were calculated, as is recommended –33. FirsIn 2001, five percent of the Belgian men belonging to the population eligible to be at work was unemployed and looking for a job, while for women, this percentage was twice as high .Compared with employed men and women, the unemployed were more likely to be in a socially disadvantaged position. While women were more often higher educated than men, both unemployed men and women were more often lower educated compared with their employed counterparts. Almost three out of four employed men and women were owner of a dwelling, but this percentage decreased among the unemployed to about 50% of the unemployed men and 60% of the unemployed women. Among men, the unemployed were more likely to be living without partner, whereas the majority of the women was living with a partner even if the proportion of women living without partner was higher among the unemployed. Finally, the percentage of men and women with a migrant background was higher among the unemployed than among the employed.unemployed = 195.1/100,000 –ASMRemployed = 121.9/100,000). In relative terms, male all-cause mortality was twice as high among the unemployed compared with the employed , while among unemployed women, all-cause mortality was 64% higher compared with employed women   .This adverse association between unemployment and mortality (measured both absolute and relative) was persistent for all major groups of COD, as well as for all major single COD, both among men and women. The only exceptions were diseases of the nervous system among women  and hypertensive diseases among men and women . For cause-specific mortality also, the association between unemployment and mortality was larger among men than among women.Among the major groups of COD (highlighted in grey), in absolute terms, the largest inequalities between employed and unemployed people were found for cancers, diseases of the circulatory system and external causes (only men), as these are also the largest COD . The larFor the other major groups of COD, there also was a large excess mortality among unemployed men and women. For digestive, endocrine, infectious and respiratory diseases as well as external COD, mortality among the unemployed was more than three times as high among men and more than two times higher among women, compared with the employed.men: 3.12; 95% CI: 2.12–4.59 and MRRwomen: 3.56; 95% CI: 1.96–6.45) compared with employed men and women.To be more specific by taking a look at the major single COD, excess mortality among unemployed men and women was observed for all these COD. The largest relative mortality inequality between employed and unemployed men and women was noted for mortality due to mental disorders related to alcohol, resulting in MRRs of respectively 7.60 (95% CI: 6.17–9.37) for men and 4.26 (95% CI: 2.84–6.38) for women . The excFor instance, high-educated employed men have an all-cause ASMR of 175.2 (95% CI: 171.8–178.7) whereas the ASMR for high-educated unemployed men was 434.5 (95% CI: 397.4–471.6) as compared to 604.1 (95% CI: 578.8–629.5) among low-educated unemployed men . Howevermen: 1.86; 95% CI: 1.01–3.43 and MRRwomen: 2.37; 95% CI: 1.10–5.12) where in the adjusted model the effect was explained. For all other COD among women, adding the indicators of social disadvantage to the model did not result in a significant decrease of the association between unemployment and mortality. However, among men, adjusting for indicators of social disadvantage resulted quite often in a decrease of the association, which was the case for mortality due to cancer, mental disorders, circulatory diseases, respiratory diseases, digestive diseases and external COD.Additionally, we estimated the association between unemployment and all-cause and cause-specific mortality, adjusted for educational level, home ownership, living situation and migrant background , model 2This study precisely assessed the relation of unemployment and cause-specific mortality among the working age population in Belgium, both in absolute and relative terms. For doing so, we disposed of an exhaustive, high-quality database including the total de jure population in Belgium. Moreover, the data from the three different sources  have been individually linked, thereby avoiding a numerator-denominator bias. The wealth of this individual-level dataset enabled us to adjust the association between unemployment and cause-specific mortality for other measures of social disadvantage. Unemployment is correlated with other sources of social disadvantage, such as reduced financial means or increased likelihood of divorce ,20. At tUnemployment status was measured at baseline (census 2001), however we did not have information on the history of the employment trajectory, nor on the reasons for the job loss. Timing is an important indicator in this regard because the association between joblessness and health might be stronger with longer durations of unemployment ,21. CumuFinally, we should address the issue of health selection. The causal link between unemployment and poor health is likely to be bidirectional ,13–17,21This study revealed a distinct all-cause and cause-specific mortality disadvantage for unemployed men and women compared with their employed counterparts. This finding is consistent with the literature on unemployment and health ,12,17,20The causal mechanisms is related to the rewards that are involved with paid work: financial security, social contacts, a sense of meaning, structured daily activities, as well as psychosocial rewards such as self-esteem or prestige ,14. ConsThe excess mortality among unemployed men and women was particularly elevated for the COD related to adverse health behaviours, especially to alcohol and tobacco consumption and external COD. This is in line with several studies that observed a correlation between being unemployed and problematic alcohol consumption ,12, alcoBoth unemployed men and women were at a higher risk of dying compared with their employed counterparts. However, the association was more pronounced among men, as was observed in other studies as well ,10,13,19Furthermore, the results proved that unemployment was indeed associated with other measures of social disadvantage: low education, being tenant of a dwelling, living without partner and having a migrant background. On the other hand, notwithstanding having a high position on other social scales (e.g. being high-educated or being owner of a dwelling), being unemployed remained associated with increased all-cause and cause-specific mortality, although mortality was higher among the lower SE groups. Moreover, the results showed that the other measures of social disadvantage did only slightly decrease the elevated cause-specific mortality risks among the unemployed. Yet, the results suggested that employment status seemed to be a more important marker for one’s health than the other indicators of social disadvantage. The results also proved clearly that the association between unemployment and mortality not only varied by gender, but also by other measures of social disadvantage, especially the living situation and the material means (i.e. ownership), which is in line with previous research ,21. ThusFollowing the higher unemployment levels among the lower social strata, especially in combination with simultaneously being in other lower social strata, implies for urgent matters . SpecialWe observed a strong association between unemployment and mortality. Yet, we cannot make conclusion on the causal directions. To enhance our knowledge, future research should repeat this kind of analyses in contexts with high unemployment levels . This st