ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animal's natural gut flora. Overall, these findings support the premise that long‐term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development.Recent epidemiological evidence suggests that exposure to antibiotics in early‐to‐middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long‐term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the  The gut microbiome is integral to gastrointestinal tract function and is connected to a variety of health issues Colorectal cancer is the second leading cause of cancer‐related death in the United States and ranks fourth in estimated new cases Despite these lines of evidence, there are significant gaps in our understanding of how antibiotics increase the risk of colorectal cancer. Current studies show that tetracycline mediates upregulation of cyclooxygenase‐2 and prostaglandin production ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis In the current study, we address this knowledge gap by examining the effects of long‐term administration of an antibiotic cocktail of Vancomycin, Neomycin, and Streptomycin on gut polyposis in the ApcMin/+ mice were obtained from Jackson Laboratories and bred in‐house at the Animal Resource Facility at the, University of South Carolina. Food (Purina chow) and drinking water were available to the mice ad libidum under a 12:12‐hour light–dark cycle and a low‐stress environment . At 4 weeks of age, littermates were randomly assigned to the following six groups  ApcMin/+ untreated controls sacrificed after 12 weeks, (3) ApcMin/+ untreated controls sacrificed after 16 weeks, (4) ApcMin/+ administered with antibiotics and sacrificed after 8 weeks, (5) ApcMin/+ administered with antibiotics and sacrificed after 12 weeks and (6) ApcMin/+ administered with antibiotics and sacrificed after 16 weeks. All procedures and animal care followed institutional guidelines and were approved by the Institutional Animal Care and Use Committee at the University of South Carolina. Four mice were assigned to each of the six treatment groups, and this sample size was based on statistical power analyses conducted in previous microbiome studies A mixture containing Vancomycin , Neomycin , and Ampicillin  was administered to antibiotic treatment group (+Abx). The antibiotic mixture was added to the drinking water at age 6, 10, and 14 weeks , two‐way repeated‐measure ANOVA, and one‐way ANOVA were used to analyze the data. A Tukey post hoc analysis was used to determine differences in physiological responses upon antibiotic‐administered mice and the controls. All statistical analyses were performed with SigmaStat 3.5 . For fecal bacteriome analyses, Kruskal–Wallis and Mann–Whitney statistical analyses were performed to calculate significance in diversity and relative abundance, respectively. A ApcMin/+ mice were exposed to the antibiotic cocktail beginning at 6, 10, and 14 weeks of age, and polyp numbers and sizes were assessed at 8, 12, and 16 weeks , as there were no significant differences for polyps <1 mm2. Thus, antibiotic exposure promoted development of intestinal polyps.To mimic long‐term antibiotic exposure, As shown in Figure Clinical scores derived from an integral assessment of weight loss, diarrhea, and fecal hemoccult were observed to increase in antibiotic administered as compared to control mice at all three ages Fig. . Crypt‐tAs antibiotics impact the thickness of the intestinal mucus layer ApcMin/+ mice retained a stable microbiome during the time window of 8–16 weeks. However, for all age groups, alpha‐diversity was significantly decreased by antibiotic treatment, as measured by total operational taxonomic units (OTUs), the Chao1 index, or the Shannon index  was measured in response to antibiotic treatment, several probiotic genera  were nearly eliminated. The shifts in bacterial abundance upon antibiotic administration were also reflected by the beta‐diversity patterns .Alterations at the genus level were also assessed Fig. C. While rns Fig. D, in thaBacteroides and several beneficial genera within Firmicutes.Overall, the results demonstrate that administration of antibiotics eliminated the majority of bacterial flora, with the most drastic depletion being observed for the phylum In the current study, we provide direct experimental evidence in support of the notion that long‐term exposure to antibiotics can promote polyp development in the gut of a genetically susceptible mouse strain, as suggested by previous epidemiological reports that linked colorectal carcinogenesis to antibiotic use in humans An intriguing and novel aspect of the current study is the observation that depletion of the natural bacterial flora upon antibiotic exposure correlates with reduction in mucus‐producing goblet cell numbers, along with an increase in both colon histopathological scores and intestinal crypt‐to‐villus ratios. The functional link between antibiotic‐mediated microbial dysbiosis and the inhibitory effects of antibiotics on development of goblet cells is of particular interest, as these cells are integral to protection against inflammation and polyposis. In all, this is consistent with previous findings suggesting that gut microbiota impact the thickness of the mucus layer Our results imply that the intestinal microbiome has a profound impact on the global physical properties of the gut, which in turn determines the severity of inflammation and cancer. This is illustrated by our ‘cyclical microbiome protection model’ depicted in Figure The choice of the antibiotics for this study was based on their known mechanisms of action in bacterial cells and their minimal nontoxic effects on the host. Neomycin is used against both Gram‐positive and Gram‐negative bacteria. To minimize nephrotoxic effects of the antibiotic, it is prescribed as an oral antibiotic. Its inhibits bacterial growth by binding RNA duplexes Bacteroides and some ‘beneficial’ genera such as Lactobacillus and Desulfovibrio. This implicates the possible role of these genera in protection against cancer progression. The increase in larger polyps during cancer progression may be due to selective depletion of these bacterial genera. Alternatively, the dramatic increase in relative abundance of Firmicutes upon antibiotic administration may underlie increased polyposis. Distinguishing between these and other possibilities will require follow‐up studies with gnotobiotic rodent models. Our findings are different from observations described by Hamoya et al. ApcMin/+ mice. It may be that different antibiotic exposures may result in distinct microbial profiles, which in turn, may lead to variation in disease outcomes.Interestingly, the antibiotic cocktail used currently selectively depleted the genus Our follow‐up studies will investigate the effect of these potential ‘therapeutic microbes’ on cancer development and progression. Other aspects to be investigated in our follow‐up studies are use of different antibiotics, and the timing of antibiotic exposures relative to polyp development. Such studies will provide additional mechanistic information on the association of antibiotic exposure, effects on the gut microbiome, and development of colorectal carcinogenesis.The authors declare no conflict of interest.Figure S1. Representative Hemeatoxylin and eosin (H&E) stained colon tissues belonging to control and +Abx mice at different ages.Click here for additional data file.


Date of publication: 8 August 2016http://ecdc.europa.eu/en/publications/Publications/01-08-2016-RRA-Enterovirus%2071-Spain,%20France,%20Netherlands.pdfDate of publication: 5 August 2016http://ecdc.europa.eu/en/publications/_layouts/forms/Publication_DispForm.aspx?List=4f55ad51-4aed-4d32-b960-af70113dbb90&ID=1545Date of publication: 15 August 2016http://ecdc.europa.eu/en/publications/Publications/whole-genome-sequencing-for-public-health-surveillance.pdfDate of publication: 29 August 2016http://ecdc.europa.eu/en/publications/Publications/laboratory-capability-monitoring-2014-eu-labcap.pdfDate of publication: 19 August 2016http://ecdc.europa.eu/en/publications/Publications/salmonella-typing-seventh-external-quality-assessment.pdfDate of publication: 10 August 2016http://ecdc.europa.eu/en/publications/Publications/molecular-typing-EU-surveillance-epidemic-preparedness-2016-19-roadmap.pdfDate of publication: 10 August 2016http://ecdc.europa.eu/en/publications/Publications/molecular-typing-EU-surveillance-epidemic-preparedness-2013.pdfDate of publication: 31 August 2016http://ecdc.europa.eu/en/publications/Publications/gonococcal-antimicrobial-susceptibility-surveillance-Europe-2014.pdfDate of publication: 9 August 2016http://ecdc.europa.eu/en/publications/Publications/influenza-virus-characterisation-july-2016.pdfDate of publication: every Fridayhttp://ecdc.europa.eu/en/publications/surveillance_reports/Communicable-Disease-Threats-Report/Pages/default.aspx


IgG4‐related disease (IgG4‐RD) is a systemic fibroinflammatory disease characterized by tumefactive lesions in various organ systems, including the lungs. Clinical and radiological manifestations of IgG4‐RD are relatively non‐specific, and we report a case highlighting the importance of histopathological confirmation in cases of suspected IgG4‐related lung disease. A 44‐year‐old male with significantly elevated serum IgG4 levels, patchy consolidation on thoracic CT imaging, and cough was referred with suspected IgG4‐related lung disease. However, surgical lung biopsy revealed an unexpected diagnosis of pulmonary schistosomiasis, and following treatment with praziquantel, cough resolved and IgG4 levels significantly declined. This case highlights the potentially diverse array of conditions that may mimic IgG4‐related lung disease and the importance of comprehensive evaluation including histopathological confirmation where possible. IgG4‐related disease (IgG4‐RD) is a systemic fibroinflammatory disease characterized by elevated serum IgG4 levels and typical histological features, including a lymphoplasmacytic inflammatory tissue infiltrate rich in IgG4‐positive plasma cells and varying degrees of tissue fibrosis We report a case of a 44‐year‐old male referred with suspected IgG4‐related lung disease that highlights the importance of a comprehensive clinical assessment, including a confirmatory tissue biopsy. Despite elevated serum IgG4 levels coupled with suggestive symptoms and radiological changes, a surgical lung biopsy revealed an unexpected diagnosis of pulmonary schistosomiasis.9/L , however, was elevated as a proportion of white cells at 8%.A 44‐year‐old Zimbabwean‐born male was referred with a 12‐month history of cough, areas of patchy sub‐pleural consolidation on thoracic Computed Tomography (CT) , split into two doses administered 4 h apart. At three‐ and 12‐month follow up, his cough had resolved, and serum IgG4 levels had reduced significantly (from 4.61 to 1.59 g/L). Stool microscopy became negative for schistosome ova, and the eosinophil percentage of total white cells normalized (4%). Repeat CT imaging 12 months after eradication treatment revealed unchanged patchy consolidation, consistent with localized fibrotic pulmonary change.In patients with suspected IgG4‐related lung disease, our case highlights the importance of histopathological confirmation given the non‐specific symptoms and radiology and the variety of causes for elevated serum IgG4 levels  Although cases of IgG4‐related lung disease are increasingly reported, the underlying pathogenesis of the disease remains poorly understood. Hypothesized mechanisms suggest either an allergic‐type reaction with overexpression of Th2‐related cytokines, or as a result of circulating B cells entering inflamed tissue with subsequent differentiation and proliferation into IgG4‐switched B cells and, subsequently, plasma cells Schistosomiasis is an endemic parasitic infection seen mainly in tropical regions, with humans infected as a result of schistosoma entering the circulation via the skin during contact with fresh water. The circulating parasites then pass through the heart, lungs, and liver to reach their target venous plexus where the adult worms mature, mate, and eventually release eggs into the environment With increasing recognition of IgG4‐RD (including IgG4‐related lung disease), histopathological confirmation and clinico‐pathological correlation is vital. Given the diverse array of conditions that may potentially ‘mimic’ IgG4 RD, and the need for glucocorticoid therapy in the treatment in many confirmed cases, failure to exclude infective and malignant causes of elevated serum IgG4 levels may result in potentially serious consequences.Appropriate written informed consent was obtained for the publication of this case report and accompanying images.


Extensive antibiotic use over the years has led to the emergence and spread of antibiotic resistant bacteria (ARB). Antibiotic resistance poses a major threat to public health since for many infections antibiotic treatment is no longer effective. Hospitals are focal points for ARB spread. Antibiotic use in hospitals exerts selective pressure, accelerating the spread of ARB. We used an agent-based model to explore the impact of antibiotics on the transmission dynamics and to examine the potential of stewardship interventions in limiting ARB spread in a hospital. Agents in the model consist of patients and health care workers (HCW). The transmission of ARB occurs through contacts between patients and HCW and between adjacent patients. In the model, antibiotic use affects the risk of transmission by increasing the vulnerability of susceptible patients and the contagiousness of colonized patients who are treated with antibiotics. The model shows that increasing the proportion of patients receiving antibiotics increases the rate of acquisition non-linearly. The effect of antibiotics on the spread of resistance depends on characteristics of the antibiotic agent and the density of antibiotic use. Antibiotic's impact on the spread increases when the bacterial strain is more transmissible, and decreases as resistance prevalence rises. The individual risk for acquiring ARB increases in parallel with antibiotic density both for patients treated and not treated with antibiotics. Antibiotic treatment in the hospital setting plays an important role in determining the spread of resistance. Interventions to limit antibiotic use have the potential to reduce the spread of resistance, mainly by choosing an agent with a favorable profile in terms of its impact on patient's vulnerability and contagiousness. Methods to measure these impacts of antibiotics should be developed, standardized, and incorporated into drug development programs and approval packages. Some resistance mechanisms  arose in human pathogens only in a few instances during evolution, but have become widespread through transmission . The setting of the model is a typical hospital  βH—probability of HCW contamination during contact with a colonized patient; c) α- probability per day of susceptible patients to acquire ARB from an adjacent colonized patient. In the model, antibiotic use increases the risk of transmission. V and C represent the fold increase in the risk of ARB acquisition (for susceptible patient) or of transmission (for colonized patient), respectively, during antibiotic treatment. When antibiotic is not used by the patient then V = 1 and C = 1. The following equations determine the probability of transmission between agents:ARB transmission is defined by three basic probabilities: a) βp_by_p) from an adjacent colonized patient, per day:Probability for susceptible patient to acquire ARB (Pp_by_h) during a contact with a contaminated HCW:Probability for susceptible patient to acquire ARB (Ph_by_p) during a contact with a colonized patient:Probability for HCW to be contaminated , we selected values slightly lower than what was found in the literature as the baseline probabilities for patients who are not treated with antibiotics. . PatientCharacteristics of the antibiotic agent: the fold increase in the risk of ARB acquisition (V) or transmission (C) during antibiotic treatment; these values vary in simulations between 1 and 4. The tested values are within the range of increased risk for acquisition observed among patients treated with various antibiotics –25, and Antibiotic density: the prevalence of antibiotic use is varied by changing either the proportion of admitted patients which are treated with antibiotics (0–100%) or the duration of antibiotic treatment (7 or 10 days).ARB prevalence among admitted patients: an early stage of ARB spread in which 1% of admitted patients are carriers, and an endemic stage in which 10% are carriers.Transmissibility of the ARB: a less transmissible strain (ARB-L) and a highly transmissible strain (ARB-H) .For each scenario, the average of 100 simulations is presented as the results.Antibiotic agents may differ in their effects on patients' vulnerability (V) and contagiousness (C). The effect of these antibiotic characteristics on the transmission of ARB was examined. Transmission of ARB-L and ARB-H was simulated for various combinations of V and C. In these simulations 1% of admitted patients carry the ARB strain and 40% of admitted patients receive antibiotics.Under conditions of no antibiotic pressure , the acquisition incidence for the ARB-L strain is 20 per 100,000 patient-days (PD) . For theWe can also infer that an antibiotic's effect on increasing the vulnerability of susceptible patients has a greater influence on acquisition dynamics than its effect on increasing the contagiousness of colonized patients. We varied antibiotic density by changing the proportion of admitted patients prescribed antibiotics for 10 days, and explored the effect on the incidence of ARB-L and ARB-H acquisition. In these simulations we modeled an antibiotic that doubles both vulnerability and contagiousness , and an early stage of ARB spread (1% are carriers upon admission). The simulations demonstrated that an increase in antibiotic density leads to a non-linear increase in the incidence of ARB acquisition, which approaches exponential increase in the case of ARB-H . When anTo examine the significance of ARB prevalence on transmission dynamics, we modeled an antibiotic agent that doubles vulnerability and contagiousness . We varied antibiotic density by changing the proportion of admitted patients treated with antibiotics. Simulations included both early and established stages of ARB spread (1% vs. 10% carriers upon admission).First, we examined how increasing antibiotic density affects the incidence of acquisition of ARB-H and ABR-L compared to a baseline transmission with no antibiotic use  comparedIncreasing antibiotic density affects an individual patient's risk of acquiring ARB. We measured the risk as the probability of acquisition during a typical hospital stay of 6 days. The probability of acquisition for a patient not treated with antibiotics is calculated as: the number of patients not treated with antibiotics who acquired ARB divided by the total number of patients not treated with antibiotics.The probability of acquisition for a patient treated with antibiotics is calculated as: the number of patients treated with antibiotics who acquired ARB divided by the total number of patients treated with antibiotics. Since the average antibiotic treatment time was 4.5 days, we adjusted the probability to account for 6 days with antibiotic treatment.The individual risk increases in parallel to the proportion of patients treated with antibiotics . When 20of America (SHEA) in order to limit resistance [Last, we explored the potential effect of antibiotic stewardship interventions recommended by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology sistance . We examAs presented in Our results are based on a hospital with characteristics as specified in Transmission is the main driver for the spread of most ARB. Controlled experiments to study the effect of antibiotic interventions to reduce transmission of ARB at the hospital level are difficult to perform because of the need to control all potential confounders. This is especially challenging because antibiotic interventions are often implemented as part of a bundle of infection control measures that affect ARB transmission .Therefore, we used ABM to understand the effect of antibiotics on the transmission dynamics and the potential of stewardship interventions. We demonstrated that an increase in antibiotic use increases the incidence of ARB acquisition. At the individual level, the patient's risk increases in parallel with antibiotic density, not only for patients treated with antibiotics but also for those not treated. These effects translate into an exponential increase in incidence of ARB acquisitions when antibiotic density increases and when the antibiotic agent has a high affect.We found that characteristics of the antibiotic agent used, i.e., its effect on contagiousness and vulnerability, are crucial in determining the antibiotic's impact on the spread of resistance. Our models showed that choosing an agent with a favorable profile in terms of V and C is an important antibiotic stewardship intervention. Yet, in the real world these effects are understudied and the values of V and C for different antibiotic agents are mostly unknown. Moreover, it is very likely that each antibiotic agent has different effects for different ARB. Methods to measure the effects of C and V of antibiotics should be developed and standardized and should be incorporated into drug development programs and drug approval packages.Our simulations revealed that antibiotic density affects ARB transmission more considerably in the early stages of antibiotic resistance spread, when prevalence among admitted patients is low. Antibiotics have a greater impact on the incidence of ARB acquisition when the ARB strain is highly transmissible. Since highly transmissible strains pose a greater risk to become widespread, antibiotic stewardship interventions can be a powerful tool to combat their spread. We found that reducing antibiotic density has a greater impact on the incidence of ARB acquisition in settings of high antibiotic use. This is an important finding, as variability in antibiotic use between similar wards suggests that reduction in antibiotic density can be achieved in high use settings; such reductions will result in a highly beneficial effect on acquisition of ARB.Antibiotic use can be viewed as "tragedy of the commons" where individuals, for their own good, exploit a shared limited resource, eventually leading to its depletion , 51. Antde novo emergence of resistance. Second, for simplicity in our scenarios, all antibiotics used in the hospital have uniform characteristics. In the real world a mixture of agents are used simultaneously. This should not change the conclusions derived from our results but will make translation into the hospital setting more complex. Third, we modeled a typical hospital with certain transmission and infection control characteristics. The sensitivity analysis we conducted indicates that the level of staff member compliance with infection control has a significant impact on the rate of acquisitions but the relative effects of antibiotics on the spread of ARB are consistent.Our study has several limitations. First, we did not take into account the effect of antibiotics on In conclusion, our simulations demonstrate that antibiotic treatment in the hospital setting plays an important role in determining the spread of resistance. It shows that interventions to limit antibiotic use have the potential to rapidly reduce the spread of resistance, and that the risk to the individual patient treated with antibiotics of acquiring antibiotic-resistant bacteria is substantial.S1 FigARB acquisitions per 100,000 patient days (PD) as antibiotic density increases. (A) The level of nurses' compliance with infection control is: 40%, 50% and 60%; (B) Number of patients per ward is: 8, 16 and 40; (C) Nurse-patient ratio is: 1:8, 1:4, 1:2. In all simulations the resistant bacteria is ARB-H, the characteristics of the antibiotic agent are V = 2 and C = 2, and prevalence of colonization among admitted patients is 1%.(DOCX)Click here for additional data file.


Estimates suggest that more than 25,000 to 125,000 people die annually from snakebite envenomation worldwide. In contrast to this major disease burden, thorough bibliometric studies do not exist so far that illustrate the overall research activity over a long time span. Therefore, the NewQIS-platform conducted an analysis on snakebite envenoming using the Thomson Reuters database Web of Science. To determine and assess changes regarding the scientific activities and to specifically address the more recent situation we analyzed two time intervals (t). During the first time interval from 1900 to 2007 (t1) 13,015 publications (p) were identified. In the following period (2008–2016 = t2) 4,982 publications were identified by the same search strategy. They originate from 114 (t1) respectively 121 countries (t2), with the USA (p = 3518), Brazil (p = 1100) and Japan (p = 961) being most productive in the first period, and the USA (p = 1087), Brazil (p = 991) and China (p = 378) in the second period, respectively. Setting the publication numbers in relation to GDP/capita, Brazil leads with 92 publications per 10,000 Int$GDP/capita, followed by India with 79 publications per 10000 Int$GDP/capita (t1). Comparing the country’s publication activity with the Human Development Index level indicates that the majority of the publications is published by highly developed countries. When calculating the average citation rates (citations per published item = CR) mainly European countries show the highest ranks: From 1900–2007 Sweden ranks first with a CR = 27, followed by the Netherlands (CR = 24.8), Switzerland (CR = 23), Spain, Austria and the USA (CR = 22). From 2008 to 2016 the highest rate achieves Switzerland with a value of 24.6, followed by Belgium (CR = 18.1), Spain (CR = 16.7), Costa Rica (CR = 14.9) and Netherlands (CR = 14). Compared with this, the USA was placed at rank 13 .In summary, the present study represents the first density-equalizing map projection and in-depth scientometric analysis of the global research output on snakebites and its venoms. So it draws a sketch of the worldwide publication architecture and indicates that countries with a high incidence of snakebites and a low economical level still need to be empowered in carrying out research in this area. Snakebite injury is a neglected tropical disease and lead to an enormous burden of disease in many parts of the world with about 25,000–125,000 estimated deaths. Therefore, research on this area of medicine is crucial since new diagnostic and therapeutic pathways may help to diminish disease burden. This study provides the first detailed landscape of the global snakebite research, which can be used by funding agencies and politicians to plan new programs. From 1900 to 2007 we found over 13,000 publications related to snakebites originating from over 110 countries, with the USA, Brazil and Japan being most active. The second period from 2008 until 2016 was characterized by 4,982 publications out of 121 countries. Here, the rank order was USA, Brazil and China. When efforts are analyzed from a socioeconomic perspective applying the GDP per Capita, Brazil and India take a lead position. The Human Development Index indicates that the vast majority of research is performed by highly developed countries. Closer investigations demonstrated that a large part of the research deals with scientific studies that used venom ingredients to unravel basic mechanisms of human physiology or to develop new pharmaceutical compounds. In summary, we here draw the first sketch of the overall global research architecture concerning snakebite envenoming. We found that countries with a high incidence of snakebites and a low economical level need to be empowered to carry out research in this area. Snakebites envenomation is a neglected tropical disease and lead to an enormous burden of disease in many parts of the world –3. PreciIndia plays a prominent role in snakebite epidemiology due to the vast size of the country and the number of inhabitants. However, potentially biased hospital-based statistics has led to widely ranging estimates of total annual snakebite mortality . Therefore, Mohapatra et al. calculated estimates of direct snakebite mortality from a national mortality survey using data from 123,000 deaths from 6,671 randomly selected areas between the years 2001 and 2003 . They reDespite this substantial global burden, snakebite injuries have received only little attention from governmental and non-governmental institutions all over the world, the pharmaceutical industry, and public health authorities and advocacy groups. Also, research funding and resources for health programs are on a low level in comparison to other diseases. In this respect, stakeholders and decision-makers have a huge requirement for scientifically validated recommendations that are still not sufficiently available. The inclusion of snakebites in the WHO list of Neglected Tropical Diseases (NTDs) as well as the development of project and initiatives by the WHO may help to improve global awareness.The fight against snakebite-related diseases is also crucially dependent on research funding. Usually, the funding allocation processes get improved by adding scientometric features to the election processes. Unfortunately, there is a lack of basic information about snakebite research. Therefore, we carried out a combined density equalizing mapping and scientometric analysis. The here presented patterns of the research efforts and the publication output empower scientific institutions, planners, and stakeholders to allocate research funding better, and support the most affected regions.The present study is part of the NewQiS-platform, which uses novel visualizing techniques in combination with new and established scientometric analysis tools ,14.The principle algorithm of density-equalizing map projections (DEMP) was reported by Gastner and Newman  and incoth century . In . In 35].In t1 a total number of 13,015 publications were identified, and the second evaluation period (t2) delivered 4,982 publications. A strong increase between the years 1990 and 1991 is due to the inclusion of abstracts and keywords in the search mode of WoS. In the first evaluation period (t1) 87% of the publications were attributable to one or more countries, viz. 11,323 publications, whereas in t2 only 1,4% was not attributable, so that 4,913 publications were assigned to one or more countries. In total, 114 (t1), respectively 106 countries (t2) contributed to the overall publication output. Ninety-four percent (t1) and alternatively 97% in t2 of all publications were written in English. The most common non-English articles were published in French (2%), Russian (0.97%), and German (0.96%) in timespan t1, while in t2 French , Spanish  and Portuguese  were the most frequent non-English languages. Despite the already high level of English-written publications in t1, this proportion has even more increased in t2.The USA was the leading country concerning research output with a total of 3,518 published items representing 31% of the attributable publications (t1), respectively 1,087 publications (22%) in t2. On second position in both periods, Brazil was listed with 1,100 publications (10%) in t1 and 991 publications (20%) in t2, respectively.In t1, these two countries were followed by Japan with p = 961 (9%), the UK with p = 862 (8%), France with p = 700 (6%), Taiwan with p = 617 (5%), Australia with p = 506 (4%), Germany with p = 496 (4%), China with p = 454 (4%), and India with 317 publications (3%). Costa Rica , Italy , South Africa , Israel , and Russia . Sweden , Switzerland , Singapore , the Netherlands , Thailand , Canada  and Spain  have more than 100 published items each. The other 92 countries, with less than 100 publications each, accounted for 1594 publications in total .In the second evaluation period (t2) the third most active country was China with 378 items (7.7%). The next countries were Australia with p = 373 (7.6%), India with p = 335 (6.8%), UK with p = 303 (6.2%), Germany with p = 224 (4.5%), France with p = 210 (4.3%), Costa Rica with p = 202 (4.1%), Japan with p = 185 (3.8%), Spain with p = 178 (3.6%), Taiwan with p = 140 (2.8%), and Italy with p = 113 (2.3%). Less than 100 publications were published by another 108 countries .When comparing the research activity to incidence of snakebites and economic data of the publishing countries, a two-fold result was obtained (Tab. 1): Due to the low incidence, the country with the highest research output (USA) was increasing its distance to the second ranked country, publications per snakebites per 100,000 inhabitants in the US versus 356 for Japan. Other countries with low incidences such as the UK, or France and Germany also raised in this ranking. By contrast, when relating the output data to GDP/capita, Brazil with 92 publications per 10,000 Int$ GDP/capita was ranked number one. Second was India with 79 publications per 10,000 Int$ GDP/capita.The adjustment of the research activity data to the six WHO regions  led to the following ranking: The WHO Region of the Americas was leading with p = 5,343 (47%) attributable publications, followed by the WHO European Region with p = 4,015 (36%) and the WHO Western Pacific Region . By contWhen adjusting the output data to the HDI level according to the Human Development Report, in the majority of the publications  a highly developed country was at least collaborating . By contThe number of international collaborations between two or more countries increased steadily since 1972  to the end with c = 17,908, followed by Japan , France  and Brazil  (In respect to the number of citations (c), the USA led in both time intervals with t1: c = 75,614 and t2: c = 10,420. Until 2007 (t1) the UK is ranked 2 12,028) . In cont 12,028) .When calculating the citation rate per published item of each country in a DEMP with a threshold of at least 30 publications per country, a different global research landscape has been obtained with European countries taking the lead position. In the first time span (t1), Sweden ranked number 1 with a citation rate (CR) of 27, followed by the Netherlands (CR = 24.8), Switzerland (CR = 23), Spain and Austria (CR = 22). At position six, the USA came up with a citation rate of 22, followed by other European countries . At position 11, non-European countries followed with Costa Rica (CR = 19), Japan (CR = 18), Canada (CR = 17) and Taiwan (CR = 16) leading the field. Brazil has a citation rate of 11 citations per publication .th with a rate even under 10 (CR = 9.6)  revealed a different picture. Here, Switzerland had the leading position with CR = 24.6, followed by Belgium (CR = 18). Placed next were Spain (CR = 16.7), Costa Rica (14.8), the Netherlands (CR = 14), UK (CR = 12.8), France (CR = 12.2), Australia (CR = 11.3), Italy (CR = 11.2) and Colombia (CR = 10.9). The USA was ranked only 13R = 9.6) .The 13,014 identified publications of t1 were published by a total of 3,922 institutions (i). When analyzing the number of institutions per country, the USA were leading with i = 896 institutions, followed by Japan with i = 284, Brazil with i = 283, France with i = 259 and the UK with i = 217 .The analysis of the institutions participating in t1 showed a range of 1 to 279 publications per single institution. The National Taiwan University was ranked number one with 279 publications, followed by the Brazilian Instituto Butantan with p = 277 and the Universidad de Costa Rica (Instituto Clodomiro Picado) with p = 275. The highest modified country-specific h-index within the analyzed set of p = 11,302 was found for the Universidad de Costa Rica with a value of 38 (i.e. 38 publications that were at least cited 38 times) ; all of In t2 there were 705 institutions in the USA publishing on snakebites, followed by Brazil with i = 540, China (i = 291), India (i = 284), and France (i = 158) . The ranPLOS Neglected Tropical Diseases has published in the past years numerous studies related to the field of snakebites [akebites ,38. Theyakebites , immune akebites , phylogeakebites  to basicakebites –43 and pakebites . DespiteBibliometric tools are commonly used to dissect research profiles also for neglected tropical diseases –47 and uOver two hundred years ago, the Scottish surgeon Patrick Russell published a work entitled "An Account of Indian Serpents Collected on the Coast of Coromandel" (1796) which can be regarded as one of the first scientific publications that point to the need of differentiating between venomous and non-venomous snakes and the necessity to develop therapeutic options for snakebite envenoming . About oWe therefore decided to start the analysis at the beginning of WoS entries in 1900. Thenceforward, we analyzed two different time intervals. The first time frame was closed in 2007 due to the time that is needed for each publication to show their highest impact measured as Cited Half-Life. This value has been introduced by the originator of the JCR  Eugene Garfield, meaning the time span that is necessary to get at least 50% of the citations . RegardiThe analysis shows that from 1900 to 2016, the yearly published amount of snakebite related publications increases from 5 (1900) to 677 (2012). This exemplifies the increase in scientific activity in this scientific area but is also related to the general bibliometric principle that research articles usually double within a time frame of 10 to 20 years . The yeaBothrops jararaca). Also, the maximum in 1985 (281 publications) is most likely related to the finding of dendrotoxin in 1980, which was isolated from Mamba venom.Maxima of publications numbers in single years are often related to important scientific findings and usually occur 2–5 years after the publication of the important finding. In this respect, the observed maximum in 1978 (198 publications) is most likely related to the development of Captopril from the venom of the South American Jararaca  nor the mortality  but the general standing of the USA as the world leading country concerning research activity points to the large gap in overall snakebite-research activity. This indicates that countries with a high incidence of snakebites and a low economical level need to be empowered to carry out research.In striking contrast to other scientometric studies that addresses diseases such as gout , silicosIn contrast, the current analysis shows that Brazil, a country with a relatively high incidence and mortality and with a rather low GDP contributed with the second highest research activity. The Brazilian publication performance corresponds with the findings of another neglected disease study on yellow fever . Here, aThe difference of the overall numbers of publications between yellow fever and snakebite related publications is most probably caused by the inclusion (search term) of studies that use venom ingredients to address basic mechanisms of human physiology and to develop novel pharmaceutics.Until now basic research on snakebites and venoms is more or less privileged to high-income countries, firstly, because they have the means for high tech research and secondly, there are no or only very little problems with snake envenomation. This is obviously the opposite in middle-income and low-income countries. The lack of resources limits the research on snakebite envenoming in these countries. Nevertheless, the emerging nation Brazil established–even enhanced–an important role in snakebite research. Also, as shown here, other countries from South and Middle America, like Costa Rica and Colombia, have appeared in the recent decade on the global landscape of snakebite research. Hence, it should be requested that other directly affected low and middle nations are also integrated to the worldwide research networks.The present study represents the first density-equalizing mapping and scientometric analysis of the worldwide research activities on the subject of snakebites and draws a sketch of its overall global research architecture. The ten and more years old calls for global snake-bite control and procurement funding needs to be re-emphasized .


Pseudokirchneriella subcapitata, Daphnia magna and D. pulex in four Swedish soft water lakes.The EU member countries are currently implementing the Water Framework Directive to promote better water quality and overview of their waters. The directive recommends the usage of bioavailability tools, such as biotic ligand models (BLM), for setting environmental quality standards (EQS) for metals. These models are mainly calibrated towards a water chemistry found in the south central parts of Europe. However, freshwater chemistry in Scandinavia often has higher levels of DOC (dissolved organic carbon), Fe and Al combined with low pH compared to the central parts of Europe. In this study, copper (Cu) toxicities derived by two different BLM software were compared to bioassay-derived toxicity for P. subcapitata in three of the four lakes and for the daphnids in two of the four lakes. The bioassay toxicity showed the strongest relationship with Fe concentrations and DOC. Furthermore, DOC was the best predictor of BLM results, manifested as positive relationships with calculated LC50 and NOEC for P. subcapitata and D. magna, respectively.A significant under- and over prediction between measured and BLM calculated toxicity was found; for Results from this study indicate that the two investigated BLM softwares have difficulties calculating Cu toxicity, foremost concerning the algae. The analyses made suggest that there are different chemical properties affecting the calculated toxicity as compared to the measured toxicity. We recommend that tests including Al, Fe and DOC properties as BLM input parameters should be conducted. This to observe if a better consensus between calculated and measured toxicity can be established. In the process of setting WQC it is central to try to mimic organism exposure in natural environments [50) [2+ due to the dominating soft water qualities, combined with low pH values and high levels of DOC, Fe and Al [2+ concentration is around 2 mg/L and the 90 percentile, 10 mg/L , which consequently can be characterised as soft- to ultra-soft waters, often leaving them outside of the BLM calibration range [When implementing water quality criteria (WQC) for metals in aquatic environments it is crucial to consider water chemistry parameters such as hardness, concentration of humic substances and pH, since these strongly affect the speciation of many metals –4. For ir uptake , 6. This+ levels . Total aomplexes , 6, 8. Tronments , which cnts [50) –12. For nts [50) , 14. In nts [50) . Howevere and Al . Accordion range , 17. Stuon range , 19, a wDaphnia magna, D. pulex and Pseudokirchneriella subcapitata, in water from four soft water lakes with different water chemistry. These lakes were chosen as representatives from the Swedish national monitoring program as they together represent the four most common Swedish water types . Results from the bioassays were compared with BLM-derived toxicities for chosen organisms and waters to see if there were any divergences between measured and calculated results.We hypothesize that the usage of BLMs outside of their targeted calibration range will also result in less reliable results compared to bioassay studies considering acute toxicity. To test this hypothesis, Cu toxicity was measured for three aquatic species: 4, Cl, alkalinity , pH, DOC, hardness as well as total dissolved (<0.2 µm) concentrations of Cu, Fe, Cd, Zn, Pb and Al sampled at the test start. The variability in pH, alkalinity and hardness is quite small among the lakes but they differ widely in DOC (0.9–17 mg/L), Fe (2–393 µg/L) and Al (1.5–57 µg/L) concentrations. Direct optical and integrated isotopic measurements suggest that the lakes also differ in the quality and origin of DOC. The four lakes fall within the typical ranges of Swedish lakes for these auxiliary optical and isotopic variables  ones in three of the four lakes for daphnids (bioassays with D. pulex was only available for two lakes due to cultivating problems), and higher BLM NOEC compared to measured EC50 for P. subcapitata in all four lakes  and Älgsjön (p < 0.001), however, differing only by a factor 2 and 1.3, respectively. For the alga, the difference was ranging from a factor 2.5 in Älgsjön to 9.3 in St. Envättern, proving to be significant in three of the four lakes (p < 0.001). The only exception was Älgsjön (p = 0.365) where BLM suggested higher toxicity to D. magna than the bioassays. Calculated BLM LC50 values for Abiskojaure and St. Envättern were high enough too corresponded to bioassay LC100  rather than a 50 % mortality. In contrast, for Älgsjön, the calculated LC50 value was below the measured value with a factor of 0.7. BLM calculated PNEC values (Table 5 concentration varied between 4.9 µg Cu/L (Abiskojaure) and 31.4 µg Cu/L (Älgsjön). For two of the four lakes, Abiskojaure and St. Envättern, the PNEC value was on par with or exceeded the measured algal EC50 value for growth inhibition.Both calculated and bioassay es Table . These tes Table . The dife p = 0.05 and ÄlgAlthough BLM yielded higher values than bioassays, in 8 of 10 cases, the general direction of the regression slopes was coherent between BLM and bioassay estimates for the key chemistry variables. In an attempt to find which factors that could explain the observed systematic difference, the relationship between water chemistry and the ratios between BLM and bioassay results was plotted. The difference between BLM and bioassays was related to the ratio of dissolved metals and DOC, e.g. the ratio between Fe and Al and DOC Figs. , 3. The P. subcapitata, D. magna and D. pulex (species only tested in two lakes). The Daphnia results showed that BLM v.2.2.3 both significantly over- and under-predicted Cu toxicity. In the lake where BLM overestimated toxicity, i.e. lake Älgsjön, a higher proportion of allochtonous natural organic matter (NOM), as compared to the other three lakes, was found, which indicates that lakes with these NOM properties could be less sensitive to Cu toxicity than lakes with a more autochthonous carbon source. However, for this model, both the over- and underestimation for the daphnids was within a factor of two, which could be considered a fairly good agreement. As for the algae, BLM v.0.0.0.17, underestimated the toxicity with a factor of 2.5 to 9.3, being significant in three out of four lakes , Al and Fe concentrations in order to define Cu toxicity in typical Swedish freshwaters. The performance of these BLM software versions for waters outside of the intended calibration range was examined by comparing model output to measured acute Cu toxicity for Älgsjön: Dark humic forest lake with a high TOC, some months over 30 mg C/L, St. Envättern: uncontaminated lake with relatively high TOC, Fiolen: Nutrient rich forest lake; Abiskojaure: nutrient poor clear lake with low TOC and primary production. The lakes are used as reference lakes in the Swedish national monitoring program and are not considered to be affected by any local anthropogenic activities in their catchments, apart from some forestry. The only influence comes from long-range airborne pollutants. The levels of toxic trace metals  in the waters are low , which were higher than the measured EC50 values (concentration where there was a 50 % growth inhibition). Furthermore, even though BLM v.2.2.3 is an acute model, the approach of using the conversion factor seems to be working, at least for the investigated waters.The NOEC-values (BLM v.0.0.0.17) exceeded the bioassay ECs bodies , the BLMp values decreased as more metals were added  quality is not considered in the two BLM softwares used in this study. This could be an important factor as DOM properties have been shown to influence both speciation –29 and tIn the bioassays, varying concentrations of Fe and Al may influence the toxicity of Cu, while BLM-calculated toxicity will not be affected, as these metals are not among the model input parameters. For this reason, it is not surprising that the BLM estimates were best correlated with DOC, as DOC supposedly is one of the most important input variables in current BLM versions. However, bioassay results suggested that Fe, especially in combination with Al, is as important as DOC for the Cu toxicity to the tested organisms Fig. . An addi). As Fe had the strongest correlation when single variables were considered, Fe was in this case apparently the more important of the two , chronic toxicity for D. magna (factor 8) and toxicity to larval fathead minnows in soft waters [A few other studies have indicated that BLM could underestimate Cu toxicity for a factor  and toxit waters , 19, 32.This study shows that using current BLM software (i.e. v.0.0.0.17 and v.2.2.3) outside of their intended calibration range could prove problematic since the models differed in their ability to accurately predict toxicity. The significant difference between measured and calculated toxicity was found to be between a factor of 0.7 up to 9.3. The toxicity measured in the bioassays showed the strongest relationship with concentrations of Fe, Al and DOC. In the lake where BLM overestimated Cu toxicity, different properties as regard to DOC origin was found, indicating that qualitative DOC properties can affect the performance of the BLM calculations. As our results are indicative towards Al, Fe and NOM properties influencing BLMs ability to calculate Cu toxicity we strongly recommend that studies considering the implementation of these parameters are conducted. DOM composition is extremely complex and not easily implemented in operative models like BLM; still, if the important aspects of DOC can be condensed into simple and cost effective optical properties like carbon-specific fluorescence or absorbance, as our results indicate, it could be worthwhile to further investigate.3/L) and circumneutral pH (6.5–7.6), and differ widely in TOC (0.8–17 mg/L). The water used in this study was sampled 2011. The pH values of these lakes were kept in the neutral range. Water from Abiskojaure was collected by staff at Abisko Scientific Research station , using polycarbonate water sampler from the ice, in March–April, and sent to ITM . Water from Fiolen was similarly collected by staff at the County Administrative board in Växjö and sent to ITM. These two waters were filtered upon arrival, in a clean room, within 3 days after sampling. Water from Älgsjön and St. Envättern were sampled by the authors and filtered in situ or the next day in a clean room. To avoid contamination of test waters, acid cleaned (0.1 M HCl) 5 L polypropylene containers were used. All filtrations were performed on-line by pumping water through acid cleaned (0.1 M HCl) plastic tubes  and 0.22 µm acid cleaned (0.1 M HCl) polypropylene capsule filters . The filtered water was placed in a dark cold room at 6 °C for 1 month until time of analysis and bioassay testing.The selected lakes; Abiskojaure, Fiolen, St. Envättern and Älgsjön are included in the Swedish national monitoring program, sampled 8–10 times/year for the last 20 years, and are consequently well characterized both chemically and biologically. The lakes vary regarding chemistry as well as catchment properties  and Stockholm Water Company (Stockholm Vatten) (TOC). Oxygen saturation levels and pH were determined using a SympHonic SP90N5 multimeter and a Radiometer pHM82 Standard. Trace metal levels were analysed both at the start of the bioassays and after 48 h using an ICP-MS Thermo X-series II (inductively coupled plasma mass spectrometry). The ICP-MS accuracy was checked using certified reference water  during each test batch. The labile inorganic Al fraction in the lake waters was determined by cation exchange spectrophotometry [13C) in fish  were measured by the Stable Isotope Facility, University of California at Davis, using isotope ratio mass spectrometry . This measurement has previously been shown to provide an indication of the amount of allochtonous carbon found in the water, meaning that at a higher δ13C (more negative) the DOC often is of allochtonous origin. All chemical analyses were conducted following quality assurance routines specified in the accreditation of the laboratories.Physico-chemical measurements were performed by the Swedish University of Agricultural Science (SLU) (major ions), ACES  was provided by University of Indiana, USA. Daphnids were cultured in groups of 15-20 animals in 3 L clear glass beakers containing 2.5 L of M7 medium. The M7 medium was renewed on a weekly basis and the animals were fed a mixture of Monoraphidium contortum (800 µL) and P. subcapitata (6.8 mL), approximately 0.2 mg C/day/Daphnia. The light cycle was 16:8 h light/darkness. The condition of the Daphnia culture was tested with K2Cr2O7 in synthetic soft water media (M7) and the LC50 found to be within the recommended range [ed range . One moned range . BrieflyP. subcapitata, which has been cultured at Stockholm University since 1975. It is grown in 250 mL culture flasks during constant light in 20 % Z8 culture medium [2 × s−1) for 72 h [Micro algae tests were performed using a clone of e medium . Growth e medium  during 7e medium . Prior te medium . Before for 72 h . After 750 results for D. magna and D. pulex, whereas BLM v 0.0.0.17, based on the Cu-VRA document [5 concentration, i.e. where 95 % of test organisms included in the model database will not be affected from the Cu concentration. These HC5 curves are based on species sensitivity distributions (SSDs) for those species that are included in the model’s database [P. subcapitata. These BLM softwares use the chemical equilibrium model WHAM V [D. magna and P. subcapitata, both species in the same model. The modeled and measured toxicity indices have different definitions for the two species, and hence ratios differ considerably. To obtain approximately equal variances for the two species, the ratios were log-transformed before ANCOVA analyses.The statistical software PROBIT v. 2.3 was used to calculate bioassay LC- and EC-values as well as their 95 % confidence intervals. Biotic Ligand Model v.2.2.3  was useddocument , was usedatabase . The BLMl WHAM V  to calcul WHAM V , 46. Nei


Following its publication in 2008, the Global Nutritional Index (GNI) which captures the triple burden of malnutrition, has been updated to assess the overall nutritional status and nutritional trends of countries, regions and the world, including both under-nutrition and over-nutrition.The GNI was modeled on the Human Development Index, using geometric means of three normalized indicators: protein-energy malnutrition  from PEM), micronutrient deficiency , and penalizing obesity . GNI (range 0–1) was calculated from 1990–2015 for 186 countries, in seven World Bank income and WHO region groupings.P<0.001), while for high-income countries (0.657 to 0.611) worsened significantly (P<0.001). GNI for American LMIC (0.459 to 0.457), European LMIC (0.571 to 0.575), Eastern Mediterranean LMIC (0.484 to 0.483) and Western Pacific LMIC (0.433 to 0.494) were unchanged. The disaggregation of the GNI showed that in nearly all the seven country groups there was a significant decrease in both PEM and MID  (except in HIC where only PEM dropped), and a significant increase in obesity .World GNI increased from 0.433 to 0.473 as decreased deficits overcompensated for the rise in obesity. GNI for African low- and middle-income countries (LMIC) (median 0.301 to 0.392) and South-East Asian LMIC (0.456 to 0.564) improved significantly (These trends are the result of the reciprocal changes between decreased under-nutrition and increased over-nutrition, which has become a major cause of malnutrition worldwide. We suggest, therefore, that future Sustainable Development Goals should include alongside “zero hunger”–“reduce obesity”. The United Nations has declared 2016–2025 to be the Decade of Action on Nutrition. To enable prioritization for such Action, the state of world malnutrition and its trends requires monitoring information concerning the triple burden of malnutrition–undernourishment (too little energy intake), micronutrient deficiency  and obesity (excess energy intake). In 2015, it was estimated that 795 million people were undernourished globally . The GloThe GNI was modeled on the human development index (HDI) , using tThree updated indicators for the GNI have been used in this report: protein-energy malnutrition (PEM) (age-standardized Disability-Adjusted Life Years (DALY) rates per 100,000 due to PEM) , micronuA unit-free score, using the maximum and minimum values of the three indicators was calculated for each country. The geometric mean of the (1 –dimension- specific- score) was utilized to calculate the GNI (range 0–1), which is to penalize high values of the three indicators, compared with arithmetic mean.The basic formula for GNI has been updated asWhere P = relative score of protein-energy deficiency            M = relative score of micronutrient deficiency            E = relative score of nutritional excessIn which(PEM is the DALY rates lost from protein-energy deficiency)(MID is the DALY rates lost from micronutrient deficiency)We conducted a log transformation for PEM and MID to normalize these scores. The maximum and minimum values for three indicators of the GNI from 1990 to 2015 are shown in An example of GNI calculation is shown in inter-quartile range (IQR).Calculations were made for 186 countries classified into seven groups (n = 11–52) according to WHO and World Bank income categories, separating out high-income countries (HIC) from the six WHO regions for low- and middle-income countries (LMIC) –12. The Friedman Exact test was used for the GNI comparisons between different years, and the Holm-Bonferroni method was used to correct the post hoc pairwise multiple comparisons. Wilcoxon signed rank test was used for the PEM and MID comparisons between 1990 and 2015. Paired student t test was used to compare the prevalence of female obesity between 1990 and 2014.(498.2–784.4) to 286.5 (228.9–356.6) DALYs); MID dropped approximately 20% (903.9 (613.2–1329.2) to 747.9 (511.5–1060.8) DALYs), while obesity increased by nearly 75% (8.6% (7.9–9.4) to 14.9% (13.6–16.1)).Global collective GNI increased from 0.433 in 1990 to 0.473 in 2015 . This imP values among and between years <0.001). This counter-intuitive trend was caused by a dramatic– 50%–increase in obesity from 1990 to 2014 . By contrast, the GNI for African LMIC (n = 45) improved significantly from 0.301 for 1990, to 0.366 for 2005, to 0.392 for 2015 , yet they remained the lowest ranking group. South-East Asian LMIC (n = 11) also improved from 0.456 for 1990 to 0.525 for 2005, and to 0.564 for 2015, .P value = 0.027), then declined to 0.457 for 2015 , without overall improvement , . European LMIC (n = 20) showed the same trend as American LMIC, from 0.571 for 1990 to 0.582 for 2005, to 0.575 for 2015, at borderline significance .The GNI for American LMIC (n = 26) increased from 0.459 for 1990 to 0.469 for 2005 .Eastern Mediterranean LMIC (n = 16), 0.484 for 1990 to 0.483 for 2015 and Western Pacific LMIC (n = 16), 0.433 for 1990 to 0.494 for 2015, remained stable across the MDG timespan  vs. 190.0 (146.4–469.2); MID 1290.0 (1055.1–1408.8) vs. 552.5 (429.0–881.8)), (both P <0.001), while the prevalence of female obesity was only one quarter that of Western Pacific LMIC (11.3±3.6% vs. 46.6±11.6%), (P<0.001). The different GNI patterns in bottom ranking countries showed that both under- and over-nutrition contributed to severe malnutrition.Among the bottom 30 countries for GNI 2015, African LMIC and Western Pacific LMIC showed different patterns in the three dimensions of the GNI. In African LMIC, the median DALY rates due to PEM and MID were much higher than those in Western Pacific LMIC  (except in HIC where only PEM dropped), and a significant increase in obesity . Nevertheless, three patterns could be observed in the regional GNI.The GNI may be disaggregated to show the different trends of its three dimensions as in The first was the pattern of HIC and European LMIC . Both grThe second pattern was represented by African LMIC and South-East Asian LMIC . In 1990The third pattern was shown in the remaining three country groups . In 1990The three dimension–specific scores of GNI by country group for 1990 and 2015 are presented in Substantial improvements in reducing hunger have been observed from 1990 to 2015. According to the FAO, sub-Sahara Africa is the region with the largest absolute improvement in PoU  . Howeverabsolute increase in prevalence of female obesity were all LMIC, and HIC ranked fifth among seven, leaving European LMIC and South-East Asian LMIC behind. These facts suggest that over-nutrition is overtaking undernutrition as the major cause of malnutrition. However, the attenuated increase in obesity in HIC may suggest that some progress is being made in combating this failure in public health action.It is also alarming that obesity prevalence has accelerated in developing countries, but seems to be attenuating in the developed world . In the single value to represent the GNI for one country, particularly for large countries such as China, India or Brazil. In fact, we suggest that a subnational / regional GNI is more appropriate. Such an approach has been adopted in several countries for GBD 2013, and expanded further in GBD 2015 [2) may not be appropriate (too high) for Asian populations. However, it has been decided by WHO expert consultation, to maintain the universal WHO BMI cut-off values for classification, but the values for public health actions for Asians were lowered to 27.5 kg/m2 [P values<0.001). Rather surprisingly, there was no significant negative correlation between obesity and PEM . The data for GNI-1990 followed similar partial correlations to those for GNI-2015.Some limitations to the GNI are noted. Firstly, the validity and calculation of the GNI relies on the quality of data which are mainly provided by individual countries and which may not be uniformly reliable. Secondly, it is an over-generalization to use a GBD 2015 . Thirdly.5 kg/m2 . Lastly,The Global Nutritional Index (GNI) can help international agencies and governments prioritize targets in combating malnutrition. As it is the only index to penalize a country for over-nutrition, the simple of calculation of the GNI and its easy disaggregation, can provide a practical tool to monitor and compare overall nutritional status within and between countries and groups. The GNI should be updated at regular intervals (as for the HDI) to facilitate policy making in linking food security and nutrition  and sustS1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


Antibiotic use in animal farming is one of the main drivers of antibiotic resistance both in animals and in humans. In this paper we propose that one feasible and fair way to address this problem is to tax animal products obtained with the use of antibiotics. We argue that such tax is supported both by (a) deontological arguments, which are based on the duty individuals have to compensate society for the antibiotic resistance to which they are contributing through consumption of animal products obtained with the use of antibiotics; and (b) a cost-benefit analysis of taxing such animal products and of using revenue from the tax to fund alternatives to use of antibiotics in animal farming. Finally, we argue that such a tax would be fair because individuals who consume animal products obtained with the use of antibiotics can be held morally responsible, i.e. blameworthy, for their contribution to antibiotic resistance, in spite of the fact that each individual contribution is imperceptible. It has been estimated that the total annual consumption of antibiotics in animal agriculture ranges from around 63,000 tonnes to around 240,000 tonnes , p. 5, aCampylobacter, Salmonella, Enterococcus, and Escherichia coli  internalizes the costs. Moreover, we argue that the proceeds from these taxes should be used to compensate those harmed by antibiotic resistance or to compensate society more generally, for example by fostering the development of practices that will diminish future antibiotic resistance. More precisely, in “1Introducing a tax on agricultural products produced with the aid of antibiotics is preferable to an outright ban on antibiotic use in animal farming, because producers would probably not be able to afford the cost of transitioning immediately to an antibiotic-free system of meat production; however, revenue generated by taxation could be used to fund this transition. In “In this section we are going to present a deontological reason and reasons based on a cost-benefit analysis in support of a tax on meat produced with the use of antibiotics. The deontological reason is that there is a duty to compensate society for imposing a cost on it, which translates into a duty to internalize the cost, at least as much as is possible and reasonable to do, for a negative externality produced. As for the reasons based on a cost-benefit analysis, one is that a consumption tax would probably discourage people from buying meat produced with the use of antibiotics, thus disincentivising the use of antibiotics in animal farming; a second reason is that the tax would generate revenue that could be used to fund alternatives to antibiotic use in animal farming, thus reducing the impact of antibiotic use on antibiotic resistance. Let’s consider these arguments in order.any person living now or in the future might be harmed  they can choose whether or not to contribute to the social cost. Thus, taxing consumers in order to force them to compensate society for the cost they are knowingly imposing on it seems to be justified on the basis of a moral duty of compensation that individuals anyway have. In the next section we will see how a possible way of compensating society consists in using revenue from the tax to fund alternatives to antibiotic use in animal farming.More importantly for the present purposes, labels referring to both antibiotic use and its consequences in terms of antibiotic resistance would also make people more morally responsible for the consequences of their choice. It is only when people are morally responsible that they can be required to compensate society, and as we shall see in the next section, requiring individuals to compensate society for the harm they are creating could be beneficial to society, depending on how the tax is used. This is a further reason why labelling animal products with reference to antibiotic use is desirable. A simple “no antibiotic” label, or—as proposed by the UK Review on Antimicrobial Resistance , p. 26—ainternalize the cost of antibiotic resistance. Internalization is typically achieved by “taxing negative externalities (…) at a rate that would offset the social cost of the activities that generate the externalities, and then  using the revenues from the tax to fund socially useful projects”  and local food security in developing countries . LivestoArguments for a tax on animal products obtained with the use of antibiotics that are based on a cost-benefit analysis are more straightforward than the deontological ones in that they do not require appealing to, and therefore arguing for, consumers’ moral responsibility for the acceleration of antibiotic resistance. From the perspective of a cost-benefit analysis, a tax would be justified simply if the overall benefits that would result from it outweighed the costs.Now, there are different types of costs that a tax on non antibiotic-free meat would create. A type of cost consists in the fact that people would either have to pay more for meat or consume less of it (we assume for the sake of argument that consuming meat confers at least some benefit on the consumer) or both. This state of affairs would probably also entail an economic cost for producers, if consumption of meat dropped significantly as a consequence of the increase in the costs of meat. However, the benefits that this state of affairs would bring about, in terms of reduced social and individual harms, are potentially significant. Antibiotic resistance represents a high cost not only for people currently living, but also for future generations, who might not avail themselves of antibiotics to treat serious infections, as the examples provided in the introductory section suggest. Considering both present and future generations, the number of people harmed by antibiotic resistance is potentially enormous. By contrast, it is not clear that the costs of reduced meat consumption and production would be comparably large. It is therefore reasonable to claim that the benefits of a tax would outweigh the costs if the tax resulted in a significant reduction of antibiotic use in animal farming and therefore in a significant deceleration of antibiotic resistance . We argue that a tax could have this desirable effect. More in particular, there are two types of benefits that could derive from a tax on non-antibiotic free meat, namely: (a) the likely effects of the tax on consumers’ behaviour, in terms of reduced consumption of meat produced with the use of antibiotics, and (b) the fact that revenue generated through the tax could be used to fund alternatives to antibiotics: supporting such alternatives, besides yielding a benefit in terms of deceleration of antibiotic resistance, would minimize the economic costs for farmers of transitioning to alternative methods of animal husbandry. Let us consider these two types of benefits more in details.As for the former type, it is likely that the tax would discourage people from consuming animal products obtained with the use of antibiotics, which would in turn contribute to the deceleration of antibiotic resistance. Without such tax, the price of antibiotic-free meat would probably be higher than the price of meat produced with the use of antibiotics, because, as we shall see below, alternatives such as vaccines are often more expensive than antibiotics. Thus, without the tax, many consumers would likely be oriented towards consuming meat produced with the use of antibiotics in consideration of its lower price. Although we saw above that a significant proportion of consumers would be willing to pay more for antibiotic-free meat, it is still the case that more consumers would opt for antibiotic-free meat if antibiotic-free meat cost the same or less than meat produced with use of antibiotics. Thus, reducing or, ideally, eliminating the difference in price between the two types of meat through taxation would significantly reduce the consumption of meat produced with the use of antibiotics and therefore reduce consumers’ contribution to antibiotic resistance.Of course, other things being equal, there would still be an overall increase in average price of animal products, since consumers would have to either pay the tax, or purchase the more expensive antibiotic-free meat. Some might think this is a morally significant type of cost of the tax, for example because it makes it more difficult for individuals with low income to be adequately nourished or to enjoy the pleasures of meat-eating. There are two responses to this objection. First, as we suggest below, use of alternatives to antibiotics could be financially supported through the revenue generated through the tax: it might thus be possible to reduce the cost of producing antibiotic-free meat to such an extent that its price on the market would not only be lower than the price of the taxed meat, but perhaps even lower than the current price of meat obtained with the use of antibiotics. Admittedly, one might reply here that it is unlikely that the revenue generated through the tax would be so large as to allow to incentivize alternatives to antibiotics to such an extent that antibiotic-free meat would be priced less than the meat currently on the market. However—and this is the second response to the objection—even if meat will end up being overall more expensive as a consequence of the introduction of the tax, to the extent that the tax would have costs for (prospective) meat eaters, it is doubtful that these individuals would have legitimate grounds for complaint. After all, in the absence of the tax and therefore of incentives to consume antibiotic-free meat, there would be increased costs for others in the form of increased antibiotic resistance. As the deontological arguments discussed above suggest, it seems preferable that the costs of meat eating are borne by those who choose to engage in this practice than that they are borne by others.The second type of benefit of a Pigovian tax on consumption of animal products obtained with the use of antibiotics would occur if, as we suggest in “Along similar lines, and considering the cost in terms of antibiotic resistance of antibiotic consumption, some have argued that antibiotics sold for use in humans should be taxed , and thaIn the next two sections we will explain in more detail how the revenue generated through taxation could be used to fund alternative methods of animal husbandry that do not require antibiotic use. Granted, there might be other good uses of the revenue generated through the tax, perhaps uses which have nothing to do with funding alternatives to antibiotics. But using the revenue to fund alternatives to antibiotic use would strengthen the justification for such a tax, making it more likely to be accepted by consumers and population at large and therefore more politically palatable.In some countries antibiotics are currently used, officially, only for prophylactic or therapeutic purposes. This is the case, for example, in the EU countries, where GPAs have been banned since 2006. However, even in these countries the use of antibiotics continues to be significant , p. 17 IOne alternative is the use of vaccines to prevent the infections that would otherwise have to be prevented or treated with antibiotics. According to the WHO, “sustainable husbandry practices, including the use of vaccines, can reduce infection rates and dependence on antibiotics, as well as the risk that antibiotic resistant organisms will develop and spread through the food chain” , p. 10.Regulation of stocking density could drastically reduce the need to use AB. Barn hygiene status, including air quality, the moisture of litter substrate, and pathogen load are factors that are very closely linked to stocking density. .Another strategy to prevent infections is that of using nutritional supplements instead of antibiotics: for example, zinc oxide is commonly used in pigs , probiotA fourth alternative strategy is that of breeding animals with better immunity to common diseases, which would reduce the need for therapeutic use of antibiotics. There is a large body of literature on attempts to breed for disease resistance in various species . Especiacould be used to subsidize the transition to a system of meat production characterized by better infection control, better hygiene, reduced stock density, nutritional supplement instead of antibiotics, breeding of animals with better immunity to common diseases, and a wider use of vaccines. In other words, revenue from the consumption tax could be used to fund the transition to a system in which the need for prophylactic or therapeutic use of antibiotics is strongly reduced. The cost-benefit analysis we have discussed in the previous section does support this type of use of the revenue generated through the consumption tax, and, as said above, using the revenue to fund alternatives to antibiotic use would make the tax more likely to be accepted and more palatable. In this way, the negative externality represented by antibiotic resistance would in the long run be reduced as antibiotics are replaced by alternative methods.As is easy to imagine, however, most of these alternatives, as well as the transition to a system that employs these alternatives, do have a cost, and often a higher cost for producers than simply using antibiotics. For example, vaccines are currently very expensive compared to antibiotics as a prophylactic measure , p. 34. The final aim of this type of consumption tax is the transition to a system in which the source of the tax revenue—namely the use of antibiotics in animal husbandry—is progressively eliminated. In order to favour a complete transition, then, other sources of subsidization are necessary. In particular, states should subsidize alternative methods of animal husbandry that do not require the use of antibiotics, independently of the revenue generated by the proposed tax.Part of the reason why antibiotic consumption remained high in EU after the 2006 ban on GPAs was the lack of clarity and of transparency regarding what represents therapeutic and non-therapeutic use , p. 17. Whatever explains the high antibiotic use in animal farming in the EU, we know for sure that antibiotics are currently used for growth promoting purposes in the US and in many other countries. Interestingly, the use of GPAs in animals remains high in spite of the emerging evidence suggesting that “antibiotics used as growth promoters do not have as much economic benefit as previously thought, particularly in countries with advanced farming techniques” , p. 15. where advanced breeding and husbandry techniques are in use would not have significant economic consequences for meat producers.It is true that previous studies had found increases in body weight of poultry up to 11% (with penicillin) e.g. ; howeverHowever, the economic consequences of eliminating GPAs would probably be greater in other contexts, where advanced techniques are less accessible and therefore less used. Studies have shown that while the growth response to GPAs is reduced in optimized production systems , p. 15, It is worth noting that the factors that account for an optimized production system are typically less developed in lower income countries , p. 5. Gcontribute towards reducing dependence on antibiotics in animal farming.We acknowledge, however, that the revenue generated through the tax would probably not be so large as to allow to fully (or perhaps even significantly) fund the transition to a production system characterized by reduced dependence on GPAs, as well as by reduced dependence on antibiotics used for prophylactic or therapeutic purposes. Therefore, independent forms of subsidization could (and should) be provided by states, including subsidization of alternatives to GPAs in poor countries. Our claim is simply that revenue from the tax could at least In this section we are going to address a possible objection to our arguments in favour of a tax on animal products obtained with the use of antibiotics. The objection is that each individual contribution to antibiotic resistance through individual meat consumption is imperceptible; accordingly, individuals are not individually causally responsible for antibiotic resistance. Because her contribution makes only an imperceptible difference, i.e. it is causally irrelevant,—so the objection might go—an individual does not have an individual moral obligation to abstain from consuming meat produced with the use of antibiotics. Single individuals should therefore not be required to compensate society for a harm for which they cannot be held morally and causally responsible. In contrast, we argue that the tax would be fair despite the imperceptibility of individual contributions to antibiotic resistance through individual consumption of meat.collectively, and not individually, responsible for antibiotic resistance caused by such use: only when considered collectively do their purchases support the practice of feeding antibiotics to animals. Any single purchase would probably not make a relevant difference to the total amount of antibiotics used in animal farming and therefore to antibiotic resistance. Broadly speaking, to be responsible for a certain negative outcome, such as a negative externality, means, in the retrospective sense of responsibility, to be blameworthy for the outcome and, in the prospective sense of responsibility, to have a moral obligation to either prevent that outcome or to make up for it. As we have seen above, in the case of consumption of meat produced with the use of antibiotics, “making up” means compensating those affected by the negative externality of antibiotic use. When there is an obligation to make up for a certain negative outcome, retrospective and prospective responsibilities are logically and morally connected, in the following sense: from a logical point of view, the moral (prospective) responsibility to “make up” for a certain outcome presupposes the retrospective responsibility for that outcome (otherwise it would not be a case of “making up”); and, from a moral point of view, being blameworthy for something generates a prima facie moral reason to make up for it. The deontological argument for a tax on antibiotic resistance we have presented above is based on this moral claim. However, we can see now how that deontological argument, by itself, only establishes collective duties, and not individual duties. Let’s see in more details why.Let us start by acknowledging the fact that people who buy meat produced with the use of antibiotics are As said above, the fact that the responsibility in question is collective means that any single purchase of meat is unlikely to make a significant difference to the amount of antibiotics used in animal farming, and therefore to antibiotic resistance. It is often held that “ought” implies “can”: someone cannot have the obligation to bring about or to prevent a certain outcome if she does not have the causal power to realise or to prevent it. And in fact it has been argued that in similar cases, i.e. when one’s contribution to a negative externality is imperceptible and therefore does not have any causal significance (such as for example in the case of one’s contribution to air pollution through driving on Sundays just for fun), such contribution also lacks moral significance, and therefore one does not have a moral obligation to refrain from contributing to the externality—although states might have the right or the duty to intervene to prevent or discourage individual behaviours that contribute to the externality . Lack ofNow, the view that individuals are not blameworthy for a negative externality caused by a collective and to which they make an imperceptible contribution can be challenged. Accordingly, we can also challenge the view that such individuals do not have the related prospective moral obligation to contribute to the internalization of a collective negative externality or to compensate society for it.relevant difference to the amount of antibiotics used in factory farming, i.e. a difference that would have significant consequences in terms of acceleration of antibiotic resistance. Whether this objection works is largely an empirical issue: one could reply that, as a matter of fact, any small increase in the number of animals brought into existence and raised in contemporary factory farming does increase the amount of antibiotic used in animal farming to an extent that it does have significant consequences in terms of antibiotic resistance. As said above, this is an empirical issue which we are happy to leave open. For those who are sceptical about the application of Kagan’s argument to the case of antibiotic use, we provide here a different, and non-consequentialist, argument for why individuals might still be considered individually blameworthy for their contribution to antibiotic resistance through consumption of meat, even assuming that their contribution to antibiotic use is imperceptible. The argument is the following.Let us first examine one possible argument against such views which, although appealing, seems to turn on an empirical issue that we are happy to leave open, and which therefore we will not take as a conclusive argument to the effect that an individual is blameworthy for a negative externality caused by a collective (those interested only in the argument we propose can skip the rest of this paragraph and jump directly to the next). Following Shelly Kagan’s argument against purchasing meat , one migaggregate actions of individuals, the collective is to be identified not as an independent “super-entity”—as might be the case when we talk, for example, of a state or of a corporation. Such “super-entities” are characterized by internal constitutions or codified decision procedures that, at least on some views, qualify them as moral agents, and in virtue of which they might be attributed responsibility independently of attribution of responsibility to their members  produced through the ers e.g. . The typers e.g. . The profair share of the burdens entailed by the collective responsibility, both in a retrospective sense—i.e. they should be considered partially blameworthy for their contributory behaviour, even if their impact is imperceptible-, and in a prospective sense—i.e. they should do their fair share to prevent the outcome, or to make up for it. Accordingly, we can say that individuals are not responsible for the actual impact of their contributions to antibiotic resistance, but they are responsible for the act itself of contributing. Such an act is rendered morally relevant by the fact that it violates the requirement to make one’s fair contribution to fulfilling the collective obligation to prevent antibiotic resistance, rather than by consequentialist considerations about its actual impact on the collective effect.We can answer such questions by shifting our attention from consequentialist considerations about the actual impact each individual has on the collective effect to considerations of fairness, and more precisely of fairness in the distribution of the burdens entailed by collective responsibility. Fairness is an important value that, in general, we do and should promote, and which should therefore play a role also in defining the relationship between collective and individual responsibility. Thus, it is reasonable to assume that individual members of a collective that is morally responsible for a negative outcome ought to take on themselves a outcomes, individual members of the collective, even if they do not have the causal power to affect such outcomes, can be held responsible for their contributory actions  an accumulation of X-ing sets back other people’s welfare interests, and if (2) the harm is serious enough such that its prevention warrants limiting the liberty to X (either by regulating or prohibiting X-ing), then (3) everyone should carry their fair share of the burden (…), and (4) everyone who Xs is responsible for a share of the harm done , p. 197Distributing fairly the burdens of the collective responsibility of aggregative collectives is consistent with what Gerald Gaus called the “Public Harm Principle”, according to which Thus, any individual who purchases animal products obtained with the use of antibiotics is morally responsible for failing to do her fair share to avoid the negative externality of antibiotic resistance: the imperceptibility of her contribution to the collective effect does not mean that she is not blameworthy. But if an individual is blameworthy for her contribution to a negative collective externality, then, in virtue of the moral connection between retrospective and prospective moral responsibility, she has a moral obligation to make up for her contribution. Accordingly, a tax could be seen as a way of ensuring that each individual who, in violation of the demands of fairness, consumes meat produced with the use of antibiotics fulfils her moral obligation to contribute to compensating society for the externalities associated with antibiotic use.collectively morally responsible (i.e. blameworthy) for the acceleration of antibiotic resistance caused by antibiotic use in animal farming, but also (2) individually morally responsible for their contribution to such outcome, even if each individual act of consuming animal products makes a very small, imperceptible, difference to the development antibiotic resistance. Such individual responsibility implies that each individual has a duty to “make up” for the contribution for which she is morally responsible, i.e. to contribute to the internalization of the negative externality of antibiotic resistance and to compensating society for the harm that such negative externality creates. While these represent deontological considerations in favour of a tax on consumption of meat produced with the use of antibiotics, there are also considerations based on a cost-benefit analysis in support of such a tax: the benefits of the tax could outweigh the costs because (a) the tax would discourage people from consuming meat produced with the use of antibiotics, thus contributing to slowing down antibiotic resistance; and (b) because it would generate revenue that could be used to support alternatives to the use of antibiotics in animal husbandry for prophylactic, therapeutic, and growth promoting purposes, thus reducing the economic cost for producers of transitioning to an antibiotic-free production system and, consequently, contributing to reducing antibiotic resistance caused by use of antibiotics in animal farming. Thus, there are both deontological arguments and arguments based on a cost-benefit analysis for taxing animal products obtained with the use of antibiotics.Use and abuse of antibiotics in animal farming is one of the main causes of the acceleration of antibiotic resistance. Once informed about the consequences of antibiotic use in terms of antibiotic resistance, individuals who choose to consume animal products which they know have been produced with the use of antibiotics are (1)