Objectives. This study collected and evaluated data on the costs of outpatient medical care and family burden associated with osteoporosis-related fracture rehabilitation following hospital discharge in China. Materials and Methods. Data were collected using a patient questionnaire from osteoporosis-related fracture patients (N = 123) who aged 50 years and older who were discharged between January 2011 and January 2013 from 3 large hospitals in China. The survey captured posthospital discharge direct medical costs, indirect medical costs, lost work time for caregivers, and patient ambulatory status. Results. Hip fracture was the most frequent fracture site (62.6%), followed by vertebral fracture (34.2%). The mean direct medical care costs per patient totaled 3,910¥, while mean indirect medical costs totaled 743¥. Lost work time for unpaid family caregivers was 16.4 days, resulting in an average lost income of 3,233¥. The average posthospital direct medical cost, indirect medical cost, and caregiver lost income associated with a fracture patient totaled 7,886¥. Patients' ambulatory status was negatively impacted following fracture. Conclusions. Significant time and cost of care are placed on patients and caregivers during rehabilitation after discharge for osteoporotic fracture. It is important to evaluate the role and responsibility for creating the growing and inequitable burden placed on patients and caregivers following osteoporotic fracture. Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk . BecauseThe prevalence of osteoporosis increases with age. In China, the prevalence of osteoporosis in the general population has been estimated at 7.0% , which aAnother significant consequence of osteoporosis-related fracture is the economic and social burden on the health care system and on society . OsteopoThe overall prevalence of osteoporosis, as well as the clinical and economic burden, may grow substantially due to China's rapidly aging population. By 2030, the population aging 65 and older is expected to double to more than 238 million . ConversEstimates of the national total posthospital direct medical and nonmedical costs and indirect nonmedical costs are quite limited for China. Costs per hip fracture in China have been reported to range between 22,088¥  and 34,202¥ , while average costs per vertebral fracture and nonhip/nonvertebral fracture were estimated to be 19,239¥ US $3,175) and 22,034¥ , respectively –15. The 5 and 22,New research is needed on the full clinical and economic impact of osteoporosis in China to raise the disease awareness and to guide future health policy-making for reducing the potential increase of inequity and burden of osteoporosis in the country. The China public health insurance system now covers 95% of the population due to efforts to establish universal coverage under three primary government programs: Urban Employee Basic Medical Insurance (UEBMI), Urban Resident Basic Medical Insurance (URBMI), and New Rural Cooperative Medical Scheme (NRCMS). At this time, UEBMI covers inpatient costs and most outpatient costs, and URBMI and RNCMS only cover inpatient costs. However, there are limitations in the coverage of this insurance, potentially placing excess burden of costs and care on the patient and family.Therefore, the objective of this study was to obtain and evaluate new data on the economic and social burden of osteoporotic fractures in China by conducting a survey of fracture patients between January 2011 and January 2013 of posthospital discharge direct and indirect medical care costs, indirect costs on families, and patients' disability status.A retrospective survey was administered by doctors using a questionnaire completed by their patients and/or caregivers about postdischarge care. The questionnaire collected data on demographics; ambulatory status; direct medical care services and costs ; pharmaceutical drugs; rehabilitation care; nursing care; and devices and supplies); indirect medical services and costs ; disability (before fracture and after fracture); and lost work time for caregivers. Caregivers were defined as family members of the patient for whom they provided care.Age of 50 years or above at hospital admission;T-score 2.5 standard deviations or more below the young adult peak mean);Confirmed diagnosis of osteoporosis by physician or diagnostic guidelines ;Any significant comorbidities including stroke, dementia, and incurable cancers that have significant impact on health resource utilization were excluded;Exclusion of patients with fractures of skull, facial, finger, and toe bones;Discharge between January 1, 2011, and January 31, 2013.The survey was conducted by a panel of 6 experienced physicians in the osteoporosis-related field in three Tier 3 comprehensive hospitals representing eastern, middle, and western China. The interviews were performed between November 15, 2012 and March 31, 2013.Potential patients for inclusion in the survey were identified after hospitalization for osteoporotic fracture using the following criteria:Descriptive statistical methods were used to produce a profile of patients' baseline characteristics, fracture sites, costs, and ambulatory status for osteoporotic fracture patients. McNemar's test was used to compare patient mobility status before fracture and after hospital discharge.The median number of days between fracture and survey interview was 149, with a minimum of 6 days and a maximum of 728 days. About 55% of responses were 3 to 6 months from fracture, and about 39% were between 6 and 12 months. A total of 189 patients met the inclusion criteria and were called by doctors; 172 patients answered the calls and responded for a response rate of 91.0%. A total of 123 questionnaires were completed, validated, and used for analysis for an effective rate of 71.5%.The discharge distribution for the 123 patients across the three hospitals was Beijing hospital (42.3%), Wuhan hospital (24.4%), and the Chongqing hospital (33.3%) . PatientAmong the 123 patients, all received fracture-related surgery, and most patients (91.1%) had sustained only one fracture, whereas 10 (8.1%) patients had sustained 2 fractures and only 1 (0.8%) patient had sustained 3 fractures . Hip fraThe average number of outpatient visits from discharge until interview was 1.7 per patient. While most patients (78.9%) had between 1 to 3 outpatient postdischarge visits, 4% of patients had more than 3 follow-up visits and 17.1% of patients had no follow-up visits.The costs of outpatient direct medical and indirect medical care are provided in Reported work time lost for caregivers to care for family members for recovery at home was the largest portion of nonhospital costs. The mean number of lost workdays was 16.4 days and varied widely between the three districts: It was the greatest in Wuhan , followed by Chongqing , and Beijing  . The meaThe overall estimate for total average nonhospital costs per patient was 7,886¥, which is the sum of nonhospital direct medical costs , indirect medical costs (743¥), and average caregiver lost income  for the 123 patients in the sample.P < 0.001). Of the 123 patients, 12% were able to walk with assistance before their fracture, but after fracture 27% required assistance with walking (P < 0.001). Only 1 patient was confined to a wheelchair before the fracture, but, after fracture, there were 7 patients confined to wheelchairs (P = 0.014), whereas none were confined to the house (bedridden) due to immobility before fracture, and 4 patients were confined to the house after fracture.The burden of osteoporosis is expected to increase in China due to the rapidly aging population. Some limited data exist regarding inpatient costs of fractures in China , 20–23. The burden on families appears to be substantial from these findings. Possible reasons for this high family burden include a lack of formal rehabilitation facilities , currentOur study provides some insights on costs following discharge from the hospital. We found that families are bearing a substantial burden which consists of nursing services, devices and supplies, transportation, and nutrition. However, the amount of work time and income lost for caregivers was more than direct and indirect medical care costs combined. The burden may fall unevenly across families, thus resulting in extreme hardships and social inequities. The study surveys recent fracture patients and is comprehensive in posthospital direct and indirect medical costs, as well as nonmedical costs. Some important limitations are the inclusion of geographic areas that may not be fully representative of all China, a small sample size relative to the national population, and patients' memory recall that may be diminished or less accurate, especially for those with a longer gap between the hospital discharge and interview date. In addition, this analysis was not able to validate the medical encounters or the costs. Also, we could not ascertain causality of osteoporosis and hip fractures, which mostly occur following a fall . As manyNevertheless, this study provides important new information and insights about the additional burden fracture and potential social and family inequities after hospital discharge. This study may serve as an important guide for a larger, nationally based survey.The expected growth in osteoporosis and osteoporotic fractures will impose a growing clinical, economic, and humanistic burden on many developing and nondeveloping countries in the world. However, China, a country with recently expanding economic advantages and unique population policy, has a far more complex situation. As the majority of postfracture osteoporotic patients lack health insurance coverage for rehabilitation care and also relatively few community rehabilitation facilities, rehabilitation is mostly conducted at home where the typical family has fewer caregivers than caregiving families in other countries. The current family burden in China may grow even faster as the shifts in demographics move closer toward an increasing older population and declining working-age population over the coming decades. With the rising incomes, even larger indirect costs may be incurred due to lost workdays by family members/caregivers. Further research is needed to better quantify the full clinical, economic, and social burden and to guide resource allocations to improve outcomes and reduce inequities across China.


In the continental US, four terrestrial mammalian species are reservoirs for seven antigenic rabies virus variants. Cross species transmission (CST) occurs when a rabies virus variant causes disease in non-reservoir species.This study analyzed national surveillance data for rabies in terrestrial mammals. The CST rate was defined as: number of rabid non-reservoir animals/number of rabid reservoir animals. CST rates were analyzed for trend. Clusters of high CST rate counties were evaluated using space-time scanning statistics.The number of counties reporting a raccoon variant CST rate >1.0 increased from 75 in 1992 to 187 in 2011; counties with skunk variant CST rates >1.0 remained unchanged during the same period. As of 2011, for every rabid raccoon reported within the raccoon variant region, there were 0.73 cases of this variant reported in non-reservoir animals. Skunks were the most common non-reservoir animal reported with the raccoon rabies variant. Domestic animals were the most common non-reservoir animal diagnosed with a skunk rabies virus variant . Cross species transmission rates increased fastest among domestic animals.Cross species transmission of rabies virus variants into non-reservoir animals increases the risk of human exposures and threatens current advances toward rabies control. Cross species transmission in raccoon rabies enzootic regions increased dramatically during the study period. Pet owners should vaccinate their dogs and cats to ensure against CST, particularly in regions with active foci of rabies circulation. Clusters of high CST activity represent areas for further study to better understand interspecies disease transmission dynamics. Each CST event has the potential to result in a rabies virus adapted for sustained transmission in a new species; therefore further understanding of the dynamics of CST may help in early detection or prevention of the emergence of new terrestrial rabies virus variants. Rabies has one of the highest known infectious disease case fatality rates, with an estimated 55,000 deaths per year occurring primarily in developing countries where canine rabies has not been controlled In 1977, translocation of raccoons from Florida to West Virginia for hunting purposes ignited a rabies epizootic in the local rabies-naïve raccoon populations Carnivora and Chiroptera are responsible for enzootic circulation of rabies virus. These include: foxes (Vulpes lagopus and Urocyon cinereoargenteus), raccoons (Procyon lotor), skunks (Mephitis spp), and bats (multiple species) In the continental US, wildlife species in the orders Despite the apparent host adaptation and affinity displayed by rabies virus, all mammals are susceptible to this disease. Cross species transmission (CST) occurs when a rabies virus variant adapted to transmission in a specific reservoir animal is transmitted to a non-reservoir animal. Cross species transmission rarely results in successful propagation within a non-reservoir population, referred to as a host shift event Rabies in animals is a nationally notifiable condition in the U.S. Nearly all animals tested for rabies are submitted due to a bite or other concerning interaction with a human or domestic animal. A small proportion of animals  are reported through enhanced rabies surveillance involving wildlife that have not exposed humans or domestic animals P. lotor), skunks , foxes , domestic animals (cats and dogs), cattle, and other terrestrial mammals .Reports of all rabid terrestrial mammals within the continental US were compiled from 1990–2011. Rabid bats and humans were excluded from the study, as were data from Alaska, Hawaii, and Puerto Rico. States where only bat rabies virus variants have been reported were also excluded from the analysis . Rabies virus variant typing was not available for the majority of reported rabid animals. However, the variant associated with a terrestrial rabies case was assumed based on the geographic location where the animal was reported (e.g. a rabid raccoon in Texas was assumed to be infected with a skunk rabies virus variant). This assumption is based on previously published reports that have found that nearly all rabid terrestrial mammals were infected with the terrestrial rabies variant associated with the geographic region in which the case was reported Counties that reported fewer than three rabid reservoir animals during a 5-year period were excluded from analysis to control for jurisdictions with low surveillance activity. An epizootic of a Mexican canine rabies virus variant occurred in coyotes in southern Texas counties from 1990–1997, therefore rabid coyotes in select southern Texas counties in this time frame were excluded from analysis The reported rabies CST rate was defined as the rabid non-reservoir animals/rabid reservoir animals. These rates were calculated at the county and HHS regional level, annually and in 5-year aggregate time periods. Annual rates of animal submissions for rabies testing were calculated per 100,000 human population, 2007–2011; the only years when reliable submission data were available. To evaluate the impact of bias, a linear regression model was used to evaluate potential relationship between total submissions of reservoir animals for rabies diagnosis on the CST rate. All comparisons were evaluated at α = 0.05.Trends in CST rates from 1990–2011 were evaluated using a Monte Carlo permutation model, which detected up to three time intervals where the trend in CST changed significantly A total of 67,058 rabid raccoons and 30,876 other animals were reported with raccoon rabies virus variant from 1990–2011. The CST rate ranged from 0.31 in 1990 to a high of 0.73 in 2011, representing a 138% overall increase . Three tA total of 19,247 rabid skunks and 3,778 other animals were reported from skunk rabies enzootic regions from 1990–2011. Overall, there was a 40.3% decrease in the CST rate of skunk rabies from 1990–2011 , with an average decrease of 2.0% (95% CI: −3.6–−0.4) per year .DomesticReported CST of raccoon rabies into skunks was 18.7 times more frequent in comparison to skunk rabies transmitted into raccoons (95% CI 14.2–24.5) . TransmiDuring 1992–2011, 741 raccoon variant counties met the criteria for inclusion and reported an average of 6.2 rabid terrestrial animals each year. The CST rate doubled during the study period to 0.62 non-reservoir animals diagnosed for every rabid raccoon for time period 2007–2011.During 2007–2011, 187 of 592 (31.6%) counties reported a rate ≥1.0, and increase from 75 counties during 1992–1996 . From 19During 1992–2011, 754 skunk variant counties met the criteria for inclusion and reported an average of 1.4 rabid terrestrial animals each year. During 1992–1996, 0.22 other terrestrial animals were diagnosed rabid for every reported rabid skunk, and 35 of 392 (8.9%) counties reported a CST rate ≥1.0. During 2007–2011, the CST rate fell to 0.18 and only 20 of 324 (6.2%) counties reported a CST rate ≥1.0 .In the Southeastern United States, the skunk rabies CST rate trend increased 13.6% per year from 2001–2011 (95% CI 1.9–26.7) . In the Three significant clusters of rabid non-reservoir animals were identified controlling for the number of reported rabid raccoons in the space-time scan statistic at a MSCS of 50% . The twoPresence of variant typing data were examined for all 15,359 animals analyzed in this study between 2007–2011 . The stuData on submission of rabies suspect animals for testing were available for 2007–2011. During this time period, 53,877 raccoons and 137,517 other terrestrial animals were submitted for rabies diagnosis in the raccoon variant region . The average annual number of submissions for rabies diagnosis was 57.9 per 100,000 persons residing in the raccoon variant region. From 2007–2011, 7,485 skunks and 45,530 other terrestrial animals were submitted for diagnosis from the skunk variant regions . The average annual number of submissions for rabies diagnosis was 67.9 per 100,000 persons residing in the skunk variant region.A linear regression model revealed a relationship between CST and submission of raccoons for rabies diagnosis in the raccoon variant region (P = 0.012) . HoweverInterspecies rabies transmission can be important in the process of virus adaptation and perpetuation in new hosts The rate of rabies virus transmission to non-reservoir animals was dynamic over the study period. Perhaps the most dramatic trend observed was the increase in CST of the raccoon rabies variant in the northeastern United States. This increase is most likely explained by the epizootic spread of this rabies virus variant into a previously rabies naïve region. The raccoon rabies variant did not expand into the Northeastern-Atlantic states until the mid-1980's, largely reaching its full northern distribution by 2000 The apparent relationship between the CST rate and length of enzootic status, suggests that the increases in CST in the mid-Atlantic and Northeastern states might be expected to stabilize over time. However, interpretation of this apparent association is difficult, as many potential confounding factors are not collected during routine rabies surveillance efforts. Regional differences in animal population densities and species diversity have the potential to alter disease transmission dynamics. Therefore, ecological studies focusing on inter and intra-species contact rates may help explain the differences in the observed CST trends. Climate change, specifically drought, may also affect CST rates; regions experiencing drought may drive animal populations together as water sources become scarce. Likewise, changes in land use characteristics, such as deforestation or human encroachment into wildlife habitats may also result in changes in animal behaviors. Studies focusing on changing environmental features may help to explain regional differences in rabies transmission dynamics. This analysis describes general trends observed over the past 20 years and is meant to serve as a guide for more focused studies, as described above, to aid in the control of rabies in wildlife reservoir species.Raccoons were four times more likely to transmit rabies to other species when compared to skunks. All animal groups, with the exception of cattle, were more likely to be infected with the raccoon variant. Host and environmental factors which facilitate CST are largely unexplored. However, certain behavioral and anthropogenic factors are well described in skunks and raccoons which may explain some of the differences observed in the CST rates of these two species.Transmission of diseases such as rabies that require direct contact are heavily influenced by the density of susceptible animals and their contact rate with infected animals Factors other than population density, such as predation or interspecies interactions at communal resources, play integral roles in disease transmission dynamics Cross species transmission of rabies among terrestrial animals is a complex interaction that likely depends on animal susceptibility to the virus, animal population densities, animal behavior, niche overlap, landscape characteristics, human population distribution, environmental conditions, and other factors. These multivariate associations can be difficult to evaluate over large geographic areas, even within a single virus variant region. Ecological studies of interspecies rabies transmission should focus on the geographic clusters of high CST rates to maximize detection of CST-related factors. Spatial models should be developed to evaluate the association of these factors with CST rates and identify significant factors that might provide insights which could be used to better understand local epidemiology of rabies and possibly targeted for interventions.Classically, rabies virus variants have been associated with a single species which maintains the variant in nature by conspecific transmission. Cross species transmission of the raccoon variant was unexpectedly high, and the most commonly reported non-reservoir species were skunks. There are multiple theories for increased transmission of raccoon variant into skunks including aforementioned behavioral and ecological patterns that would cause increased interactions between the species One potential theory for the unusually high rate of raccoon variant rabies diagnosed in skunks is that this virus has already undergone a host shift into the skunk population. This would artificially inflate the raccoon variant CST rates observed in this study Nationally, rabies virus variant typing is prioritized among non-reservoir animals or locations where there is increased concern for new variant introduction. Variant typing is an added cost and burden for public health programs, and has no direct treatment impact for the human or domestic animal that was exposed. Therefore, rabies virus variant typing is performed on only a subset of samples, nationally. A critical assumption of this study was that all terrestrial animals were infected with the predicted rabies virus variant based on geographic epidemiology. The validity of this assumption is supported by the finding that nearly all variant typed animals were infected with the predicted study-defined variant, as has been reported in the literature Public health testing of animals for rabies is directly related to the animal's probability of interacting with people or their companion animals. Differing state and local health department policies may also impact and bias animal submissions. Raccoons are often found at high population densities close to human habitats, which could potentially account for higher rates of submission for rabies testing Rabies virus host shift events could threaten the rabies prevention success achieved in the past several decades in the United States. Traditionally, host shift events have been detected through astute local health programs. Given the consequences of delayed host shift recognition, new surveillance methods must be developed to rapidly identify potential high risk areas. This study provides two such methods for further exploration; monitoring of CST trends and evaluation of high CST areas. The development of the unique CST analysis has provided epidemiologic support to the theory of independent skunk to skunk transmission of the raccoon rabies virus variant. The development of algorithms to analyze areas at high risk for CST could be incorporated into standard reporting systems to raise awareness for host shift events among relevant health departments, thereby improving early detection of such events. Dogs and cats may have frequent opportunities for encounters with rabid animals and remain a critical barrier to human rabies exposure. The finding that CST rates increased in cats and dogs is a reminder of the importance of maintaining current vaccination status to protect animal health and prevent human exposure. Currently available animal rabies vaccines are effective against all known rabies virus variants in North America. The higher CST rate in the raccoon variant region highlights the burden of rabies in this region and increased risk even when encountering non-reservoir species. Each CST event has the potential to result in the establishment of a new reservoir species; therefore advancing our understanding of the dynamics of CST may help to prevent the emergence of new terrestrial rabies reservoir species.


Onchocerciasis (river blindness) is a parasitic disease transmitted by blackflies. Symptoms include severe itching, skin lesions, and vision impairment including blindness. More than 99% of all cases are concentrated in sub-Saharan Africa. Fortunately, vector control and community-directed treatment with ivermectin have significantly decreased morbidity, and the treatment goal is shifting from control to elimination in Africa.We estimated financial resources and societal opportunity costs associated with scaling up community-directed treatment with ivermectin and implementing surveillance and response systems in endemic African regions for alternative treatment goals—control, elimination, and eradication. We used a micro-costing approach that allows adjustment for time-variant resource utilization and for the heterogeneity in the demographic, epidemiological, and political situation.The elimination and eradication scenarios, which include scaling up treatments to hypo-endemic and operationally challenging areas at the latest by 2021 and implementing intensive surveillance, would allow savings of $1.5 billion and $1.6 billion over 2013–2045 as compared to the control scenario. Although the elimination and eradication scenarios would require higher surveillance costs ($215 million and $242 million) than the control scenario ($47 million), intensive surveillance would enable treatments to be safely stopped earlier, thereby saving unnecessary costs for prolonged treatments as in the control scenario lacking such surveillance and response systems.The elimination and eradication of onchocerciasis are predicted to allow substantial cost-savings in the long run. To realize cost-savings, policymakers should keep empowering community volunteers, and pharmaceutical companies would need to continue drug donation. To sustain high surveillance costs required for elimination and eradication, endemic countries would need to enhance their domestic funding capacity. Societal and political will would be critical to sustaining all of these efforts in the long term. River blindness (onchocerciasis) is a parasitic disease transmitted by blackflies. Symptoms include severe itching, skin lesions, and vision impairment including blindness. More than 99% of all cases are concentrated in sub-Saharan Africa. Fortunately, vector control and community-directed treatment with ivermectin have significantly decreased morbidity, and the treatment goal is shifting from control to elimination in Africa. To inform policymakers’ and donors’ decisions, we estimated financial resources and societal opportunity costs associated with alternative treatment goals—control, elimination, and eradication. We found that rapid scale-up of ivermectin treatment for elimination and eradication would result in substantial cost-savings in the long term as compared to staying in a control mode, because regular active surveillance would allow treatments to end earlier, thereby saving the economic costs of community volunteers and donated ivermectin. To realize cost-savings, policymakers should keep empowering community volunteers, and pharmaceutical companies would need to continue drug donation. To sustain high surveillance costs required for elimination and eradication, endemic countries would need to enhance their domestic funding capacity. Societal and political will would be critical to sustaining all of these efforts. The treatment goal for onchocerciasis (river blindness) has shifted from control to elimination as shown by the World Health Organization’s (WHO’s) roadmap for neglected tropical diseases (NTDs) and the London Declaration on NTDs in 2012 . The disOnchocerciasis elimination and subsequent eradication will generate health benefits by reducing the incidence of infection to zero, first in a defined area and then globally. These benefits would be higher than those of staying in a control mode that keeps disease prevalence at a locally acceptable level. In addition to epidemiological evidence, national and global policymakers must consider economic, social, and political aspects when deciding whether to invest in elimination in settings with limited resources and competing health priorities. To assess these broad aspects, a working group at the Ernst Strüngmann Forum suggested developing and analyzing eradication/elimination investment cases . TediosiTo reduce disease prevalence to a locally acceptable level , all enTo reduce the incidence of infection to zero in a defined area, all endemic African countries except those with epidemiological and political challenges implement annual or biannual CDTi, and conduct regular active epidemiological and entomological surveillance to evaluate epidemiological trends, to decide a proper time to stop CDTi, and to detect and respond to possible recrudescence.To reduce the incidence of infection to zero in Africa, which would lead to global eradication, all endemic African countries implement not only annual or biannual CDTi but also locally tailored treatment strategies to deliver sustainable treatments to areas with operational challenges, and implement regular active epidemiological and entomological surveillance to evaluate epidemiological trends, to decide a proper time to stop CDTi, and to detect and respond to possible recrudescence.We estimated financial resources and societal opportunity costs for endemic African countries  associatWe estimated financial costs to predict how much the governments of endemic countries and donors would have to pay for implementing the required interventions for alternative treatment goals of control, elimination, and eradication, and economic costs to assess societal opportunity costs of donated services and goods. The time horizon of the analysis was from 2013 to 2045, based on the predicted timeline for reaching the post-elimination phase in endemic African regions .There are different methods for estimating health intervention costs, ranging from micro-costing (bottom-up approach) to gross-costing (top-down approach) . We usedWe defined the key activities and resources required for onchocerciasis elimination and eradication with reference to an APOC report of the technical consultative committee , an APOCWe obtained 2012 budgets from APOC, approved for onchocerciasis CDTi, that cover 67 of all 112 ongoing projects (as of November 2013) in sub-Saharan Africa. All budget documents include information on the unit cost and the unit quantity of each resource, demography, available human resources , and funding from the ministry of health, APOC, and non-governmental organizations. These data were used as the main sources to estimate financial costs. To estimate economic costs, agriculture value added per worker was used as an opportunity cost of community volunteers’ unpaid time , consideFor projects with missing unit costs, we used the national average if relevant unit costs were available; otherwise, the regional average  across aFrom an operational perspective, financial costs consist of those of CDTi and of surveillance. At project level, we multiplied the unit cost with the unit quantity for each cost item and every year. Costs of capital goods were annuitized over a useful time of each item with 3%. We assumed the useful time to be six years based on the capital-goods replacement policy specified in a Burundi’s budget document. We aggregated the costs across cost items relevant to CDTi and surveillance separately. We split the capital and administrative costs (for the years when both CDTi and surveillance were conducted) and the financial support costs for (post) conflict areas (over the entire time horizon) equally between CDTi and surveillance. To estimate annual financial costs, we added the CDTi and surveillance costs .Economic costs consist of those of community volunteers, who play a central operational role in CDTi , and of To estimate annual economic costs of donated ivermectin, we multiplied the drug and delivery cost per treatment with the number of required treatments (population multiplied by treatment coverage and the number of CDTi rounds per year). To estimate annual economic costs for a project, we summed the annual economic costs of community volunteers and donated ivermectin .To estimate annual total costs, we summed annual financial and economic costs. To estimate total costs over the entire time horizon, we summed annual costs from 2013 to 2045 with discounting . The disAll costs were reported in 2012 US dollars (USD). Local currency before 2012 was inflated using country-specific inflation rates  and convWe conducted sensitivity analysis to assess the robustness of results to parametric uncertainties. The parameters included either cost items for which unit costs were missing for more than one third of total projects or total countries with available budgets. Also the parameters included the time-variant determinants of unit quantities: population living in endemic areas, the number of required treatments , the number of required community volunteers (determined by population and the ratio of community volunteers over population), and the number of required community health workers . We conducted one-way sensitivity analysis to examine the impact of parameters related to CDTi performance, the cost items with high uncertainty, and discount rates on total costs. We conducted multivariate probabilistic sensitivity analysis (PSA) to examine the joint effects of uncertainties about all selected variables on total costs. For PSA, we attached statistical distributions to the selected cost items and the determinants of unit quantities, and fitted to relevant data. Total financial and economic costs would be concentrated in the early stage during which treatments are scaled up to remaining endemic areas, and decrease as the treatment phase nears the end . In endeUnit financial and economic cost per treatment for the control scenario would decrease from $2.5 to $0.9 over 2013–2045. For the elimination scenario, it would decrease from $2.5 to $1.3 until 2035, and increase to $1.6 afterwards. For the eradication scenario, it would decrease from $2.5 to $1.5 over 2013–2030, and increase to $3.9 afterwards until the end of the treatment phase in endemic African regions .Total financial costs over the period 2013–2045 would be $640 million ($572M–$711M) for the control scenario, $650 million ($574M–$751M) for the elimination scenario, and $649 million ($566M –$745M) for the eradication scenario . That isUnit financial cost per treatment for the control scenario would decrease from $0.4 to $0.1 over 2013–2045. For the elimination scenario, it would stay between $0.4 and $0.5 until 2035, and increase to $0.9 afterwards. For the eradication scenario, it would stay between $0.4 and $0.5 until 2030, and increase to $3.1 as the treatment phase nears the end in endemic African regions .Economic costs would be six times higher than financial costs under the control scenario and three times higher under the elimination and eradiation scenarios. Total economic costs over 2013–2045 would be $3.7 billion ($3.3bn–$4.3bn) for the control scenario, $2.2 billion ($2.0bn–$2.7bn) for the elimination scenario, and $2.1 billion ($1.8bn–$2.5bn) for the eradication scenario . That isOne-way sensitivity analysis  shows thThe elimination and eradication scenarios are predicted to generate substantial cost-savings in the long run compared to the control scenario. The main factors contributing to cost-savings are the reduction in economic costs of community volunteers and donated ivermectin due to a shorter treatment phase as a result of regular active surveillance. This finding implies that the saved volunteers’ time and ivermectin can be used for other health programs. Willing volunteers and their well-established networks, which have enabled successful implementation of CDTi in Africa, could contribute to improving access to primary health care in remote rural areas with insufficient human resources. In addition, the saved ivermectin drugs could be used for other disease programs, for example, anti-LF mass drug administration. To realize these possibilities, policymakers would need to keep empowering community volunteers through training and societal or economic appreciation. Also, pharmaceutical companies’ continuous commitment to donating drugs would be needed.The main operational difference between the elimination/eradication scenarios and the control scenario is regular active surveillance. Our analysis shows that the cumulative financial costs for surveillance over 2013–2045 in the elimination and eradication scenarios would be five times higher those in the control scenario. This implies that endemic countries would need to improve their domestic funding capacity to sustain high surveillance costs to achieve elimination, as the post-treatment surveillance period could last beyond 2045  and exteThe financial unit cost per treatment in the elimination and eradication scenarios would increase by factors of respective two and eight as the regional intervention phase nears the end. This increase is driven by the reduction in the number of people in need of treatment and steady or increasing costs for surveillance and capital goods. Additionally, in the last stage, the majority of people in need of treatment are expected to live in areas with epidemiological and political challenges . This imThe uncertainty analysis showed that the delay in ending CDTi would have the highest impact among those related to CDTi performance on total costs. Thus, planning to move towards the post-treatment phase, along with regular monitoring and evaluation to decide the proper time of stopping treatments, would be important to avoid the delay in ending CDTi.The uncertainty analysis also showed that the salary top-ups for stabilizing new projects would have the most influence of all cost items on total costs. Many new projects are in potential hypo-endemic areas where parasitological surveys are still needed to confirm endemicity . This suThe results presented in this study should be interpreted considering the limitations of the approach and data used. To calculate financial costs for projects without available budgets, we relied on national or regional average unit costs which might only approximately represent the actual costs in those projects. For economic costs, we assumed agriculture value added per worker as an opportunity cost of community volunteers’ unpaid time. However, other studies used different proxies such as national minimum wage and GNI per capita ,40. We dThere were some other factors that could affect resource utilization, but were not included in the analysis. We assumed no recrudescence, because it was difficult to predict when recrudescence would happen. If that were to happen, costs would increase because the treatment phase would have to be restarted. We did not consider the potential impact of new diagnostic and treatment tools, because it was difficult to predict when they would be developed and operationalized. If new effective and affordable tools are operationalized, the strategies of treatment and surveillance could change, thereby influencing costs. We assumed no unexpected political unrest that could interrupt interventions and would increase costs to restart the interventions.Despite these limitations, to our knowledge and based on literature review see , our stuS1 Text(DOCX)Click here for additional data file.S1 FigCN: control scenario, EL: elimination scenario, ER: eradication scenario(TIF)Click here for additional data file.S2 FigCN: control scenario, EL: elimination scenario, ER: eradication scenario(TIF)Click here for additional data file.S3 FigCN: control scenario, EL: elimination scenario, ER: eradication scenario(TIF)Click here for additional data file.


Bladder cancer (BC) has the highest lifetime treatment costs per patient of all cancers. The objective of this study was to characterize the use of health-care services and costs associated with BC among patients who underwent radical cystectomy (RC) in the province of Quebec.We conducted a descriptive study in a retrospective cohort of patients who underwent RC for BC between 2000 and 2009. Data was obtained from two health administrative databases (RAMQ and ISQ). We calculated average costs per patient and total costs in 2014 Canadian dollars for the following components of costs: 1) Pre-surgery costs ; 2) Costs of radical cystectomy and 3) Post-surgery costs . ARIMA models were used to evaluate trends in average costs per patient over the study period.Among 2759 patients included in the study (75 % men), average pre-surgery costs, RC costs, and post-surgery costs were estimated at 3762$, 18979$ and 4770$, respectively. RC cost was responsible for 69 % of total costs, followed by post-operative consultations (7.8 %), post-operative complications and TURBTs . Academic hospitals performed RC at a lower average cost, compared to community hospitals . A decreased trend in post-surgery costs was detected in the year 2009.Costs of RC, TURBT, consultations and post-operative complications were the most important economic components of total RC cost per patient in Quebec. Academic hospitals performed RC at a lower cost, compared to community hospitals. Bladder cancer (BC) has the highest lifetime treatment costs per patient of all cancers, from diagnosis to death , 2. PeriWe conducted a descriptive study analyzing health-care services utilization and costs associated with BC in a retrospective cohort of patients who underwent radical cystectomy in Quebec between the years 2000 and 2009.Régie de l’assurance maladie du Québec (RAMQ), and the Fichier des évenements démographiques de l’Institut de la statistique du Québec (ISQ). The RAMQ is the government body that administers healthcare provision in the province. All healthcare services are recorded in the RAMQ administrative databases and its associated claims files. The RAMQ claim file provides information on medical services dispensed to all Quebec residents . The ISQ administers the Fichier des événements démographiques which provides vital status data. The linkage between RAMQ and ISQ data is possible using a patients’ anonymous identifier . The use of the data was approved by the Comission de l’acces a l’information (CAI) of Quebec. Ethics approval was obtained from the Research Ethics Board of the McGill University Health Centre.The cohort was built with the linkage of two provincial health administrative databases: the medical billing records database of the Patients were selected from January 1st 2000 to September 30th 2009. We excluded subjects aged less than 40 years-old (the age cut-off point for micro-hematuria workup in Canada) [We identified health-care services utilization for patients who underwent RC for BC cancer during the 4 months period before RC. The 4 months’ time frame was adopted to assure that all medical services consumed by patients were associated to RC for BC. We identified the following components of health-care utilization: 1) Pre-surgery period , 2) Surgical period (RC), and 3) Post-surgery period . Post-surgery health services were determined up to one year after surgery.Ministere de la Sante et des Services Sociaux (MSSS) du Quebec and the McGill University Health Centre administration, respectively [Analogously to the time frame adopted for the identification of health-care services, we calculated average costs per patient and total costs for the following components of costs on the continuum of care for BC : 1) Pre-surgery costs  Costs of RC, and 3) Post-surgery costs . The unit cost of each medical service for consultations and imaging procedures was documented from the RAMQ’s list of medical procedures act codes approved for physician reimbursement fees in Quebec , 11. We ectively , 14. TheWe analysed BC-associated costs across two groups of variables: 1) Patient-related variables: age  and gender (dichotomous); and 2) Health-care services related variables: hospital facility where RC was performed, hospitals hosting an urology teaching program (dichotomous), surgeons’ annual RC case load , geo-administrative region where RC was performed  and calendar date of RC. Geo-administrative division is based on the MSSS’s Academic Integrated Network of Health which divides the province of Quebec into four regions according to provision of medical services and university affiliation .Demographic characteristics, age and gender-specific information of the study population was retrieved. Descriptive statistical analyses, including mean, median, standard deviation (SD) and range of costs were calculated, along with patient’s units of medical services related to each component of costs. Normality of data distribution was analysed by the Shapiro–Wilk test. Comparisons of average costs between groups were performed by t-tests and ANOVA tests, when applicable. We used autoregressive integrated moving average (ARIMA) models to evaluate trends in average total costs per patient, average radical cystectomy costs per patient and post-surgery costs per patient. We analysed differences between observed and forecasted average costs per patient over 117-month periods ranging from January 2000 to September 2009. Cut-off points for comparison between observed and forecasted values were established after seasonal trends inspection of the time series plot for each component of cost. Stationarity was assessed using the autocorrelation function and the augmented Dickey Fuller test. The autocorrelation, partial autocorrelation, and inverse autocorrelation graphic functions were used to model parameter appropriateness and seasonality. The presence of white noise was assessed by examining the autocorrelation at various lags using the Lung-Box chi squared test. All analyses were two-sided with p ≤ 0.05 being considered significant. SAS 9.3  was used to conduct the calculations.Baseline characteristics of the cohort are summarized in Table Average costs per patient and mean units of medical services for each component are summarized in Table Cost of RC is shown in Table Cost of post-operative complications is shown in Table Units of health services utilization and its total costs are described in Table Figure Previous studies have shown that radical cystectomy accounts for the largest proportion of payments for bladder cancer care; these costs showing great variability depending on the country , 16. ForOur findings also showed variations in costs for RC within the provincial health-care system. Costs of surgery varied across patient gender, patient age group, and administrative region where RC was performed. Cost variations were also detected across individual hospitals, with the majority of facilities performing surgeries at a higher than the average cost. Although these disparities were relatively small, we detected a significant 1000 $ greater average cost per patient between community hospitals compared to hospitals hosting a urology training program. Given that hospitalization and operation room costs were estimated with the provincial ministry of health’s data and attributed equally to all surgical procedures in all hospitals in our cohort, we believe that this difference is caused by the greater amount of medical fees reimbursed to physicians in community hospitals. Indeed, we found that among community hospitals, surgeries are performed by an average of 2.9 surgeons (SD: 1.15), compared to 1.76 (SD: 0.9) among hospitals hosting a urology training program. This is likely explained by the fact that in academic centers the primary surgeon is often assisted by resident house staff that does not require reimbursement by the RAMQ, as opposed to community hospitals where 2 or more surgeons are involved, each billing the RAMQ. It has been reported that logistical difficulties inherent to the additional burden of excess travel time for patients and physicians and the potential marginalization of lower-volume hospitals may increase the indirect costs attributable to surgery in community hospitals . Our resGiven that BC requires patients to undergo laboratory tests and invasive procedures for diagnosis, much of the costs during the management of the disease are attributed to cystoscopy and TURBT . The freSurgery for bladder cancer carries a high risk for perioperative and post-operative complications with rates varying from 20 % to 60 % , 23. A rAverage total costs per patient in Quebec was found to be lower than the Canadian province of Ontario (27 388 $ in Quebec versus 33 759 $ in Ontario) . AlthougDuring the study period, total costs of bladder cancer requiring RC from diagnosis up to one year of follow up were estimated at more than 70 million dollars, with more than 70 % of this total expenditure attributed to health care associated to surgery. Total costs of surgery and post-operative complications were estimated at 50 million dollars and 4 million dollars, respectively. Total costs in our cohort represent a small fraction of what was estimated in the USA for 2010  . ReasonsTo our knowledge, this is the first study to describe costs attributed to the number of pre and post-urologist consultations to general practitioners and other specialists, as well as the costs associated to urologist consultation during the pre and post-operative period. Given the paucity of detailed descriptive studies on the health economics of BC in Canada , our resThis study had some significant limitations inherent to the use of administrative databases. We were unable to measure some factors that can play an important role on costs of BC requiring RC, such as grade, stage and severity of the tumor. Data on comorbidity and patient functional status are also lacking. More importantly, since we did not know the actual hospitalization period for each patient undergoing RC, we could not be more precise in attributing costs to RC and post-operative complications. The actual variance of health services costs is hence, mainly due to the overall differences in billing codes for physicians’ payments. This information would be very important in order to compare costs and efficiencies between administrative regions, individual hospitals, and surgeons. The imputation of some economic component for medical services may have caused some degree of information bias in the calculation of average costs per patient. Nevertheless, if information bias is present, it is certainly non-differential, which not undermine internal validity of our findings. Given that we do not have data on some medical services such as prescriptions filled by patients, we could not compare our findings with an external cohort of patients that would serve as control group for estimation and comparison of attributable and net costs. Moreover, considering the intrinsic discrepancies in the management of BC across different health care systems, we are not convinced that comparing of our findings in the province of Quebec with a different “control cohort” would decrease the possibility of information bias.Also, our study did not account for the burden of indirect costs in our analyses, for which we acknowledge that these costs in the form of patients’ and caregivers’ time, as well as reduced physical and social functioning contribute to the overall burden of bladder cancer on society. On the other hand, the fact that the RAMQ is single-payer and public funded system with universal healthcare coverage allows the collection of prospective information for a large sample size, which increases external validity of our findings. The linkage between the two databases was done using a unique patient identifier, which permitted a very reliable correspondence of medical services data .Costs of RC surgery, TURBT, medical consultations, and post-operative complications were the most important economic components of total bladder cancer cost per patient requiring radical cystectomy in Quebec. Significant variations in costs were detected between academic and community hospital, as well as between geo-administrative regions across the province. More studies are needed to evaluate predictors of costs and the impact of bladder cancer expenditures on patient’s clinic outcome and survival.


Melanisation – the production and deposition of a layer of melanin that encapsulates many pathogens, including bacteria, filarial nematodes and malaria parasites is one of the main immune responses in mosquitoes. Can a high parasite load overload this immune response? If so, how is the melanisation response distributed among the individual parasites?Anopheles gambiae by inoculating individuals simultaneously with one, two or three negatively charged Sephadex beads, and estimating the melanisation as the darkness of the bead (which ranges from about 0 for unmelanised beads to 100 for the most melanised beads of our experiment).We considered these questions with the mosquito As the number of beads increased, the average degree to which beads were melanised decreased from 71 to 50. While the darkness of the least melanised bead in a mosquito decreased from an average of 71 to 35, the darkness of the most strongly melanised one did not change with the number of beads.As the number of beads increased, the mosquito’s immune response became overloaded. The mosquito’s response was to prioritise the melanisation of one bead rather than distributing its response over all beads. Such immune overloading may be an important factor underlying the evolution of resistance against vector-borne diseases.The online version of this article (doi:10.1186/s13071-016-1491-8) contains supplementary material, which is available to authorized users. Immune responses are complex pathways that can kill invading pathogens and thus protect individuals from harmful infections. Many parasites have therefore evolved mechanisms to avoid the immune response by, for example, hiding within cells , 2, switAlternatively, the immune response may simply be overloaded by the immune challenge. In other words, if the infectious dose is high enough, the immune response might no longer cope with all of the parasites. Although this possibility appears to be generally overlooked, it finds support, for example, by experimental data suggesting that the immune melanisation response of honey bees is limited by their ability to replenish the phenoloxidase reserves needed for melanisation .An overloaded immune system would be visible as an outcome lying between two extremes. At one extreme, few parasites could be targeted and dealt with optimally, while the remaining ones cannot be dealt with. At the other extreme, all parasites could be dealt with similar, but weak efficacy.Anopheles gambiae ) into the left side of the thoracic cavity [Two days after emergence, 60 females were chilled on ice. We inoculated each female with 1, 2 or 3 negatively charged Sephadex CM C-25 beads , injected simultaneously together with 0.1 μl sterile saline solution  with the software ImageJ (version 1.47f7). We used the mean length of the two wings in our analyses. On a glass microscope slide we then separated the thorax from the head and from the abdomen using forceps in the same saline solution used for injection. We opened the thorax with forceps, retrieved the beads and put them onto a slide in solution to take the picture. In this, and previous experiments, the beads were found in the thorax and had not moved to the abdomen. When we found several beads, they were not in contact with each other. Most beads were floating freely in the haemocoel, but some had tissues attached. In this and other experiments, we did not find any effect of the presence of tissue to bead melanisation. We took a digital image of each bead at a standard lighting setting with a microscope , and measured the cross-sectional area of each bead and its mean grey value with the software ImageJ. The grey-value was standardized by linear interpolation to a value between 0  and 100 (corresponding to a heavily melanised bead).We tested the data for normality with Shapiro tests and for homoscedasticity of the variance with Bartlett tests. As initial analyses of full models with interactions terms and models without non-significant interactions showed that the size of beads had no influence on the conclusions, we omitted bead size from the analyses shown here.To assay whether the number of beads influenced the melanisation response, we analysed the melanisation of each bead with a linear mixed model (function lmer) that included the number of injected beads and wing length as independent variables and the mosquito as a random factor. In a second analysis, we assayed the variability of the melanisation response as a function of the number of beads. As there is no variability in mosquitoes inoculated with one bead, we could not perform a standard assay of repeatability. Therefore, we analysed the bead with the highest melanisation or the lowest melanisation in each mosquito with an ANCOVA, again including the number of injected beads and wing length as independent variables. We analysed the survival rate two days after injection with a binomial GLM including the number of beads inoculated and wing length as independent variables. All analyses were performed with R version 3.0.2.P  = 0.076).Of the 60 mosquitoes we had inoculated, 44 were analysed . This difference in survival was statistically not significant . There was no effect of wing length  or the interaction of number of beads and wing length .The mean level of melanisation decreased from 71 (± sd = 14) in mosquitoes inoculated with one bead, to 50 (± sd = 27) in those inoculated with three beads ; the lowest melanisation decreased from 71 (± sd = 14) in mosquitoes inoculated with one bead, to 35 (± sd = 25) in mosquitoes inoculated with three . Neither highest  nor lowest  melanisation were affected by wing length.While the highest melanisation per mosquito was independent of the number of beads  among the three groups of mosquitoes, we analysed a non-random subset of mosquitoes that could have different immune responses than dead mosquitoes. However, we suggest that this had no impact on our conclusions for two reasons. First, the mortality pattern did not follow the melanisation pattern: mortality was highest after injection of two beads, but melanisation was weakest in mosquitoes inoculated with three beads. Second, we performed two tests that included the dead mosquitoes  stimulate a slightly greater response will continue to stimulate the immune response more strongly and reach a greater level of melanisation. However, mechanisms for such a feedback are not known, and indeed, postulated feedback loops are negative , 21.Whatever the mechanism, the fact that the immune response can be overloaded in a way that leads to variability of its outcome within individuals may have considerable implications for the transmission of infectious diseases. Mosquitoes, for example, clear most of the malaria parasites that infect them , but, inThe importance of this variability in the melanisation response could vary according to the type of parasite and some uncertainties remain, some parasites may be killed by the encapsulation, others may be killed by the oxidative cytotoxic compounds produced , 24. So The efficacy of the mosquito’s melanisation immune response strongly decreased with the antigen load that stimulates it. Understanding the possible constraints on mosquito immunity by overloading the system, be it with regard to the melanisation response or other immune pathways, may help to understand the evolution of resistance and the transmission of disease.


Caedibacter varicaedens is a kappa killer endosymbiont bacterium of the ciliate Paramecium biaurelia. Here, we present the draft genome sequence of C. varicaedens. Caedibacter comprises species “Candidatus Caedibacter acanthamoebae” (endosymbiont of acanthamoebae), Caedibacter caryophilus (Paramecium caudatum symbiont), Caedibacter macronucleorum (Paramecium duboscqui symbiont), Caedibacter paraconjugatus (Paramecium biaurelia symbiont), Caedibacter pseudomutans (Paramecium tetraurelia symbiont), Caedibacter taeniospiralis (Paramecium caudatum symbiont), and Caedibacter varicaedens (Paramecium biaurelia symbiont)  . Of the termined . Caedibaiaurelia . To studhttp://www.g-language.org.Whole-genome sequencing was performed using the Roche 454 pyrosequencing platform at the Center for Genomics and Bioinformatics (CGB), Indiana University. The sequencing reads were assembled using Newbler version 2.5.3. After removal of possible contaminant sequences, i.e., contigs with unusual values of statistics such as %GC content and coverage (sequencing depth), the resulting assembly contains 142 contigs consisting of 1,686,852 bp, with a G+C content of 42.1%. Genome annotation was performed using Prokka v1.11 , availabCa. Caedibacter acanthamoebae,” followed by “Candidatus Paracaedibacter symbiosus” with 36 (2.9%) best BLAST hits. Both of the species, as well as C. varicaedens, belong to the order Rickettsiales of Alphaproteobacteria .The sequence has been deposited as a whole-genome shotgun project at DDBJ/EMBL/GenBank under the accession number


The concept of frailty is rapidly gaining attention as an independent syndrome with high prevalence in older adults. Thereby, frailty is often related to certain adverse outcomes like mortality or disability. Another adverse outcome discussed is increased health care utilization. However, only few studies examined the impact of frailty on health care utilization and corresponding costs. The aim of this study was therefore to investigate comprehensively the relationship between frailty, health care utilization and costs.Cross sectional data from 2598 older participants (57–84 years) recruited in the Saarland, Germany, between 2008 and 2010 was used. Participants passed geriatric assessments that included Fried’s five frailty criteria: weakness, slowness, exhaustion, unintentional weight loss, and physical inactivity. Health care utilization was recorded in the sectors of inpatient treatment, outpatient treatment, pharmaceuticals, and nursing care.p < .05 (4 or 5 symptoms) and €680; p < .05 (3 symptoms). Among the 5 symptoms of frailty, weight loss and exhaustion were significantly associated with total costs after controlling for comorbidity.Prevalence of frailty (≥3 symptoms) was 8.0 %. Mean total 3-month costs of frail participants were €3659 (4 or 5 symptoms) and €1616 (3 symptoms) as compared to €642 of nonfrail participants (no symptom). Controlling for comorbidity and general socio-demographic characteristics in multiple regression models, the difference in total costs between frail and non-frail participants still amounted to €1917; The study provides evidence that frailty is associated with increased health care costs. The analyses furthermore indicate that frailty is an important factor for health care costs independent from pure age and comorbidity. Costs were rather attributable to frailty (and comorbidity) than to age. This stresses that the overlapping concepts of multimorbidity and frailty are both necessary to explain health care use and corresponding costs among older adults.The online version of this article (doi:10.1186/s12913-016-1360-3) contains supplementary material, which is available to authorized users. Life expectancy increases substantially in virtually all developed countries , leadingAnother medical phenomenon associated with age is people’s vulnerability to negative health outcomes and the general loss of resources. This phenomenon of frailty has increasingly received attention during the past decades. Thus, it has been shown that frailty is frequent in old age , and theDespite the great attention in the gerontological field, there is no generally accepted definition of frailty –8. FriedIn order to extend these studies and provide evidence from a representative large population-based sample, we aimed at examining comprehensively the effect of frailty on health care utilization and corresponding costs in all important health care sectors, including inpatient services, outpatient services, pharmaceuticals, and nursing care. Thus, it was our goal to present cost estimates for frailty. In particular, the aims of this study were i) to investigate the relationship between frailty and health care costs in a large sample of older adults and ii) to determine the respective associations of the different frailty criteria and health care costs.n = 2598 participants). Figure The cross-sectional analyses presented in this manuscript are based on the 8-year follow-up wave of the “Epidemiological investigations on chances of preventing, recognizing early and optimally treating chronic diseases in an elderly population”, the ESTHER-Study. ESTHER is a large prospective observational cohort study of older Germans. For this study, 9949 patients, aged 50–75 years, were recruited via their GPs in the Saarland, Germany between July 2000 and December 2002. Participants’ socio-demographic and lifestyle factors were collected by standardized questionnaires and clinical data by their general practitioners (GPs) and study physicians. Follow-up questionnaires were sent to the participants and their GPs 2, 5 and 8 years after recruitment. From baseline-recruitment to the 8-year follow-up, 1033 participants had died, 1904 had discontinued further active participation, thereof 253 for health reasons. The questionnaire of the 8-year follow-up was provided either by the GPs or by the patient for 7012 study participants. This corresponds to an 80.9 % response rate among survivors still mentally and physically able to respond. Information from both the GP’s and the patient’s questionnaires was collected for 5057 of the participants. At the 8-year follow-up, participants were invited in written form by the study secretariat to take part in detailed geriatric assessments that were conducted at the participants’ homes by trained study doctors. Participation was optional and reasons for denying participation were not collected. For the geriatric assessments several data were collected, e.g. on  activities of daily living, body weight, height, cognitive abilities, measures and constitution. Moreover, the assessments included interviews to collect the health service use as well as measurement of frailty symptoms to be used for the analysis in the present study. 3124 study participants in whom home visits were completed accepted the additional offer. Further detailed information about ESTHER can be found elsewhere , 22–25. The ESTHER study has been approved by the ethics committees of the Medical Faculty of the University of Heidelberg and the Medical Association of Saarland. A signed statement of informed consent has been obtained from all participants included in the ESTHER study.As recommended , we adopFor the second step, data on the resource consumption was collected retrospectively for a 3-month period using a previously developed and tested questionnaire , 29. TheThe third step contained the monetary valuation of the quantities of the resource used with corresponding unit costs for inpatient care –33, outpWe create a frailty index according to Fried et al.  based onIn order to calculate the net impact of frailty on health care costs, i.e. the impact irrespective of the potential influence of chronic conditions, cost estimates were adjusted for the influence of comorbidity. As measure of comorbidity, we considered the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) , 50. TheThe statistical models include the covariates age, sex, marital status, educational level and type of health insurance. Marital status distinguished between single, married, divorced, and widowed. The educational level was operationalized as duration of primary and secondary school education, consisting of three classes: ≤9 years, 10–11 years, and ≥12 years. Participants’ type of health insurance could vary between statutory health insurance and private health insurance, reflecting the dualistic system of health insurance in Germany. While the majority of about 90 % of the overall German population are a members of a Statutory Health Insurance (SHI), the remaining 10 % are privately insured. Mandatory members of a SHI are especially employees under an income-threshold and, in general, their spouses and children. Both types of health insurance offer comprehensive coverage of costs in the inpatient and outpatient physician setting, and of prescription drugs. Moreover, permanent nursing care (both ambulatory and in nursing homes) is partially reimbursed by compulsory long-term care insurances.All statistical analyses were done using Stata Release 14. The relationship between frailty as well as the single frailty symptoms and health care costs was analyzed using generalized linear models (glm) with log link function and gamma distribution, a commonly used type of model for skewed cost data . For theIn order to examine robustness of regression models, the possible effect of frailty on sectoral and total health care costs was also investigated using multiple Tobit regression models. The characteristics of our dependent variables, in particular inpatient and nursing care cost with many zero values, were similar to those of censored data, for which Tobit models are recommended .All regression analyses were performed with and without including the comorbidity status, operationalized as the CIRS-G. Thus, regression analyses firstly show the results of excess costs associated with frailty irrespective of morbidity status. Then, adjusting for morbidity status, they show the net excess costs associated with frailty with constant comorbidity. These models were run separately since frailty and comorbidity are overlapping concepts  with uncWe performed complete case analyses (listwise deletion) because missing values in any variable occurred in only 90 out of 2598 observations (3.5 %). The level of significance was set to α = 0.05.Table The frailty syndrome with population-independent cut-points could be calculated for 2589 individuals, as the weight loss could not be documented for 9 observations. For one individual, both the status of potential weight loss and the symptom of physical activity were missing. The remaining symptoms of exhaustion, slowness and weakness were documented completely for all participants. About one third of the sample was non-frail. A majority of 58 % of participants had a score of ‘1’ or ‘2’ on the frailty index and was therefore classified as pre-frail. The frailty syndrome was present in 8 % of participants who scored at least 3 points. The prevalence of slowness was highest among frailty symptoms, with about 36 % being affected, followed by weakness (31 %) and low physical activity (20 %). In contrast, exhaustion occurred in only 12 % and weight loss in only 4 % of participants.Table Regarding the five constituting symptoms of frailty, mean costs always increased if one of the symptoms was present. This applied to costs in all considered health care sectors and to total costs. The increase in costs was most pronounced for unintentional weight loss where mean total costs of affected participants were €1630 higher compared to participants without this symptom. This difference was mainly due to inpatient costs which differed by about €1400.Table p < .001) as well as with all sectoral health care costs. None of the other covariates was significantly associated with total costs. In particular, age was not associated with higher total costs when controlling for frailty, whereas age was strongly associated with total costs when the variable ‘frailty’ was removed from the regression model (model not shown here). Besides frailty, age was significantly associated with higher costs for nursing care, while being divorced was significantly associated with lower costs for nursing care.In the models without controlling for comorbidity (1), a frailty index ≥4 was statistically significantly associated with total costs , frailty was still associated with higher total costs. However, corresponding marginal effects were generally lower compared to the model without comorbidity. In the outpatient and the nursing care sector, there was no significant association between frailty and costs. In contrast, frailty index scores of 2, 3 or ≥4 were significantly associated with increased costs for pharmaceuticals. A frailty index ≥4 increased inpatient costs by about €1279. In all health care sector as well as in total, comorbidity was associated with increased costs.Table p < .01) compared to no weight loss. The symptom of exhaustion had the second highest on total costs  followed by low physical activity . With respect to inpatient costs, besides the effect of unintentional weight loss, only exhaustion had a statistically significant positive effect. In the outpatient sector, exhaustion and weakness were statistically significantly associated with costs. For nursing care only ‘low activity’ was statistically significantly associated with costs.Without controlling for comorbidity (1), there was a statistically significant association between each single symptom of frailty and total costs except for ‘slowness’ and ‘weakness’. Among the three symptoms, unintentional weight loss was most strongly associated with total costs with higher total costs of €1329 (When controlling for comorbidity (2), the marginal effects of frailty symptoms generally decreased as compared to the previous models. Yet ‘exhaustion’ and ‘weight loss’ were still significantly associated with total costs and inpatient costs. The associations of ‘low activity’, ‘exhaustion’ and ‘slowness’ with pharmaceutical costs found in models (1) persisted in models (2) with their estimated marginal effect being somewhat decreased.p < .01).We ran Tobit regression models analogous to the glms in Table This study analyzed the relationship between frailty and health care costs in a cross-sectional design of a population-based sample of community-dwelling older Germans. Frailty was operationalized by the five criteria suggested by Fried et al. , using population-independent cut-off-points.Frailty was strongly associated with total health care costs with this association persisting in regression models that additionally controlled for comorbidity. In particular, the frailty index was associated with inpatient costs and pharmaceutical costs, with the latter association also persisting after controlling for comorbidity. An observed strong significant association between age and total health care costs did not persist when controlling for frailty. Among the five symptoms of frailty, the presence of low activity, exhaustion, and weight loss were associated with higher total costs, with unintentional weight loss and exhaustion having the greatest effects even after controlling for comorbidity.Except for Hastings et al., who found no association between frailty and health care utilization in the outpatient sector , most prBeyond that, Peters et al.  evaluateBeyond the costing studies cited above, our study adds insights into the relationship of single frailty symptoms and health care costs. Table A limiting factor of our study was that data on health service utilization were self-reported by participants; therefore recall bias cannot not be ruled out. In addition, although not excluded from participation in the ESTHER study, there were only two participants living in nursing homes and three participants living in assisted living facilities, limiting the representativeness of the study and impeding any conclusions for institutionalized persons. Participants were only included when agreeing to pass the geriatric assessments. Thus, effects of sample selection might have influenced cost estimates. This might especially be the case for persons suffering from a high level of multimorbidity or frailty who potentially refrained from participating. Thus, cost estimates of frailty in this study are likely to be rather conservative, which is, for instance, indicated by the low number of participants with a frailty index of 5, or the mean age of about 70 years without considering age brackets older than 84. A particular strength of our study was the use of population-independent cut points so that the prevalence of frailty did not rely on the specific sample, facilitating comparison with other studies.Participants of our sample were slightly more often married than people of comparable age from the entire German population: 74 % vs. about 66 % . The eduThe study provides evidence that frailty is associated with increased health care costs. The analyses furthermore indicate that frailty is an important factor independent from pure age and comorbidity for analyzing health care costs. Costs were rather attributable to frailty (and comorbidity) than to age. This stresses that the overlapping concepts of multimorbidity and frailty are both necessary to explain health care use and corresponding costs among older adults.This study furthermore underlines the health economic importance of frailty. The phenomenon of frailty will certainly require more attention in the aging societies of industrialized countries and be a major task for their health care systems.Future research should further analyze the relationship of frailty and costs by using broader definitions of frailty that include e.g. emotional dimensions. Beyond that, future studies based on panel data should examine the longitudinal relationship between frailty, comorbidity and health care costs.Data protection standards and assurances made as part of the informed consent procedure of ESTHER preclude the publication of the source data in publicly available repositories. However, individual data access may be granted within a framework of scientific cooperation.


Papaya meleira virus (PMeV) is the causal agent of papaya sticky disease, which is characterized by a spontaneous exudation of fluid and aqueous latex from the papaya fruit and leaves. The latex oxidizes after atmospheric exposure, resulting in a sticky feature on the fruit from which the name of the disease originates. PMeV is an isometric virus particle with a double-stranded RNA (dsRNA) genome of approximately 12 Kb. Unusual for a plant virus, PMeV particles are localized on and linked to the polymers present in the latex. The ability of the PMeV to inhabit such a hostile environment demonstrates an intriguing interaction of the virus with the papaya. A hypersensitivity response is triggered against PMeV infection, and there is a reduction in the proteolytic activity of papaya latex during sticky disease. In papaya leaf tissues, stress responsive proteins, mostly calreticulin and proteasome-related proteins, are up regulated and proteins related to metabolism are down-regulated. Additionally, PMeV modifies the transcription of several miRNAs involved in the modulation of genes related to the ubiquitin-proteasome system. Until now, no PMeV resistant papaya genotype has been identified and roguing is the only viral control strategy available. However, a single inoculation of papaya plants with PMeV dsRNA delayed the progress of viral infection. Plant viruses cause many diseases of international importance and are responsible for huge losses of crop production and quality in all parts of the world. The production is impaired due to the susceptibility of the plants to the viruses. The main producers of papaya are India, Brazil, Indonesia, Dominican Republic, Nigeria and Mexico, and combined they produce approximately 10 million tons per year [Brazil is one of the main papaya producers; in 2012, the country produced 1.52 million tons, which was approximately 12.2% of the world supply. The production area was 31.3 thousand hectares with an average yield of 48.5 t/ha, and the production value estimated at $ 786 million [Papaya ringspot virus (PRSV), the Papaya leaf distortion mosaic virus (PLDMV), the Papaya lethal yellowing virus (PLYV), the Papaya mosaic virus (PapMV) and the Papaya meleira virus (PMeV), which have been known to cause serious damage to the crop production throughout the world. Papaya viruses cause diseases of international importance with serious reductions in fruit production that may even totally destroy affected orchards. Until now, more than ten different viruses have been reported in papaya worldwide. Nevertheless, the most important viruses that affect papaya are the PRSV causes the most destructive viral disease of papaya crop, the papaya ringspot, and has been found in many tropical and subtropical areas where papaya is grown, including the USA, South America, Mexico and Japan . PLDMV, In Brazil, the percentage of plants eradicated with papaya ringspot is about 2% per year in well-managed orchards. In traditional orchards, the losses may reach 80% . In MexiLittle information exists about PYLV and its economic importance for fruit production, but in some orchards the disease may have an incidence of up to 40% of the plants. The disease caused by PLDMV has low economic importance to the papaya production in Brazil , and in Papaya meleira virus, as well as on strategies for eradicating the papaya sticky disease. A search in the Derwent Innovations Index yielded approximately 160 patents related to papaya viruses, but most of these patents involved the Papaya ringspot virus or the Papaya mosaic virus. In our view, research groups all over the world face a significant opportunity to reduce production losses in papaya cultivation by doing basic research on papaya infestation by PMeV.Little has been published in the patent databases concerning methods for the detection of the PMeV, the causal agent of Papaya sticky disease or “meleira”, was reported in the 1980s in Brazil , and in Papaya sticky diseased affected plants are characterized by spontaneous exudation of fluid and aqueous latex from the fruit and leaves. The latex oxidizes after atmospheric exposure, resulting in small necrotic lesions on the edges of young leaves A and a sInitially, symptoms of the disease were attributed to a disturbance in the calcium and boron absorption that resulted from water stress or an imbalance of these elements in the soil . In addiMonitoring the sticky disease dispersal in commercial orchards indicated a pathogen involvement . The bioPapaya meleira virus is a dsRNA genome virus [The viral nucleic acid with approximately 12,000 base pairs was extracted from purified viral particles and visualized in an agarose gel ,15. The Viruses with a dsRNA genome are unusual among plant viruses, which have, in most cases, a genome consisting of single stranded RNA (ssRNA). dsRNA viruses represent a small group among plant viruses, and they are grouped in the Endornaviridae, Partitiviridae and Reoviridae families .Moreover, unusually for a plant virus, PMeV appears to reside primarily in the laticifers, which is an inhospitable environment, where it the modifies potassium levels and the osmotic balance that leads to cellular rupture . The resSticky disease spreads rapidly, and currently it occurs mostly in Northeast Brazil . Outsideet al. in 2003 [Agricultural practices are responsible for the spread of the disease within the orchard because the dispersion of the sticky disease often occurs along the array of the crop row . Therefo in 2003  , which influenced the culture lifespan permanence [As for the progress of the disease with time, the epidemiological behavior varied according to different factors, such as environmental factors, possible vectors and cultural practices. A positive correlation has been observed between the temperature and precipitation in the course of the disease ,22. In trmanence .et al. [C. papaya cultivar Golden seeds. They also developed a method for the diagnosis of the viral infection in seedlings. No PMeV was detected by conventional RT-PCR on the numbers of seedlings that were derived from the seeds of healthy (n = 187) and infected (p = 172) plants. However, another study conducted with seeds from C. papaya cultivar Maradol demonstrated that PMeV is seed-borne and that it can be transmitted to the next generation via contaminated seeds. Furthermore, this finding may explain how this virus appeared in Mexico [C. papaya cultivar Golden that requires a larger number of seedlings in order to be analyzed, and it is very high for C. papaya cultivar Maradol accounted for the high incidence of PMeV in Mexico. Moreover, for the seed transmission of plant viruses, the seed might be infected in the generative cells and the virus is maintained in the germ cells or, less often, in the seed coat [Identifying the mode of transmission of the papaya sticky disease has been an issue. Abreu et al.  investign Mexico . The fren Mexico ,26. Thereed coat . Papaya It is worth mentioning that it is extremely important to conduct surveys in other papaya producing countries of the region and with the major producers worldwide in order to verify the virus presence in these areas, especially given the increase in the movement of seeds among the producing countries.Bemisia tabaci type B) [Trialeurodes variabilis, a pest to Brazilian papaya and other fruit trees, [T. variabilis was unable to transmit PMeV from diseased to healthy papayas, even though the presence of the virus was ascertained in adults and nymphs [The possible involvement of insects as sticky disease vectors has been considered based upon early studies on the field spread pattern of this disease ,28, espe type B) , althougt trees,  possess t trees, . A greend nymphs . CurrentCeratitis capitata (Wied.), a pest of quarantine importance that usually only infests papaya fruits in the advanced stages of maturity. There is a direct relationship between the time of plant infection with the virus and the infestation of the papaya fruits by the fruit fly C. capitata [Sticky disease also interferes with the natural resistance of papaya fruits to fruit flies (Diptera: Tephretidae). Green unripe fruits from PMeV infected plants are susceptible to the Mediterranean fruit fly (Medfly), capitata .Brachiaria decunbens, which is present in the papaya orchards that are affected by the sticky disease in the south of Bahia [Another important aspect in plant disease epidemiology is the alternative hosts. In this sense, the presence of dsRNA with a molecular weight similar to that associated with sticky disease was detected in samples of the Gramineae species of Bahia . Aiming for the earlier identification of infected plants, two different molecular approaches have been developed. The first strategy is based upon the extraction of PMeV genomic dsRNA from the plant latex using organic solvents followed by gel electrophoresis to visualization the resultant ~12 kb viral dsRNA band . This meThe second method applies conventional reverse transcription PCR (RT-PCR) to latex diluted in ammonium citrate. Viral dsRNA was used as a template in RT-RAPD (Reverse Transcription-Random Amplified Polymorphic DNA) to randomly produce DNA sequences from the PMeV genome. RAPD does not require prior DNA sequence information because it uses single, short random primers so it can be applied to generate random DNA sequence data from an uncharacterized virus RNA genome. RT-RAPD fragments were cloned and sequenced. The nucleotide sequences of the viral dsRNA were used to designed specific primers for PMeV. Through RT-PCR, one of these primers (C05-3) amplified a 669-nucleotide fragment that, after sequencing, showed a high similarity to other viral RNA dependent RNA polymerases (RDRP) . This meThe efficiency of either molecular diagnosis strategy, the direct PMeV dsRNA extraction or the amplification by RT-PCR, depends upon previous latex processing. Usually papaya producers send fruits, leaves and stems inside plastic bags to diagnostic laboratories. Sometimes the conditions during plant transport makes diagnosis from the latex impracticable as it must be correctly stored and processed to avoid dsRNA destruction and consequent diagnosis failure. Rodrigues and colleagues  evaluateNew diagnostic methods have been proposed using conventional and quantitative RT-PCR (qRT-PCR), allowing for the molecular diagnosis in papaya tissues . Two priUntil now, a papaya genotype that is resistant to PMeV has not been identified despite all of the efforts coming from Brazil and Mexico. Symptoms are triggered only after flowering and, therefore, an infected plant without fruit or symptoms can remain unnoticed for months in the field acting as an inoculum source until it is finally detected and eliminated ,9. Thus,Papaya latex is mostly comprised of cysteine proteinases in addition to the carbohydrates, lipids, salts, phenols and glutathione . These p2O2) in the laticifers of the plant, indicating a hypersensitive response (HR) of papaya laticifers against PMeV infection [PMeV particles are found only in papaya laticifers and not in other cell types ; therefonfection . Latex fluidity and exudation in PMeV infected papaya suggest that the virus uses the host laticifers to move itself through the plant . ElectroPapaya latex is known to be mainly composed of proteins ,39; for 2O2 in the laticifers of the infected papaya [Moreover, a reduction in the proteolytic activity of papaya latex during sticky disease has also been demonstrated, specifically associated with cysteine proteases, showing that these proteins are important in the response of the papaya to stress and that PMeV is able to overcome this process . The redd papaya  played ad papaya ,44, mostd papaya  and the 2O2) [2O2 production in the papaya laticifers during PMeV infection has already been demonstrated [A major defense mechanism in plants is the “hypersensitive response” (HR) whereby cells infected with pathogens, and often surrounding cells as well, are instructed to self-destruct by the host plant . This is2O2) . The incnstrated . To assenstrated .2O2 is a well-known systemic response elicitor, and, as mentioned above, PMeV infected papaya laticifers have an increased production of this molecule. Additionally, necrotic lesions in the plant leaf tip is the first disease symptom [H symptom ,9. There symptom . Stress responsive proteins, mostly calreticulin and proteasome-related proteins, are up regulated and proteins related to metabolism are down regulated in sticky diseased papaya leaf tissues , showingThe upregulation of proteasome-related proteins supports the assumption that PMeV proteins, or even host proteins, which are essential for the viral infection can be targeted for degradation . SeveralNoncoding RNAs comprise the majority of transcribed RNA, and they perform a wide range of functions in cellular and developmental processes. As a result, noncoding RNAs are also implicated in the development and pathophysiology of many diseases, and they represent potential targets for therapeutic intervention. MicroRNAs (miRNAs) are one of a number of classes of endogenous, small (21–24 nucleotide), non-coding RNAs found in both animals and plants ,57. C. papaya genome [C. papaya genome; additionally, these miRNAs were classified into 72 miRNAs families [In the papaya, 24  and 75  conservea genome . 462 knofamilies .Arabidopsis [Nicotiana tabacum [C. papaya, and, consequently, the mechanisms involved in the onset of sticky disease symptoms, the miRNA response of the plant to infection was investigated [Changes in miRNA expression are associated with viral infection in bidopsis , and vir tabacum . Therefostigated . The Micstigated . The expstigated . PMeV mostigated . PMeV infection also influences the production of reactive oxygen species (ROS) ,60. ThisTherefore, evidence suggests that the PMeV uses the plant UPS response as a strategy to favor its replication and maintain host viability, and it modifies the accumulation of miRNAs that modulate important defense genes eliciting the onset of sticky disease symptoms .Efforts to control viral papaya diseases are long-standing. The currently used methods are vector control, the use of papaya plants that are resistant to certain viruses, and cross-protection, among others. Chemical or biological vector controls are used as well, and can be very effective considering vectors that need to feed for some time on a crop before the virus is transmitted, but are of much less value when the transmission occurs very rapidly and may already have taken place before the vector succumbs to the pesticide. As the sticky disease vector is still unknown, chemical or biological control cannot be used. The cross-protection strategy involves the use of a mild virus strain to control severe strains of the same virus. However, cross protection depends upon the availability of mild strains that can be used for effective protection against the target virus, and it requires extra agricultural practice and care that limits the benefits of this approach . Until nConsidering the lack of effectiveness of the methods mentioned above for PMeV control, the development of resistant papaya plants to viruses is the main goal, and virus-resistant transgenic plants are currently the most effective control of viral diseases.Pathogen resistant plants can arise naturally or be developed by classic genetics or through the use of transgenic plants. The development of viral resistant varieties through conventional breeding methods has been complicated due to the sexual incompatibility of wild species and cultivated papaya . A promising development in agricultural virus control is the concept that plants can initiate defense responses based upon RNA silencing when challenged by viral RNA. The use of transgenic plants that constituently express viral material has been successfully developed in different crops ,65. GeneAlternatively, one way of inducing viral resistance in plants is to introduce artificially viral dsRNA molecules that are able to trigger the post-transcriptional gene silencing (PTGS) ,67. It hPlant hormones may play a role in regulating signaling networks involved in plant defense. When a pathogen attack occurs, the plant produces these hormones, and the amounts and compositions vary depending upon the strategy of infection and the type of pathogen. At present, there has been significant progress in identifying the key components and the understanding of the role of phytohormones in plant responses to biotic attacks ,69. StudSince the first report of the sticky disease in Brazil a few decades ago, many researchers have conducted several studies that have focused on different aspects of the disease; from this research, progress has been made in the molecular diagnosis of PMeV as well as in the knowledge of some of the mechanisms of transmission and spatiotemporal spreading of the virus. More recently, studies have focused on the proteomics of the most cultivated varieties of papaya in Mexico and Brazil, especially with a search for genes that are expressed in the presence of the virus because these genes can be molecular markers useful in searching for resistance to PMeV in papaya plants. Additionally, studies on the possible insect vectors for PMeV transmission have been conducted. More importantly, the virus genome is being sequenced as well.To date, no variety of papaya has been found to be PMeV resistant. It is very important to focus on obtaining papaya plants that are resistant or tolerant to this virus through breeding programs that are based upon the information provided by the aforementioned studies or by the more effective genetic modification of papaya, which may be the best strategy for the efficient control of PMeV and for long-term protection.