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Introduction: Dengue has become a more serious human health concern in China, with increased incidence and expanded outbreak regions. The knowledge of the cross-sectional and longitudinal epidemiological characteristics and the evolutionary dynamics of dengue in high-risk areas of China is limited. Methods: Records of dengue cases from 2013 to 2016 were obtained from the China Notifiable Disease Surveillance System. Full envelope gene sequences of dengue viruses detected from the high-risk areas of China were collected. Maximum Likelihood tree and haplotype network analyses were conducted to explore the phylogenetic relationship of viruses from high-risk areas of China. Results: A total of 56,520 cases was reported in China from 2013 to 2016. During this time, Yunnan, Guangdong and Fujian provinces were the high-risk areas. Imported cases occurred almost year-round, and were mainly introduced from Southeast Asia. The first indigenous case usually occurred in June to August, and the last one occurred before December in Yunnan and Fujian provinces but in December in Guangdong Province. Seven genotypes of DENV 1-3 were detected in the high-risk areas, with DENV 1-I the main genotype and DENV 2-Cosmopolitan the secondary one. The Maximum Likelihood trees show that almost all the indigenous viruses separated into different clusters. DENV 1-I viruses were found to be clustered in Guangdong Province, but not in Fujian and Yunnan, from 2013 to 2015. The ancestors of the Guangdong viruses in the cluster in 2013 and 2014 were most closely related to strains from Thailand or Singapore, and the Guangdong virus in 2015 was most closely related to the Guangdong virus of 2014. Based on closest phylogenetic relationships, viruses from Myanmar possibly initiated further indigenous cases in Yunnan, those from Indonesia in Fujian, while viruses from Thailand, Malaysia, Singapore and Indonesia were predominant in Guangdong Province. Conclusions: Dengue is still an imported disease in C

The Sámi Indigenous populations, who live in the arctic Sápmi area across four countries–Norway, Sweden, Finland and the Kola Peninsula of Russia–have practiced traditional medicine (TM) for millennia. However, today Sámi TM is unknown within the Swedish health care services (HCS). The aim of this study is to describe the nature and scope of research conducted on Sámi TM among the four Sápmi countries. This study covers peer-reviewed research published in the English language up to 8 April 2020. From 15 databases, 240 abstracts were identified, and 19 publications met the inclusion criteria for full review. Seventeen studies were conducted in Norway, one in Finland and one in Sweden, none in Russia. In northern Norway, Sámi TM is actively used by the local communities, and is claimed to be effective, but is not accessible within HCS. Holistic worldviews, including spirituality, prevail in Sámi TM from practitioners’ selection criteria to health care practices to illness responsibilities. An integration of Sámi TM into HCS is clearly the desire of local communities. Comparisons were made between Sámi TM and conventional medicine on worldviews, on perspectives towards each other, and on integration. More studies are needed in Sweden, Finland and Russia.

Dengue virus serotype 4 (DENV 4) has had a relatively low prevalence worldwide for decades; however, likely due to data paucity, no study has investigated the epidemiology and evolutionary dynamics of DENV 4 genotype I (DENV 4-I). This study aims to understand the diversity, epidemiology and dynamics of DENV 4-I. We collected 404 full length DENV4-1 envelope (E) gene sequences from 14 countries using two sources: Yunnan Province in China (15 strains during 2013-2016) and GenBank (489 strains up to 2018-01-11). Conducting phylogenetic and phylogeographical analyses, we estimated the virus spread, population dynamics, and selection pressures using different statistical analysis methods (substitution saturation, likelihood mapping, Bayesian coalescent inference, and maximum likelihood estimation). Our results show that during the last 60 years (1956-2016), DENV 4-I was present in mainland and maritime Southeast Asia, the Indian subcontinent, the southern provinces of China, parts of Brazil and Australia. The recent spread of DENV 4-I likely originated in the Philippines and later spread to Thailand. From Thailand, it spread to adjacent countries and eventually the Indian subcontinent. Apparently diverging around years 1957, 1963, 1976 and 1990, the different Clades (Clade I-V) were defined. The mean overall evolution rate of DENV 4-I was 9.74 (95% HPD: 8.68-10.82) x 10(-4) nucleotide substitutions/site/year. The most recent common ancestor for DENV 4-I traces back to 1956. While the demographic history of DENV 4-I fluctuated, peaks appeared around 1982 and 2006. While purifying selection dominated the majority of E-gene evolution of DENV 4-I, positive selection characterized Clade III (Vietnam). DENV 4-I evolved in situ in Southeast Asia and the Indian subcontinent. Thailand and Indian acted as the main and secondary virus distribution hubs globally and regionally. Our phylogenetic analysis highlights the need for strengthened regional cooperation on surveillance and s

Background: Climate change allows Aedes aegyptito infest new areas. Consequently, it enables the arboviruses the mosquito transmits - e.g., dengue, chikungunya, Zika and yellow fever – to emerge in previously uninfected areas. An example is the Portuguese island of Madeira during 2012–13. Objective: We aim to understand how climate change will affect the future spread of this potent vector, as an aidin assessing the risk of disease outbreaks and effectively allocating resources for vector control. Methods: We used an empirically-informed, process-based mathematical model to study the feasibility of Aedes aegypti infestation into continental Europe. Based on established global climate-change scenario data, we assess the potential of Aedes aegypti to establish in Europe over the 21st century by estimating the vector population growth rate for five climate models (GCM5). Results: In a low carbon emission future (RCP2.6), we find minimal change to the current situation throughout the whole of the 21st century. In a high carbon future (RCP8.5), a large parts of southern Europe risks being invaded by Aedes aegypti. Conclusion: Our results show that successfully enforcing the Paris Agreement by limiting global warming to below 2 °C significantly lowers the risk for infestation of Aedes aegypti and consequently of potential large-scale arboviral disease outbreaks in Europe within the 21st century., Originally included in thesis in manuscript form with title "Climate change may enable Aedes aegypti mosquitoes infestation in major European cities by 2100"

BACKGROUND: The current esophageal cancer AJCC-TNM staging system may not capture the full prognostic implications of the primary tumor. A study is needed to explore the prognostic value of tumor size on esophageal cancer-specific mortality. METHODS: Patients who underwent surgical resection for non-metastatic esophageal cancer were selected from the Surveillance, Epidemiology and End Results Program database (United States, 1988 - 2014). Using statistics methods - maximally selected rank and two hazard models (Cox model and Fine-Gray model) - the optimum cutoff point for tumor length in each T classification was estimated and the prognostic value of tumor size on esophageal cancer-specific mortality was analyzed. RESULTS: 4,447 patients were identified. The median tumor size was significantly correlated with T classification, with the correlation coefficient of 0.43 (p < 0.001). Patients in the T1-T3 classifications who had larger tumor size showed a larger probability of cancer-specific mortality. The multivariate Cox model showed that tumor size was significantly associated with an increase in cancer-specific mortality in T1 (2.15, 95% CI [1.72, 2.69]) and T2 (1.31, 95% CI [1.06, 1.62]), but marginally significantly in T3 (1.12, 95% CI [1.00, 1.27]) and insignificantly in T4 classification (p > 0.1). Similar results were found using the multivariate Fine-Gray model. CONCLUSIONS: We have found that combining T classification with tumor size can increase the precision in identifying the high-risk groups in T1-T2 classification. Based on esophageal cancer-specific mortality our study is the first to explore the prognostic cutoff point of tumor size by T classification.

Given the speed of air travel, diseases even with a short viremia such as dengue can be easily exported to dengue naïve areas within 24 hours. We set out to estimate the risk of dengue virus introductions via travelers into Europe and number of secondary autochthonous cases as a result of the introduction. We applied mathematical modeling to estimate the number of dengue-viremic air passengers from 16 dengue-endemic countries to 27 European countries, taking into account the incidence of dengue in the exporting countries, travel volume and the probability of being viremic at the time of travel. Our models estimate a range from zero to 167 air passengers who are dengue-viremic at the time of travel from dengue endemic countries to each of the 27 receiving countries in one year. Germany receives the highest number of imported dengue-viremic air passengers followed by France and the United Kingdom. Our findings estimate 10 autochthonous secondary asymptomatic and symptomatic dengue infections, caused by the expected 124 infected travelers who arrived in Italy in 2012. The risk of onward transmission in Europe is reassuringly low, except where Aedes aegypti is present.

Warming temperatures may increase the geographic spread of vector-borne diseases into temperate areas. Although a tropical mosquito-borne viral disease, a dengue outbreak occurred in Madeira, Portugal, in 2012; the first in Europe since 1920s. This outbreak emphasizes the potential for dengue re-emergence in Europe given changing climates. We present estimates of dengue epidemic potential using vectorial capacity (VC) based on historic and projected temperature (1901–2099). VC indicates the vectors' ability to spread disease among humans. We calculated temperature-dependent VC for Europe, highlighting 10 European cities and three non-European reference cities. Compared with the tropics, Europe shows pronounced seasonality and geographical heterogeneity. Although low, VC during summer is currently sufficient for dengue outbreaks in Southern Europe to commence–if sufficient vector populations (either Ae. aegypti and Ae. albopictus) were active and virus were introduced. Under various climate change scenarios, the seasonal peak and time window for dengue epidemic potential increases during the 21st century. Our study maps dengue epidemic potential in Europe and identifies seasonal time windows when major cities are most conducive for dengue transmission from 1901 to 2099. Our findings illustrate, that besides vector control, mitigating greenhouse gas emissions crucially reduces the future epidemic potential of dengue in Europe., This study is part of the DengueTools project funded by the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. 282589.Originally included in thesis 1 as submitted manuscript.

The explosive Zika virus epidemic in the Americas is amplifying spread of this emerging pathogen into previously unaffected regions of the world, including Europe (Gulland, 2016), where local populations are immunologically naïve. As summertime approaches in the northern hemisphere, Aedes mosquitoes in Europe may find suitable climatic conditions to acquire and subsequently transmit Zika virus from viremic travellers to local populations. While Aedes albopictus has proven to be a vector for the transmission of dengue and chikungunya viruses in Europe (Delisle et al., 2015; ECDC, n.d.) there is growing experimental and ecological evidence to suggest that it may also be competent for Zika virus(Chouin-Carneiro et al., 2016; Grard et al., 2014; Li et al., 2012; Wong et al., 2013). Here we analyze and overlay the monthly flows of airline travellers arriving into European cities from Zika affected areas across the Americas, the predicted monthly estimates of the basic reproduction number of Zika virus in areas where Aedes mosquito populations reside in Europe (Aedes aegypti in Madeira, Portugal and Ae. albopictus in continental Europe), and human populations living within areas where mosquito-borne transmission of Zika virus may be possible. We highlight specific geographic areas and timing of risk for Zika virus introduction and possible spread within Europe to inform the efficient use of human disease surveillance, vector surveillance and control, and public education resources.

Introduction: A dengue outbreak in 2012 having 2000 + reported cases, followed vector introduction to the Portuguese island of Madeira in 2005. We describe contributing factors for the 2012 outbreak through modeling of temperature dependent vectorial capacity, meteorological observations of environmental factors pertinent to vector lifecycle, and dynamics of travellers arriving from dengue endemic areas. In combination with reported vector and human surveillance, the temporal onset of the 2012 outbreak and factors setting 2012 apart from other years were used to generate a predictive model for potential re- emergence of dengue in Madeira. Methods: Relative Vectorial capacity (rVC) was calculated with previously published methods for Madeira (Island) and Funchal (City) from 2005 to 2014 based on both remotely sensed satellite data and observation stations. We also estimated potentially imported dengue infections using previously published methods. Epidemiological features of the 2012 outbreak combined with generated data to inform a predictive model. Projected travel and seasonal weather forecasting inputs for the predictive model described the dengue importation-driven transmission likelihood for Madeira in 2015. Results: Longitudinal comparisons of available data were displayed simultaneously to show periods of greatest potential for dengue emergence in Madeira, historically. The modeled outputs especially during the months before the outbreak provide more precise quantification and visualization of the temporal coincidence, which may have primed Madeira for emergence of dengue in late summer 2012. When seasonal forecast information is applied to the historically informed model for spring and summer 2015, potential for local dengue transmission in Madeira was determined. Conclusions Local transmission of dengue in Madeira may re occur given the environmental envelope and continuous importation of the dengue virus via travelers, even with strengthened vector control

Introduction: Endemic in at least 100 countries, dengue is currently regarded as world's most important mosquito borne viral disease. While most of the disease burden is limited to areas with tropical and sub-tropical climates, evidence suggests that temperate areas may be increasingly at risk as the geographic distribution of relevant vectors expands. Japan, a country with a temperate climate, reported the first major dengue outbreak in 2014. We examined the factors that may have facilitated the dengue outbreak in Tokyo during 2014. Methods: Multiple sequence alignment of the dengue virus 1 (DENV1) sequence from the 2014 dengue outbreak in Tokyo was carried out using a fast Fourier transformation method in MAFFT v6.940b. We collected the Japan National Tourism Organization’s data on inbound travelers between January and September 2014 from dengue endemic countries in Asia to Japan. Daily observations of temperature (minimum, maximum, and mean) and precipitation were obtained from the MIDAS dataset for Tokyo. We calculated the relative vectorial capacity (rVc) for Aedes vectors to quantify the dengue epidemic potential based on temperature dependent parameters, by applying a modified Ross-McDonald model. Findings: Tourist arrivals into Japan in 2014 coincided by 70% with its warm summer months suitable for dengue transmission, The phylogenetic similarity of DENV-1 isolated from the 2014 outbreak in Japan with viruses from China, Indonesia, Singapore, and Vietnam renders any of these four countries a likely source of importation. Several conducive climate factors converged preceding and during the time of the dengue outbreak in Tokyo, August until October 2014. Climate conditions, in particular mean temperature and precipitation, were favorable for the amplification of Aedes vectors. Furthermore, the ability for the vector to transmit dengue, as measured by the relative vectorial capacity, was highest at the time of the 2014 outbreak. Conclusions: Taking into account th

Introduction: Dengue is a mosquito-borne viral infection that has become a major public health concern. About 390 million people are infected yearly. Increased global connectivity and population movement as well as climate change affect the global distribution of both dengue vectors and the virus, facilitating the spread of dengue to new geographic areas. Weather is an important factor determining mosquito behaviour and effectiveness of dengue virus transmission. Dengue epidemic potential depends on vectorial capacity of Aedes mosquitoes, which depend on climate, such as, temperature and diurnal temperature range. This study aims at identifying high-risk areas and high-risk time windows in Europe based on temperature, in order for timely vector surveillance and control. Methods: Relative vectorial capacity (rVc) was used to estimate dengue epidemic potential. Using historical and projected temperature data over two centuries (1901–2099) and temperature dependent vector parameters for Aedes vectors, rVc was calculated for 10 selected European cities from Stockholm in the North to Malaga in the South. Results: Compared to dengue endemic areas, rVc in Europe was lower and showed more prominent seasonality. The peak and width of the seasonal windows in rVc were generally higher in the South than the North. Currently, only South and Central-East Europe and the summer season corresponds to rVc that is over the threshold for possible dengue transmission. By the end of this century, in the best case scenario, all the Central and Southern European cities would be at risk for dengue transmission during the warmer months; in the worst case scenario, this risk would extend to Northern European to include Stockholm if dengue vectors were established and virus introduced. Conclusion: As travel and globalization become more frequent channels for dengue vector and virus introduction, Europe may face the reality of more frequent dengue outbreaks in their warmer months. Madeira's out

Dengue is a mosquito-borne viral disease that occurs mainly in the tropics and subtropics but has a high potential to spread to new areas. Dengue infections are climate sensitive, so it is important to better understand how changing climate factors affect the potential for geographic spread and future dengue epidemics. Vectorial capacity (VC) describes a vector's propensity to transmit dengue taking into account human, virus, and vector interactions. VC is highly temperature dependent, but most dengue models only take mean temperature values into account. Recent evidence shows that diurnal temperature range (DTR) plays an important role in influencing the behavior of the primary dengue vector Aedes aegypti. In this study, we used relative VC to estimate dengue epidemic potential (DEP) based on the temperature and DTR dependence of the parameters of A. aegypti. We found a strong temperature dependence of DEP; it peaked at a mean temperature of 29.3°C when DTR was 0°C and at 20°C when DTR was 20°C. Increasing average temperatures up to 29°C led to an increased DEP, but temperatures above 29°C reduced DEP. In tropical areas where the mean temperatures are close to 29°C, a small DTR increased DEP while a large DTR reduced it. In cold to temperate or extremely hot climates where the mean temperatures are far from 29°C, increasing DTR was associated with increasing DEP. Incorporating these findings using historical and predicted temperature and DTR over a two hundred year period (1901–2099), we found an increasing trend of global DEP in temperate regions. Small increases in DEP were observed over the last 100 years and large increases are expected by the end of this century in temperate Northern Hemisphere regions using climate change projections. These findings illustrate the importance of including DTR when mapping DEP based on VC.

In 2012, Madeira reported its first major outbreak of dengue. To identify the origin of the imported dengue virus, we investigated the interconnectivity via air travel between dengue-endemic countries and Madeira, and compared available sequences against GenBank. There were 22,948 air travellers to Madeira in 2012, originating from twenty-nine dengue-endemic countries; 89.6% of these international travellers originated from Venezuela and Brazil. We developed an importation index that takes into account both travel volume and the extent of dengue incidence in the country of origin. Venezuela and Brazil had by far the highest importation indices compared with all other dengue-endemic countries. The importation index for Venezuela was twice as high as that for Brazil. When taking into account seasonality in the months preceding the onset of the Madeira outbreak, this index was even seven times higher for Venezuela than for Brazil during this time. Dengue sequencing shows that the virus responsible for the Madeira outbreak was most closely related to viruses circulating in Venezuela, Brazil and Columbia. Applying the importation index, Venezuela was identified as the most likely origin of importation of dengue virus via travellers to Madeira. We propose that the importation index is a new additional tool that can help to identify and anticipate the most probable country of origin for importation of dengue into currently non-endemic countries.