Zoonotic risk assessment among farmed mammals.

Farmed mammals may act as hosts for zoonotic viruses that can cause disease outbreaks in humans. This SnapShot shows which farmed mammals, and to what extent, are of particular risk of harboring and spreading viruses from viral families that are commonly associated with zoonotic disease. It also discusses genome surveillance methods and biosafety measures. To view this SnapShot, open or download the PDF.

Farmed fur animals harbour viruses with zoonotic spillover potential.

Animals such as raccoon dogs, mink and muskrats are farmed for fur and are sometimes used as food or medicinal products1,2, yet they are also potential reservoirs of emerging pathogens3. Here we performed single-sample metatranscriptomic sequencing of internal tissues from 461 individual fur animals that were found dead due to disease. We characterized 125 virus species, including 36 that were novel and 39 at potentially high risk of cross-species transmission, including zoonotic spillover. Notably, we identified seven species of coronaviruses, expanding their known host range, and documented the cross-species transmission of a novel canine respiratory coronavirus to raccoon dogs and of bat HKU5-like coronaviruses to mink, present at a high abundance in lung tissues. Three subtypes of influenza A virus-H1N2, H5N6 and H6N2-were detected in the lungs of guinea pig, mink and muskrat, respectively. Multiple known zoonotic viruses, such as Japanese encephalitis virus and mammalian orthoreovirus4,5, were detected in guinea pigs. Raccoon dogs and mink carried the highest number of potentially high-risk viruses, while viruses from the Coronaviridae, Paramyxoviridae and Sedoreoviridae families commonly infected multiple hosts. These data also reveal potential virus transmission between farmed animals and wild animals, and from humans to farmed animals, indicating that fur farming represents an important transmission hub for viral zoonoses.

Fibrin(ogen) engagement of S. aureus promotes the host antimicrobial response and suppression of microbe dissemination following peritoneal infection.

The blood-clotting protein fibrin(ogen) plays a critical role in host defense against invading pathogens, particularly against peritoneal infection by the Gram-positive microbe Staphylococcus aureus. Here, we tested the hypothesis that direct binding between fibrin(ogen) and S. aureus is a component of the primary host antimicrobial response mechanism and prevention of secondary microbe dissemination from the peritoneal cavity. To establish a model system, we showed that fibrinogen isolated from FibγΔ5 mice, which express a mutant form lacking the final 5 amino acids of the fibrinogen γ chain (termed fibrinogenγΔ5), did not support S. aureus adherence when immobilized and clumping when in suspension. In contrast, purified wildtype fibrinogen supported robust adhesion and clumping that was largely dependent on S. aureus expression of the receptor clumping factor A (ClfA). Following peritoneal infection with S. aureus USA300, FibγΔ5 mice displayed worse survival compared to WT mice coupled to reduced bacterial killing within the peritoneal cavity and increased dissemination of the microbes into circulation and distant organs. The failure of acute bacterial killing, but not enhanced dissemination, was partially recapitulated by mice infected with S. aureus USA300 lacking ClfA. Fibrin polymer formation and coagulation transglutaminase Factor XIII each contributed to killing of the microbes within the peritoneal cavity, but only elimination of polymer formation enhanced systemic dissemination. Host macrophage depletion or selective elimination of the fibrin(ogen) ß2-integrin binding motif both compromised local bacterial killing and enhanced S. aureus systemic dissemination, suggesting fibrin polymer formation in and of itself was not sufficient to retain S. aureus within the peritoneal cavity. Collectively, these findings suggest that following peritoneal infection, the binding of S. aureus to stabilized fibrin matrices promotes a local, macrophage-mediated antimicrobial response essential for prevention of microbe dissemination and downstream host mortality.

No association of a Vascular endothelial growth factor A (VEGFA) gene polymorphism with pre-eclampsia among pregnant women in Uganda.

BACKGROUND: Vascular endothelial growth factor A (VEGFA) is a major angiogenic factor that plays an important role in the formation of blood vessels during embryonic development. VEGFA has been implicated in the pathophysiology of pre-eclampsia (PE), since pre-eclamptic women present with reduced levels of free circulating VEGFA. The 3' untranslated region (3'-UTR) of the VEGFA gene consists of elements that regulate the transcription and hence expression of the VEGFA protein in circulation. Hence it is suggested that variations thereof could underlie the reduced VEGFA levels observed in pre-eclamptic women. The purpose of this study was to investigate presence of the + 936C/T polymorphism, a common single nucleotide polymorphism (SNP) in the 3'-UTR of the VEGFA gene, and determine its association with PE among pregnant women in Uganda. RESULTS: There was no significant difference observed in the allele and genotype frequencies of the + 936C/T 3' UTR-VEGFA polymorphism between pre-eclamptic and normotensive pregnant women (P > 0.05). Additionally, there was no significant difference in the median plasma levels of free VEGFA among women with the wild type, CT and TT genotypes of the + 936C/T VEGFA polymorphism (median = 0.84 pg/mL (IQR = 0.39-1.41) Vs 1.05 (0.61-1.18) Vs 1.05 (1.05-1.05) respectively, p-value = 0.7161). CONCLUSIONS: These study findings indicate that the + 936C/T 3' UTR-VEGFA polymorphism had no significant association with increased susceptibility to PE among women in Uganda. Further studies with a larger sample size are recommended.

Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial.

BACKGROUND: The optimal time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer is unknown and has traditionally been 4-6 weeks in clinical practice. Observational studies have suggested better outcomes, especially in terms of histological response, after prolonged delay of up to 3 months after nCRT. The NeoRes II trial is the first randomised trial to compare standard to prolonged TTS after nCRT for oesophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced oesophageal cancer were randomly assigned to standard delay of surgery of 4-6 weeks or prolonged delay of 10-12 weeks after nCRT. The primary endpoint was complete histological response of the primary tumour in patients with adenocarcinoma (AC). Secondary endpoints included histological tumour response, resection margins, overall and progression-free survival in all patients and stratified by histologic type. RESULTS: Between February 2015 and March 2019, 249 patients from 10 participating centres in Sweden, Norway and Germany were randomised: 125 to standard and 124 to prolonged TTS. There was no significant difference in complete histological response between AC patients allocated to standard (21%) compared to prolonged (26%) TTS (P = 0.429). Tumour regression, resection margins and number of resected lymph nodes, total and metastatic, did not differ between the allocated interventions. The first quartile overall survival in patients allocated to standard TTS was 26.5 months compared to 14.2 months after prolonged TTS (P = 0.003) and the overall risk of death during follow-up was 35% higher after prolonged delay (hazard ratio 1.35, 95% confidence interval 0.94-1.95, P = 0.107). CONCLUSION: Prolonged TTS did not improve histological complete response or other pathological endpoints, while there was a strong trend towards worse survival, suggesting caution in routinely delaying surgery for >6 weeks after nCRT.

Fungal Planet description sheets: 1550-1613.

Novel species of fungi described in this study include those from various countries as follows: Argentina, Neocamarosporium halophilum in leaf spots of Atriplex undulata. Australia, Aschersonia merianiae on scale insect (Coccoidea), Curvularia huamulaniae isolated from air, Hevansia mainiae on dead spider, Ophiocordyceps poecilometigena on Poecilometis sp. Bolivia, Lecanora menthoides on sandstone, in open semi-desert montane areas, Sticta monlueckiorum corticolous in a forest, Trichonectria epimegalosporae on apothecia of corticolous Megalospora sulphurata var. sulphurata, Trichonectria puncteliae on the thallus of Punctelia borreri. Brazil, Catenomargarita pseudocercosporicola (incl. Catenomargarita gen. nov.) hyperparasitic on Pseudocercospora fijiensis on leaves of Musa acuminata, Tulasnella restingae on protocorms and roots of Epidendrum fulgens. Bulgaria, Anthracoidea umbrosae on Carex spp. Croatia, Hymenoscyphus radicis from surface-sterilised, asymptomatic roots of Microthlaspi erraticum, Orbilia multiserpentina on wood of decorticated branches of Quercus pubescens. France, Calosporella punctatispora on dead corticated twigs of Aceropalus. French West Indies (Martinique), Eutypella lechatii on dead corticated palm stem. Germany, Arrhenia alcalinophila on loamy soil. Iceland, Cistella blauvikensis on dead grass (Poaceae). India, Fulvifomes maritimus on living Peltophorum pterocarpum, Fulvifomes natarajanii on dead wood of Prosopis juliflora, Fulvifomes subazonatus on trunk of Azadirachta indica, Macrolepiota bharadwajii on moist soil near the forest, Narcissea delicata on decaying elephant dung, Paramyrothecium indicum on living leaves of Hibiscus hispidissimus, Trichoglossum syamviswanathii on moist soil near the base of a bamboo plantation. Iran, Vacuiphoma astragalicola from stem canker of Astragalus sarcocolla. Malaysia, Neoeriomycopsis fissistigmae (incl. Neoeriomycopsidaceae fam. nov.) on leaf spots on flower Fissistigma sp. Namibia, Exophiala lichenicola lichenicolous on Acarospora cf. luederitzensis. Netherlands, Entoloma occultatum on soil, Extremus caricis on dead leaves of Carex sp., Inocybe pseudomytiliodora on loamy soil. Norway, Inocybe guldeniae on calcareous soil, Inocybe rupestroides on gravelly soil. Pakistan, Hymenagaricus brunneodiscus on soil. Philippines, Ophiocordyceps philippinensis parasitic on Asilus sp. Poland, Hawksworthiomyces ciconiae isolated from Ciconia ciconia nest, Plectosphaerella vigrensis from leaf spots on Impatiens noli-tangere, Xenoramularia epitaxicola from sooty mould community on Taxus baccata. Portugal, Inocybe dagamae on clay soil. Saudi Arabia, Diaporthe jazanensis on branches of Coffea arabica. South Africa, Alternaria moraeae on dead leaves of Moraea sp., Bonitomyces buffels-kloofinus (incl. Bonitomyces gen. nov.) on dead twigs of unknown tree, Constrictochalara koukolii on living leaves of Itea rhamnoides colonised by a Meliola sp., Cylindromonium lichenophilum on Parmelina tiliacea, Gamszarella buffelskloofina (incl. Gamszarella gen. nov.) on dead insect, Isthmosporiella africana (incl. Isthmosporiella gen. nov.) on dead twigs of unknown tree, Nothoeucasphaeria buffelskloofina (incl. Nothoeucasphaeria gen. nov.), on dead twigs of unknown tree, Nothomicrothyrium beaucarneae (incl. Nothomicrothyrium gen. nov.) on dead leaves of Beaucarnea stricta, Paramycosphaerella proteae on living leaves of Protea caffra, Querciphoma foliicola on leaf litter, Rachicladosporium conostomii on dead twigs of Conostomium natalense var. glabrum, Rhamphoriopsis synnematosa on dead twig of unknown tree, Waltergamsia mpumalanga on dead leaves of unknown tree. Spain, Amanita fulvogrisea on limestone soil, in mixed forest, Amanita herculis in open Quercus forest, Vuilleminia beltraniae on Cistus symphytifolius. Sweden, Pachyella pulchella on decaying wood on sand-silt riverbank. Thailand, Deniquelata cassiae on dead stem of Cassia fistula, Stomiopeltis thailandica on dead twigs of Magnolia champaca. Ukraine, Circinaria podoliana on natural limestone outcrops, Neonematogonum carpinicola (incl. Neonematogonum gen. nov.) on dead branches of Carpinus betulus. USA, Exophiala wilsonii water from cooling tower, Hygrophorus aesculeticola on soil in mixed forest, and Neocelosporium aereum from air in a house attic. Morphological and culture characteristics are supported by DNA barcodes. Citation: Crous PW, Costa MM, Kandemir H, et al. 2023. Fungal Planet description sheets: 1550-1613. Persoonia 51: 280-417. doi: 10.3767/persoonia.2023.51.08.

Cancer risk in individuals with autism spectrum disorder.

BACKGROUND: Whether individuals with autism spectrum disorders (ASDs) have a higher-than-expected risk of cancer remains unknown. PATIENTS AND METHODS: We carried out a population-based cohort study including 2.3 million individuals live-born to mothers from Nordic countries during 1987-2013 in Sweden with follow-up through 2016 (up to age 30 years). Individuals with ASD were ascertained through the Swedish National Patient Register. We estimated the relative risk of cancer in relation to ASD by odds ratios (ORs) and associated 95% confidence intervals (CIs) derived from logistic regression, after detailed adjustment for potential confounders. We also carried out a sibling comparison to address familial confounding and a genetic correlation analysis using the genome-wide association study summary statistics to address confounding due to potential polygenetic pleiotropy between ASD and cancer. RESULTS: We observed an overall increased risk of any cancer among individuals with ASD (OR 1.3, 95% CI 1.2-1.5), compared with individuals without ASD. The association for any cancer was primarily noted for narrowly defined autistic disorder (OR 1.7, 95% CI 1.3-2.1) and ASD with comorbid birth defects (OR 2.1, 95% CI 1.5-2.9) or both birth defects and intellectual disability (ID; OR 4.8, 95% CI 3.4-6.6). An association was also suggested for ASD with comorbid ID (OR 1.4; 95% CI 0.9-2.1), but was not statistically significant. ASD alone (i.e. without comorbid ID or birth defects) was not associated with an increased risk of any cancer (OR 1.0, 95% CI 0.8-1.2). Sibling comparison and genetic correlation analysis showed little evidence for familial confounding or confounding due to polygenetic pleiotropy between ASD and cancer. CONCLUSIONS: ASD per se is not associated with an increased risk for cancer in early life. The increased cancer risk among individuals with ASD is likely mainly attributable to co-occurring ID and/or birth defects in ASD.

Circumpolar diversification of the Ixodes uriae tick virome.

Ticks (order: Ixodida) are a highly diverse and ecologically important group of ectoparasitic blood-feeding organisms. One such species, the seabird tick (Ixodes uriae), is widely distributed around the circumpolar regions of the northern and southern hemispheres. It has been suggested that Ix. uriae spread from the southern to the northern circumpolar region millions of years ago and has remained isolated in these regions ever since. Such a profound biographic subdivision provides a unique opportunity to determine whether viruses associated with ticks exhibit the same evolutionary patterns as their hosts. To test this, we collected Ix. uriae specimens near a Gentoo penguin (Pygoscelis papua) colony at Neko harbour, Antarctica, and from migratory birds-the Razorbill (Alca torda) and the Common murre (Uria aalge)-on Bonden island, northern Sweden. Through meta-transcriptomic next-generation sequencing we identified 16 RNA viruses, seven of which were novel. Notably, we detected the same species, Ronne virus, and two closely related species, Bonden virus and Piguzov virus, in both hemispheres indicating that there have been at least two cross-circumpolar dispersal events. Similarly, we identified viruses discovered previously in other locations several decades ago, including Gadgets Gully virus, Taggert virus and Okhotskiy virus. By identifying the same or closely related viruses in geographically disjunct sampling locations we provide evidence for virus dispersal within and between the circumpolar regions. In marked contrast, our phylogenetic analysis revealed no movement of the Ix. uriae tick hosts between the same locations. Combined, these data suggest that migratory birds are responsible for the movement of viruses at both local and global scales.

About spirals and pores: Xylariaceae with remarkable germ loci.

Based on phylogenetic analyses of a multi-gene matrix of nuITS-LSU rDNA, RPB2 and TUB2 sequences and morphology, xylariaceous species with uni- to pauciperitheciate stromata and ascospores having a spirally coiling (helicoid) germ slit are revised and reclassified, including detailed descriptions and illustrations. The genus Helicogermslita is redefined and restricted to seven species with massive, erumpent, clypeus-like carbonaceous stromata, and Rosellinia somala is combined in Helicogermslita. Within the core Xylariaceae, the poorly known Leptomassaria simplex is shown to be closely related to Anthostoma insidiosum, for which the new genus Oligostoma is established, and Anthostoma rhenanum is demonstrated to be synonymous with O. insidiosum. The new genus Albicollum, characterised by immersed ascomata and a collar of white pseudostromatic tissues surrounding the ostioles, is established for Amphisphaeria canicollis, Anthostoma chionostomum, Sordaria (= Helicogermslita) fleischhakii and Anthostoma vincensii. Anthostoma ostropoides is synomymised with Albicollum canicolle, and Al. berberidicola, Al. longisporum and Al. novomexicanum are described as new species. Rosellinia (= Helicogermslita) gaudefroyi is transferred to the new genus Spiririma. Anthostoma amoenum and Euepixylon udum, both with a poroid germ locus, are shown to be only distantly related, and An. amoenum is reclassified within the asexual genus Digitodochium. Based on phylogeny, the genus Euepixylon is treated as a synonym of Nemania. A new species, Nemania ethancrensonii, which is closely related to the two formerly accepted Euepixylon species (E. sphaeriostomum, E. udum) but strongly deviates from the morphological concept of Euepixylon and Nemania, is described from the eastern USA. The genera Anthostomelloides, Clypeosphaeria, Digitodochium, Emarcaea, Induratia, Linosporopsis, Magnostiolata, Occultitheca and Spiririma are revealed to form a morphologically heterogeneous lineage in a basal position of Xylariaceae. Anthostoma vincensii, Quaternaria simplex and Rosellinia gaudefroyi are lectotypified, and Amphisphaeria canicollis, Anthostoma amoenum, An. rhenanum, An. vincensii, Quaternaria simplex, Rosellinia gaudefroyi and Valsa insidiosa are epitypified. Keys to uni- to pauciperitheciate xylariaceous genera with sigmoid to helicoid germ slits and to species of Albicollum are provided. Citation: Voglmayr H, Tello S, Jaklitsch WM, et al. 2022. About spirals and pores: Xylariaceae with remarkable germ loci. Persoonia 49: 58-98. https://doi.org/10.3767/persoonia.2022.49.02.

Field surveys in Croatia and North Macedonia reveal two novel phleboviruses circulating in sandflies.

Sandfly-borne phleboviruses are distributed widely throughout the Mediterranean Basin, presenting a threat to public health in areas where they circulate. However, the true diversity and distribution of pathogenic and apathogenic sandfly-borne phleboviruses remains a key issue to be studied. In the Balkans, most published data rely on serology-based studies although virus isolation has occasionally been reported. Here, we report the discovery of two novel sandfly-borne phleboviruses, provisionally named Zaba virus (ZABAV) and Bregalaka virus (BREV), which were isolated in Croatia and North Macedonia, respectively. This constitutes the first isolation of phleboviruses in both countries. Genetic analysis based on complete coding sequences indicated that ZABAV and BREV are distinct from each other and belong to the genus Phlebovirus, family Phenuiviridae. Phylogenetic and amino acid modelling of viral polymerase shows that ZABAV and BREV are new members of the Salehabad phlebovirus species and the Adana phlebovirus species, respectively. Moreover, sequence-based vector identification suggests that ZABAV is mainly transmitted by Phlebotomus neglectus and BREV is mainly transmitted by Phlebotomus perfiliewi. BREV neutralizing antibodies were detected in 3.3% of human sera with rates up to 16.7% in certain districts, demonstrating that BREV frequently infects humans in North Macedonia. In vitro viral growth kinetics experiments demonstrated viral replication of both viruses in mammalian and mosquito cells. In vivo experimental studies in mice suggest that ZABAV and BREV exhibit characteristics making them possible human pathogens.

Training of vertical versus horizontal reading in patients with hemianopia - a randomized and controlled study.

HYPOTHESIS: Patients with hemianopic field defects (HFD) might benefit from reading text in vertical orientation if they place the text in the seeing hemifield along the vertical midline. METHODS: We assigned 21 patients with HFD randomly to either vertical or horizontal reading training. They trained reading single lines of texts from a computer screen at home for 2 × 30 min/day, 5 days/week, for 4 weeks. The main outcome variable was reading speed (RS) during reading standardized paragraphs of printed text (IReST) aloud. RS was assessed before training (T1), directly after training (T2) and 4 weeks later (T3). Quality of life (QoL) was assessed by Impact of Visual Impairment (IVI) questionnaire. RESULTS: Vertical training improved RS in the vertical direction significantly. Only patients with right HFD benefited. Horizontal training improved RS in horizontal diection significantly, but much more in patients with left than in those with right HFD. Both effects remained stable at T3. RS during training at the computer improved highly significantly and correlated strongly with RS of printed text (Pearson r= > 0.9). QoL: Vertical training showed a statistically significant improvement in the complete IVI-score, patients with right HFD in the emotional IVI-score. CONCLUSIONS: The improvements of RS were specific for the training. The stable effect indicates that the patients can apply the newly learned strategies to everyday life. The side of the HFD plays an essential role: Left-HFD patients benefitted from horizontal training, right-HFD patients from vertical training. However, the vertical RS did not reach the level of horizontal RS. The study was registered in the German Clinical Trials register (DRKS-ID: DRKS00018843).

Both cardiovascular and cerebrovascular events are decreased following long-term narrowband ultraviolet B phototherapy in patients with vitiligo: a propensity score matching analysis.

BACKGROUND: Systemic effects of long-term narrowband ultraviolet B (NB-UVB) phototherapy have not been well studied in vitiligo patients. An 11-year nationwide population-based retrospective cohort study was conducted using the Korean National Health Insurance claims database (2007-2017). OBJECTIVES: To investigate the effects of long-term NB-UVB phototherapy on the risk of cardiovascular and cerebrovascular events in vitiligo patients. METHODS: This study included vitiligo patients with ≥100 phototherapy sessions (phototherapy group, n = 3229) and <3 phototherapy sessions (no phototherapy group, n = 9687), in which covariables with age, sex, insurance type and comorbidities such as diabetes, hypertension and hyperlipidemia were matched by 1 : 3 propensity score matching. The outcomes of interest were cardiovascular (ischaemic heart disease and myocardial infarction) and cerebrovascular events (cerebrovascular infraction and haemorrhage). Cox proportional hazards models were used to assess the associations between NB-UVB phototherapy and each event. RESULTS: The risk of cardiovascular or cerebrovascular events was significantly decreased in the phototherapy group compared with the no phototherapy group [hazard ratio (HR) 0.637, 95% confidence interval (CI) 0.523-0.776]. Subgroup analysis revealed that the risk of cardiovascular (HR: 0.682, 95% CI: 0.495-0.940) and cerebrovascular events (HR: 0.601, 95% CI: 0.470-0.769) were significantly lower in the phototherapy group than the no phototherapy group, respectively. CONCLUSIONS: Our findings suggest that long-term NB-UVB phototherapy could decrease the risk of cardiovascular and cerebrovascular events in patients with vitiligo.

The impact of public health interventions in the Nordic countries during the first year of SARS-CoV-2 transmission and evolution.

BackgroundMany countries have attempted to mitigate and control COVID-19 through non-pharmaceutical interventions, particularly with the aim of reducing population movement and contact. However, it remains unclear how the different control strategies impacted the local phylodynamics of the causative SARS-CoV-2 virus.AimWe aimed to assess the duration of chains of virus transmission within individual countries and the extent to which countries exported viruses to their geographical neighbours.MethodsWe analysed complete SARS-CoV-2 genomes to infer the relative frequencies of virus importation and exportation, as well as virus transmission dynamics, in countries of northern Europe. We examined virus evolution and phylodynamics in Denmark, Finland, Iceland, Norway and Sweden during the first year of the COVID-19 pandemic.ResultsThe Nordic countries differed markedly in the invasiveness of control strategies, which we found reflected in transmission chain dynamics. For example, Sweden, which compared with the other Nordic countries relied more on recommendation-based rather than legislation-based mitigation interventions, had transmission chains that were more numerous and tended to have more cases. This trend increased over the first 8 months of 2020. Together with Denmark, Sweden was a net exporter of SARS-CoV-2. Norway and Finland implemented legislation-based interventions; their transmission chain dynamics were in stark contrast to their neighbouring country Sweden.ConclusionSweden constituted an epidemiological and evolutionary refugium that enabled the virus to maintain active transmission and spread to other geographical locations. Our analysis reveals the utility of genomic surveillance where monitoring of active transmission chains is a key metric.

Introduction and Dispersal of Sindbis Virus from Central Africa to Europe.

Bird-hosted viruses have the potential to be transported over large areas of the world and to be transmitted in distant geographical regions. Sindbis virus (SINV) is a mosquito-borne alphavirus that is locally amplified in a bird-mosquito enzootic cycle and distributed all over the Old World and Australia/Oceania. Sindbis virus genotype I (SINV-I) is the cause of disease outbreaks in humans in South Africa as well as in northern Europe. To trace the evolutionary history and potential strain-disease association of SINV-I, we sequenced 36 complete genomes isolated from field material in Europe, as well as in Africa and the Middle East, collected over 58 years. These were analyzed together with 30 additional published whole SINV-I genomes using Bayesian analysis. Our results suggested that SINV-I was introduced only once to northern Europe from central Africa, in the 1920s. After its first introduction to Sweden, it spread east and southward on two separate occasions in the 1960s and 1970s. Another introduction from central Africa to southern/central Europe seems to have occurred, and where these two introductions meet, one recombination event was detected in central Europe. In addition, another recombinant strain was found in central Africa, where the most divergent SINV-I strains also originated.IMPORTANCE This study shows that only a single introduction of SINV into a new geographical area is required for spread and establishment, provided that the requisite vector(s) and reservoir(s) of epizootological and epidemiological importance are present. Furthermore, we present the first report of recombination between two strains of SINV in nature. Our study increases the knowledge on new introductions and dispersal of arboviruses in general and of SINV in particular.

Coffee, tea, and caffeine intake and amyotrophic lateral sclerosis mortality in a pooled analysis of eight prospective cohort studies.

BACKGROUND AND PURPOSE: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea and caffeine intake, and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351 565 individuals (120 688 men and 230 877 women). We assessed coffee, tea and caffeine intake using validated food-frequency questionnaires administered at baseline. We used Cox regression to estimate study- and sex-specific risk ratios and 95% confidence intervals (CI) for ALS mortality, which were then pooled using a random-effects model. We conducted analyses using cohort-specific tertiles, absolute common cut-points and continuous measures of all exposures. RESULTS: During follow-up, 545 ALS deaths were documented. We did not observe statistically significant associations between coffee, tea or caffeine intake and risk of ALS mortality. The pooled multivariable risk ratio (MVRR) for ≥3 cups per day vs. >0 to <1 cup per day was 1.04 (95% CI, 0.74-1.47) for coffee and 1.17 (95% CI, 0.77-1.79) for tea. The pooled MVRR comparing the highest with the lowest tertile of caffeine intake (mg/day) was 0.99 (95% CI, 0.80-1.23). No statistically significant results were observed when exposures were modeled as tertiles or continuously. CONCLUSIONS: Our results do not support associations between coffee, tea or total caffeine intake and risk of ALS mortality.

EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Molecular epidemiology of hepatitis B virus infection in Norway.

BACKGROUND: Hepatitis B virus (HBV) infection remains a serious global health challenge. The widespread distribution of HBV is highlighted by multiple HBV genotypes associated with different geographical origin and transmission patterns, as well as, clinical outcomes. Investigating population HBV genotype composition and origin is therefore highly warranted. METHODS: In this molecular epidemiological study we analysed 1157 HBV S-gene sequences collected from patients in Norway, primarily in the period 2004-2011, and linked them to epidemiological data from the Norwegian surveillance system for communicable diseases. RESULTS: Of the patients with reported country of infection (n = 909), 10% (n = 93) were infected in Norway, but the majority (n = 816; 90%) stated that they became infected outside of Norway. Of the patients infected outside of Norway, most became infected in Southeast and East Asia (n = 465; 51%) and Central, West, and North Africa (n = 254; 28%). The distribution of HBV genotypes in Norway is dominated by genotype D (32%) followed by genotype A (22%), B and C (18 and 18%, respectively), and E (7%). Genotype B, C and E were phylogenetically categorized by a majority of sequences originating from distinct geographical regions, either Asia or Africa, whereas genotype A and D originated from multiple geographic regions. However, within genotype A and D, our molecular epidemiology analysis indicated a geographical clustering of sequences depending on their geographical origin. CONCLUSIONS: The majority of HBV patients in Norway became infected outside of Norway and were represented by most common genotypes. Patients stated to have been infected in Norway were found primarily within genotype A and D, and were phylogenetically characterized by both small local clusters and interspersed sequences that clustered with non-Norwegian sequences, indicating that a proportion of the patients assumed to have been infected in Norway likely became infected outside of Norway although assumed the contrary.

Changes in local free-living parasite populations in response to cleaner manipulation over 12 years.

Predation on parasites is an important ecological process, but few experimental studies have examined the long-term impacts on the prey. Cleaner fish prey upon large numbers and selectively feed on the larger individuals of the ectoparasitic stage of gnathiid isopods. Removal of cleaner fish Labroides dimidiatus for 1.5-12.5 years negatively affects coral reef fishes, but the mechanism is unclear. A reduction in local parasite populations or the size of individual parasites would benefit all susceptible fishes. We tested whether cleaner presence reduces local gnathiid populations using 18 patch-reefs distributed between two sites (both at Lizard Island, Great Barrier Reef) which were maintained cleaner-free or undisturbed for 12 years. Using emergence traps (1 m2), free-living gnathiid stages were sampled before and after cleaner fish were removed during the day and night, up to 11 times over the course of the experiment. There were effects of the removal in the predicted direction, driven largely by the response at one site over the other involving 200% more gnathiids, but manifested only in the daytime sampling after 4 months. There was also a main effect (36%) for the shared sample dates at both sites after 12 years. Gnathiid size occasionally differed with cleaner presence, but in no consistent way over time. Contrary to our predictions, changes in free-living gnathiid population numbers and their size structure rarely reflected the changes in fish populations and individuals observed on cleaner-free reefs. Therefore, evidence that this predator alone regulates gnathiids remains limited, suggesting other contributing processes are involved.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: long-term results of a randomized clinical trial.

NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction. Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma, T1N1 or T2-3N0-1 and M0-M1a (AJCC 6th ed.), were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1-5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by esophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate in the primary tumor. Survival and recurrence patterns were evaluated as secondary endpoints. Between 2006 and 2013, 181 patients were enrolled in Sweden and Norway. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of the patients allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received full dose radiotherapy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumor resection. Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor (28% vs. 9%). Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group. This article reports the long-term results. Five-year progression-free survival was 38.9% (95% CI 28.9%-48.8%) in the chemoradiotherapy group versus 33.0% (95% CI 23.6%-42.7%) in the chemotherapy group, P = 0.82. Five-year overall survival was 42.2% (95% CI 31.9%-52.1%) versus 39.6% (95% CI 29.5%-49.4%), P = 0.60. There were no differences in recurrence patterns between the treatment groups. This is to our knowledge that the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction. Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy, no survival advantages were seen. Consequently, the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a standard of care in patients with resectable esophageal cancer.

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis.

The "Beijing" Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan during the 1979-1989 Soviet-Afghan war and spread further after population displacement in the wake of the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time.