Potential for Zika virus transmission by mosquitoes in temperate climates.

Mosquito-borne Zika virus (ZIKV) transmission has almost exclusively been detected in the tropics despite the distributions of its primary vectors extending farther into temperate regions. Therefore, it is unknown whether ZIKV's range has reached a temperature-dependent limit, or if it can spread into temperate climates. Using field-collected mosquitoes for biological relevance, we found that two common temperate mosquito species, Aedes albopictus and Ochlerotatus detritus, were competent for ZIKV. We orally exposed mosquitoes to ZIKV and held them at between 17 and 31°C, estimated the time required for mosquitoes to become infectious, and applied these data to a ZIKV spatial risk model. We identified a minimum temperature threshold for the transmission of ZIKV by mosquitoes between 17 and 19°C. Using these data, we generated standardized basic reproduction number R0-based risk maps and we derived estimates for the length of the transmission season for recent and future climate conditions. Our standardized R0-based risk maps show potential risk of ZIKV transmission beyond the current observed range in southern USA, southern China and southern European countries. Transmission risk is simulated to increase over southern and Eastern Europe, northern USA and temperate regions of Asia (northern China, southern Japan) in future climate scenarios.

Global risk model for vector-borne transmission of Zika virus reveals the role of El Niño 2015.

Zika, a mosquito-borne viral disease that emerged in South America in 2015, was declared a Public Health Emergency of International Concern by the WHO in February of 2016. We developed a climate-driven R0 mathematical model for the transmission risk of Zika virus (ZIKV) that explicitly includes two key mosquito vector species: Aedes aegypti and Aedes albopictus The model was parameterized and calibrated using the most up to date information from the available literature. It was then driven by observed gridded temperature and rainfall datasets for the period 1950-2015. We find that the transmission risk in South America in 2015 was the highest since 1950. This maximum is related to favoring temperature conditions that caused the simulated biting rates to be largest and mosquito mortality rates and extrinsic incubation periods to be smallest in 2015. This event followed the suspected introduction of ZIKV in Brazil in 2013. The ZIKV outbreak in Latin America has very likely been fueled by the 2015-2016 El Niño climate phenomenon affecting the region. The highest transmission risk globally is in South America and tropical countries where Ae. aegypti is abundant. Transmission risk is strongly seasonal in temperate regions where Ae. albopictus is present, with significant risk of ZIKV transmission in the southeastern states of the United States, in southern China, and to a lesser extent, over southern Europe during the boreal summer season.

Wolbachia strain wMel induces cytoplasmic incompatibility and blocks dengue transmission in Aedes albopictus.

Wolbachia inherited bacteria are able to invade insect populations using cytoplasmic incompatibility and provide new strategies for controlling mosquito-borne tropical diseases, such as dengue. The overreplicating wMelPop strain was recently shown to strongly inhibit the replication of dengue virus when introduced into Aedes aegypti mosquitoes, as well as to stimulate chronic immune up-regulation. Here we show that stable introduction of the wMel strain of Drosophila melanogaster into Aedes albopictus, a vector of dengue and other arboviruses, abolished the transmission capacity of dengue virus-challenged mosquitoes. Immune up-regulation was observed in the transinfected line, but at a much lower level than that previously found for transinfected Ae. aegypti. Transient infection experiments suggest that this difference is related to Ae. albopictus immunotolerance of Wolbachia, rather than to the Wolbachia strain used. This study provides an example of strong pathogen inhibition in a naturally Wolbachia-infected mosquito species, demonstrating that this inhibition is not limited to naturally naïve species, and suggests that the Wolbachia strain is more important than host background for viral inhibition. Complete bidirectional cytoplasmic incompatibility was observed with WT strains infected with the naturally occurring Ae. albopictus Wolbachia, and this provides a mechanism for introducing wMel into natural populations of this species.

Identifying life-history patterns along the fast-slow continuum of mammalian viral carriers.

Life-history traits have been identified as major indicators of mammals' susceptibility and exposure to viruses due to evolutionary constraints that link life-history speed with species' ecology and immunity. Nonetheless, it is unclear where along the fast-slow continuum of mammalian life-history lies the greatest diversity of host species. Consequently, life-history patterns that govern host-virus associations remain largely unknown. Here we analyse the virome of 1350 wild mammals and detect the characteristics that drive species' compatibility with different groups of viruses. We highlight that mammals with larger body size and either very rapid or very slow life histories are more likely to carry different groups of viruses, particularly zoonotic ones. While some common life-history patterns emerge across carriers, eco-evolutionary characteristics of viral groups appear to determine association with certain carrier species. Our findings underline the importance of incorporating both mammals' life-history information and viruses' ecological diversity into surveillance strategies to identify potential zoonotic carriers in wildlife.

Mitochondrial and microbial diversity of the invasive mosquito vector species Culex tritaeniorhynchus across its extensive inter-continental geographic range.

Background: Culex (Cx.) tritaeniorhynchus is an invasive mosquito species with an extensive and expanding inter-continental distribution, currently reported across Asia, Africa, the Middle East, Europe and now Australia. It is an important vector of medical and veterinary pathogens which cause significant morbidity and mortality in human and animal populations. Across regions endemic for Japanese encephalitis virus (JEV), Cx. tritaeniorhynchus is considered the major vector and has also been shown to contribute to the transmission of several other zoonotic arboviruses including Rift Valley fever virus (RVFV) and West Nile virus (WNV). Methods: In this study, we used laboratory vector competence experiments to determine if Cx. tritaeniorhynchus from a Southern European population were competent JEV vectors. We also obtained samples from multiple geographically dispersed Cx. tritaeniorhynchus populations from countries within Europe, Africa, Eurasia and Asia to perform phylogenetic analysis to measure the level of mitochondrial divergence using the cytochrome oxidase subunit 1 ( CO1) gene. We also undertook bacterial 16S rRNA gene amplicon sequencing to determine microbial diversity and used multi-locus sequence typing (MLST) to determine any evidence for the presence of strains of the naturally occurring endosymbiotic bacterium Wolbachia. Results: Cx. tritaeniorhynchus from a Greek population were shown be be competent vectors of JEV with high levels of virus present in saliva. We found a signficant level of mitochondrial genetic diversity using the mosquito CO1 gene between geographically dispersed populations. Furthermore, we report diverse microbiomes identified by 16S rRNA gene amplicon sequencing within and between geographical populations. Evidence for the detection of the endosymbiotic bacteria Wolbachia was confirmed using Wolbachia-specific PCR and MLST. Conclusions: This study enhances our understanding of the diversity of Cx. tritaeniorhynchus and the associated microbiome across its inter-continental range and highlights the need for greater surveillance of this invasive vector species in Europe.

The mosquito species Culex (Cx.) tritaeniorhynchus is expanding its range and is now present in over 50 countries across Asia, Africa, the Middle East, Europe and now Australasia. It can transmit human and animal pathogens, resulting in significant morbidity and mortality. This species transmits Japanese encephalitis virus in endemic areas of Asia, and it has also been shown to contribute to the transmission of several other viruses that can infect humans, including Rift Valley fever virus and West Nile virus. In this study, we firstly undertook some lab experiments to show that Cx. tritaeniorhynchus from a Southern European population are competent vectors of Japanese encephalitis virus. We also obtained field mosquitoes from countries within Europe, Africa, Eurasia and Asia and used phylogenetic analysis to demonstrate a high level of mitochondrial divergence within and between populations. In addition, we analysed the bacteria present within mosquitoes and found a high level of microbial diversity. Finally, we present evidence for the presence of Wolbachia endosymbiotic bacteria in some populations of this mosquito species. This study highlights the need for greater surveillance of this invasive vector species ­ particularly in Europe.

Wolbachia stimulates immune gene expression and inhibits plasmodium development in Anopheles gambiae.

The over-replicating wMelPop strain of the endosymbiont Wolbachia pipientis has recently been shown to be capable of inducing immune upregulation and inhibition of pathogen transmission in Aedes aegypti mosquitoes. In order to examine whether comparable effects would be seen in the malaria vector Anopheles gambiae, transient somatic infections of wMelPop were created by intrathoracic inoculation. Upregulation of six selected immune genes was observed compared to controls, at least two of which (LRIM1 and TEP1) influence the development of malaria parasites. A stably infected An. gambiae cell line also showed increased expression of malaria-related immune genes. Highly significant reductions in Plasmodium infection intensity were observed in the wMelPop-infected cohort, and using gene knockdown, evidence for the role of TEP1 in this phenotype was obtained. Comparing the levels of upregulation in somatic and stably inherited wMelPop infections in Ae. aegypti revealed that levels of upregulation were lower in the somatic infections than in the stably transinfected line; inhibition of development of Brugia filarial nematodes was nevertheless observed in the somatic wMelPop infected females. Thus we consider that the effects observed in An. gambiae are also likely to be more pronounced if stably inherited wMelPop transinfections can be created, and that somatic infections of Wolbachia provide a useful model for examining effects on pathogen development or dissemination. The data are discussed with respect to the comparative effects on malaria vectorial capacity of life shortening and direct inhibition of Plasmodium development that can be produced by Wolbachia.

Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.

Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response.

Predicting mammalian hosts in which novel coronaviruses can be generated.

Novel pathogenic coronaviruses - such as SARS-CoV and probably SARS-CoV-2 - arise by homologous recombination between co-infecting viruses in a single cell. Identifying possible sources of novel coronaviruses therefore requires identifying hosts of multiple coronaviruses; however, most coronavirus-host interactions remain unknown. Here, by deploying a meta-ensemble of similarity learners from three complementary perspectives (viral, mammalian and network), we predict which mammals are hosts of multiple coronaviruses. We predict that there are 11.5-fold more coronavirus-host associations, over 30-fold more potential SARS-CoV-2 recombination hosts, and over 40-fold more host species with four or more different subgenera of coronaviruses than have been observed to date at >0.5 mean probability cut-off (2.4-, 4.25- and 9-fold, respectively, at >0.9821). Our results demonstrate the large underappreciation of the potential scale of novel coronavirus generation in wild and domesticated animals. We identify high-risk species for coronavirus surveillance.

Divide-and-conquer: machine-learning integrates mammalian and viral traits with network features to predict virus-mammal associations.

Our knowledge of viral host ranges remains limited. Completing this picture by identifying unknown hosts of known viruses is an important research aim that can help identify and mitigate zoonotic and animal-disease risks, such as spill-over from animal reservoirs into human populations. To address this knowledge-gap we apply a divide-and-conquer approach which separates viral, mammalian and network features into three unique perspectives, each predicting associations independently to enhance predictive power. Our approach predicts over 20,000 unknown associations between known viruses and susceptible mammalian species, suggesting that current knowledge underestimates the number of associations in wild and semi-domesticated mammals by a factor of 4.3, and the average potential mammalian host-range of viruses by a factor of 3.2. In particular, our results highlight a significant knowledge gap in the wild reservoirs of important zoonotic and domesticated mammals' viruses: specifically, lyssaviruses, bornaviruses and rotaviruses.

Impact of climatic, demographic and disease control factors on the transmission dynamics of COVID-19 in large cities worldwide.

Approximately a year into the COVID-19 pandemic caused by the SARS-CoV-2 virus, many countries have seen additional "waves" of infections, especially in the temperate northern hemisphere. Other vulnerable regions, such as South Africa and several parts of South America have also seen cases rise, further impacting local economies and livelihoods. Despite substantial research efforts to date, it remains unresolved as to whether COVID-19 transmission has the same sensitivity to climate observed for other common respiratory viruses such as seasonal influenza. Here, we look for empirical evidence of seasonality using a robust estimation framework. For 359 large cities across the world, we estimated the basic reproduction number (R0) using logistic growth curves fitted to cumulative case data. We then assess evidence for association with climatic variables through ordinary least squares (OLS) regression. We find evidence of seasonality, with lower R0 within cities experiencing greater surface radiation (coefficient = -0.005, p < 0.001), after adjusting for city-level variation in demographic and disease control factors. Additionally, we find association between R0 and temperature during the early phase of the epidemic in China. However, climatic variables had much weaker explanatory power compared to socioeconomic and disease control factors. Rates of transmission and health burden of the continuing pandemic will be ultimately determined by population factors and disease control policies.

Laboratory transmission potential of British mosquitoes for equine arboviruses.

BACKGROUND: There has been no evidence of transmission of mosquito-borne arboviruses of equine or human health concern to date in the UK. However, in recent years there have been a number of outbreaks of viral diseases spread by vectors in Europe. These events, in conjunction with increasing rates of globalisation and climate change, have led to concern over the future risk of mosquito-borne viral disease outbreaks in northern Europe and have highlighted the importance of being prepared for potential disease outbreaks. Here we assess several UK mosquito species for their potential to transmit arboviruses important for both equine and human health, as measured by the presence of viral RNA in saliva at different time points after taking an infective blood meal. RESULTS: The following wild-caught British mosquitoes were evaluated for their potential as vectors of zoonotic equine arboviruses: Ochlerotatus detritus for Venezuelan equine encephalitis virus (VEEV) and Ross River virus (RRV), and Culiseta annulata and Culex pipiens for Japanese encephalitis virus (JEV). Production of RNA in saliva was demonstrated at varying efficiencies for all mosquito-virus pairs. Ochlerotatus detritus was more permissive for production of RRV RNA in saliva than VEEV RNA. For RRV, 27.3% of mosquitoes expectorated viral RNA at 7 days post-infection when incubated at 21 °C and 50% at 24 °C. Strikingly, 72% of Cx. pipiens produced JEV RNA in saliva after 21 days at 18 °C. For some mosquito-virus pairs, infection and salivary RNA titres reduced over time, suggesting unstable infection dynamics. CONCLUSIONS: This study adds to the number of Palaearctic mosquito species that demonstrate expectoration of viral RNA, for arboviruses of importance to human and equine health. This work adds to evidence that native mosquito species should be investigated further for their potential to vector zoonotic mosquito-borne arboviral disease of equines in northern Europe. The evidence that Cx. pipiens is potentially an efficient laboratory vector of JEV at temperatures as low as 18 °C warrants further investigation, as this mosquito is abundant in cooler regions of Europe and is considered an important vector for West Nile Virus, which has a comparable transmission ecology.

Co-occurrence of viruses and mosquitoes at the vectors' optimal climate range: An underestimated risk to temperate regions?

Mosquito-borne viruses have been estimated to cause over 100 million cases of human disease annually. Many methodologies have been developed to help identify areas most at risk from transmission of these viruses. However, generally, these methodologies focus predominantly on the effects of climate on either the vectors or the pathogens they spread, and do not consider the dynamic interaction between the optimal conditions for both vector and virus. Here, we use a new approach that considers the complex interplay between the optimal temperature for virus transmission, and the optimal climate for the mosquito vectors. Using published geolocated data we identified temperature and rainfall ranges in which a number of mosquito vectors have been observed to co-occur with West Nile virus, dengue virus or chikungunya virus. We then investigated whether the optimal climate for co-occurrence of vector and virus varies between "warmer" and "cooler" adapted vectors for the same virus. We found that different mosquito vectors co-occur with the same virus at different temperatures, despite significant overlap in vector temperature ranges. Specifically, we found that co-occurrence correlates with the optimal climatic conditions for the respective vector; cooler-adapted mosquitoes tend to co-occur with the same virus in cooler conditions than their warmer-adapted counterparts. We conclude that mosquitoes appear to be most able to transmit virus in the mosquitoes' optimal climate range, and hypothesise that this may be due to proportionally over-extended vector longevity, and other increased fitness attributes, within this optimal range. These results suggest that the threat posed by vector-competent mosquito species indigenous to temperate regions may have been underestimated, whilst the threat arising from invasive tropical vectors moving to cooler temperate regions may be overestimated.

Evaluation of the vector competence of a native UK mosquito Ochlerotatus detritus (Aedes detritus) for dengue, chikungunya and West Nile viruses.

BACKGROUND: To date there has been no evidence of mosquito-borne virus transmission of public health concern in the UK, despite the occurrence of more than 30 species of mosquito, including putative vectors of arboviruses. The saltmarsh mosquito Ochlerotatus detritus [syn. Aedes (Ochlerotatus) detritus] is locally common in parts of the UK where it can be a voracious feeder on people. METHODS: Here, we assess the competence of O. detritus for three major arboviruses: dengue virus (DENV), chikungunya virus (CHIKV) and West Nile virus (WNV) using adult mosquitoes reared from wild, field-obtained immatures. RESULTS: We demonstrate laboratory competence for WNV at 21 °C, with viral RNA detected in the mosquito's saliva 17 days after oral inoculation. By contrast, there was no evidence of laboratory competence of O. detritus for either DENV or CHIKV. CONCLUSIONS: To our knowledge, this is the first study to demonstrate competence of a UK mosquito for WNV and confirms that O. detritus may present a potential risk for arbovirus transmission in the UK and that further investigation of its vector role in the wild is required.

Antidepressant prescribing practices of outpatient psychiatrists.

BACKGROUND: The authors examined recent changes in the number and proportion of patients prescribed antidepressants by psychiatrists in outpatient private practice and characterized antidepressant prescription patterns by patient age, sex, race, payment source, and clinical diagnosis. METHODS: The authors analyzed physician-reported data from the 1985 and 1993-1994 National Ambulatory Medical Care Survey, focusing on visits to physicians specializing in psychiatry. Logistic regressions were used to examine associations between survey year and antidepressant prescription, adjusting for the presence of other variables. RESULTS: The proportion of outpatient psychiatric visits in which an antidepressant was prescribed increased from 23.1% (95% confidence interval [CI], 19.7%-26.5%) in 1985 to 48.6% (95% CI, 47.5%-49.7%) in 1993-1994. After controlling for several patient variables, psychiatric patients were approximately 2.3 (95% CI, 1.8-2.9) times more likely to receive an antidepressant in 1993-1994 than in 1985. In 1993-1994, selective serotonin reuptake inhibitors accounted for approximately half of the psychiatric visits with an antidepressant prescription. Increases in the rate of antidepressant prescription were particularly evident for children and young adults; whites; new patients; and patients with adjustment disorders, personality disorders, depression not otherwise specified or dysthymia, and some anxiety disorders. CONCLUSIONS: During the late 1980s and early 1990s, there was a significant increase in the prescription of antidepressants by office-based psychiatrists. This increase was greatest for patients with less severe psychiatric disorders.

Psychiatric patients and treatments in 1997: findings from the American Psychiatric Practice Research Network.

Despite extensive studies on the epidemiology of mental disorders and advances in the treatment of these conditions, there is a paucity of detailed information concerning the characteristics of psychiatric patients and how treatments are administered in routine psychiatric practice. This 1997 observational study collected detailed information from 417 psychiatrists on the demographic, diagnostic, clinical, and treatment characteristics of a systematic sample of 1228 patients. Six hundred thirty-seven patients (51.9%) were women and the mean patient age was 41.9 years. The most common diagnostic category (53.7%) was mood disorders, followed by schizophrenia/psychotic disorders (14.6%), anxiety disorders (9.3%), and disorders of childhood (7.7%). Six hundred seventy-one patients (54.6%) had at least one comorbid Axis I condition and almost half (49.8%) had a history of psychiatric hospitalization. Patients received a mean of 2.0 psychotherapeutic medications, most commonly antidepressants (62.3%). Findings demonstrate that psychiatrists in routine practice treat a patient population with severe, complex conditions.

Trends in office-based psychiatric practice.

OBJECTIVE: The authors examine trends in the composition and duration of visits to psychiatrists in office-based psychiatric practice. METHOD: An analysis was performed of physician-reported data from the 1985 and 1995 National Ambulatory Medical Care Surveys focusing on visits to physicians specializing in psychiatry. Secular changes in visit characteristics were assessed, and mean visit durations were determined for selected sociodemographic and clinical groups. RESULTS: In the decade between 1985 and 1995, visits in office-based psychiatry became shorter, less often included psychotherapy, and more often included a medication prescription. The proportion of visits that were 10 minutes or less in length increased. A shortening in visit duration was most evident for younger patients, privately insured patients, and patients who were not prescribed a psychotropic medication. In the 1995 survey, 6.8% of the psychiatric visits included patient contact with another health care professional. CONCLUSIONS: Changing financial arrangements and new pharmacologic treatments may have contributed to these changes in practice style.

Understanding disability in mental and general medical conditions.

OBJECTIVE: This study characterized the prevalence, characteristics, and impact of mental and general medical disabilities in the United States. METHOD: The 1994-1995 National Health Interview Survey of Disability was the largest disability survey ever conducted in the United States. A national sample was screened for disability, defined as limitation or inability to participate in a major life activity. Analyses compared cohorts who attributed their disability to physical, mental, or combined conditions. RESULTS: Of 106,573 adults, 1.1% reported functional disability from mental conditions, 4.8% from general medical conditions, and 1.2% from combined mental and general medical conditions. Disabilities attributed to a mental condition were predominantly associated with social and cognitive difficulties, those attributed to general medical conditions with physical limitations, and combined disabilities with deficits spanning multiple domains. In multivariate models, comorbid medical and mental conditions were associated with a twofold increase in odds of unemployment and a two-thirds increase in odds of support on disability payments compared to respondents with a single form of disability. More than half the nonworking disabled reported that economic, social, and job-based barriers contributed to their inability to work. One-fourth of working disabled people reported discrimination on the basis of their disability during the past 5 years. CONCLUSIONS: An estimated three million Americans (one-third of disabled people) reported that a mental condition contributes to their disability. Mental, general medical, and combined conditions are associated with unique patterns of functional impairment. Social and economic factors and job discrimination may exacerbate the functional impairments resulting from clinical syndromes.

Self-reported anxiety, general medical conditions, and disability bed days.

OBJECTIVE: This study examined the effect of self-reported anxiety on the number of days persons with various general medical conditions spend in bed owing to disability. METHOD: Self-reported medical illness and disability data from a nationally representative household survey sample (N = 20,884) were analyzed. RESULTS: Among respondents with general medical conditions, those with self-reported anxiety had a nearly fourfold greater length of disability (mean = 18.0 bed days) than the nonanxious respondents (mean = 4.8 bed days). After adjustment for differences in demographic characteristics and burden of general medical illness, anxiety was associated with an additional 3.8 bed days. CONCLUSIONS: Self-reported anxiety in combination with general medical conditions may be associated with extensive functional impairment.

Therapeutic drug monitoring of mood stabilizers in Medicaid patients with bipolar disorder.

OBJECTIVE: The authors' goal was to determine the extent and pattern of blood serum monitoring of mood stabilizers in Medicaid patients with bipolar disorder. METHOD: Data were drawn from a Medicaid medical claims data set from Pittsburgh and the surrounding region. The authors identified bipolar patients using lithium, valproate, and carbamazepine (N = 718) and then examined the patient demographic, diagnostic, and service use variables associated with therapeutic drug monitoring. RESULTS: A substantial proportion of lithium users (36.5%), valproate users (42.4%), and carbamazepine users (42.2%) with bipolar disorder diagnoses did not receive therapeutic drug level testing during the 12-month study period. Carbamazepine users who were male or in the 30-49-year age range were significantly less likely to be tested for serum drug level. Lithium users who did not receive partial-hospitalization psychiatric services and valproate users who received mental health case management were also less likely to be tested for serum drug level. Over one-half of the lithium users (54.1%) did not receive thyroid function tests, and few (4.2%) received renal function tests. Patients who did receive tests for serum drug level were likely to receive the other recommended tests. CONCLUSIONS: Many Medicaid patients with bipolar disorder received no therapeutic drug monitoring. Patient sociodemographic characteristics contributed little to explaining this omission, although some types of service utilization were related to rates of serum drug level testing.