The antiviral state has shaped the CpG composition of the vertebrate interferome to avoid self-targeting.

Antiviral defenses can sense viral RNAs and mediate their destruction. This presents a challenge for host cells since they must destroy viral RNAs while sparing the host mRNAs that encode antiviral effectors. Here, we show that highly upregulated interferon-stimulated genes (ISGs), which encode antiviral proteins, have distinctive nucleotide compositions. We propose that self-targeting by antiviral effectors has selected for ISG transcripts that occupy a less self-targeted sequence space. Following interferon (IFN) stimulation, the CpG-targeting antiviral effector zinc-finger antiviral protein (ZAP) reduces the mRNA abundance of multiple host transcripts, providing a mechanistic explanation for the repression of many (but not all) interferon-repressed genes (IRGs). Notably, IRGs tend to be relatively CpG rich. In contrast, highly upregulated ISGs tend to be strongly CpG suppressed. Thus, ZAP is an example of an effector that has not only selected compositional biases in viral genomes but also appears to have notably shaped the composition of host transcripts in the vertebrate interferome.

Heritability of biting time behaviours in the major African malaria vector Anopheles arabiensis.

BACKGROUND: The use of insecticide-treated nets for malaria control has been associated with shifts in mosquito vector feeding behaviour including earlier and outdoor biting on humans. The relative contribution of phenotypic plasticity and heritability to these behavioural shifts is unknown. Elucidation of the mechanisms behind these shifts is crucial for anticipating impacts on vector control. METHODS: A novel portable semi-field system (PSFS) was used to experimentally measure heritability of biting time in the malaria vector Anopheles arabiensis in Tanzania. Wild An. arabiensis from hourly collections using the human landing catch (HLC) method were grouped into one of 3 categories based on their time of capture: early (18:00-21:00), mid (22:00-04:00), and late (05:00-07:00) biting, and placed in separate holding cages. Mosquitoes were then provided with a blood meal for egg production and formation of first filial generation (F1). The F1 generation of each biting time phenotype category was reared separately, and blood fed at the same time as their mothers were captured host-seeking. The resultant eggs were used to generate the F2 generation for use in heritability assays. Heritability was assessed by releasing F2 An. arabiensis into the PSFS, recording their biting time during a human landing catch and comparing it to that of their F0 grandmothers. RESULTS: In PSFS assays, the biting time of F2 offspring (early: 18:00-21:00, mid: 22:00-04:00 or late: 05:00-07:00) was significantly positively associated with that of their wild-caught F0 grandmothers, corresponding to an estimated heritability of 0.110 (95% CI 0.003, 0.208). F2 from early-biting F0 were more likely to bite early than F2 from mid or late-biting F0. Similarly, the probability of biting late was higher in F2 derived from mid and late-biting F0 than from early-biting F0. CONCLUSIONS: Despite modest heritability, our results suggest that some of the variation in biting time is attributable to additive genetic variation. Selection can, therefore, act efficiently on mosquito biting times, highlighting the need for control methods that target early and outdoor biting mosquitoes.

Evaluating the potential of whole-genome sequencing for tracing transmission routes in experimental infections and natural outbreaks of bovine respiratory syncytial virus.

Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in cattle. Genomic sequencing can resolve phylogenetic relationships between virus populations, which can be used to infer transmission routes and potentially inform the design of biosecurity measures. Sequencing of short (<2000 nt) segments of the 15 000-nt BRSV genome has revealed geographic and temporal clustering of BRSV populations, but insufficient variation to distinguish viruses collected from herds infected close together in space and time. This study investigated the potential for whole-genome sequencing to reveal sufficient genomic variation for inferring transmission routes between herds. Next-generation sequencing (NGS) data were generated from experimental infections and from natural outbreaks in Jämtland and Uppsala counties in Sweden. Sufficient depth of coverage for analysis of consensus and sub-consensus sequence diversity was obtained from 47 to 20 samples respectively. Few (range: 0-6 polymorphisms across the six experiments) consensus-level polymorphisms were observed along experimental transmissions. A much higher level of diversity (146 polymorphic sites) was found among the consensus sequences from the outbreak samples. The majority (144/146) of polymorphisms were between rather than within counties, suggesting that consensus whole-genome sequences show insufficient spatial resolution for inferring direct transmission routes, but might allow identification of outbreak sources at the regional scale. By contrast, within-sample diversity was generally higher in the experimental than the outbreak samples. Analyses to infer known (experimental) and suspected (outbreak) transmission links from within-sample diversity data were uninformative. In conclusion, analysis of the whole-genome sequence of BRSV from experimental samples discriminated between circulating isolates from distant areas, but insufficient diversity was observed between closely related isolates to aid local transmission route inference.

Virus-virus interactions impact the population dynamics of influenza and the common cold.

The human respiratory tract hosts a diverse community of cocirculating viruses that are responsible for acute respiratory infections. This shared niche provides the opportunity for virus-virus interactions which have the potential to affect individual infection risks and in turn influence dynamics of infection at population scales. However, quantitative evidence for interactions has lacked suitable data and appropriate analytical tools. Here, we expose and quantify interactions among respiratory viruses using bespoke analyses of infection time series at the population scale and coinfections at the individual host scale. We analyzed diagnostic data from 44,230 cases of respiratory illness that were tested for 11 taxonomically broad groups of respiratory viruses over 9 y. Key to our analyses was accounting for alternative drivers of correlated infection frequency, such as age and seasonal dependencies in infection risk, allowing us to obtain strong support for the existence of negative interactions between influenza and noninfluenza viruses and positive interactions among noninfluenza viruses. In mathematical simulations that mimic 2-pathogen dynamics, we show that transient immune-mediated interference can cause a relatively ubiquitous common cold-like virus to diminish during peak activity of a seasonal virus, supporting the potential role of innate immunity in driving the asynchronous circulation of influenza A and rhinovirus. These findings have important implications for understanding the linked epidemiological dynamics of viral respiratory infections, an important step towards improved accuracy of disease forecasting models and evaluation of disease control interventions.

Towards the elimination of dog-mediated rabies: development and application of an evidence-based management tool.

BACKGROUND: International organizations advocate for the elimination of dog-mediated rabies, but there is only limited guidance on interpreting surveillance data for managing elimination programmes. With the regional programme in Latin America approaching elimination of dog-mediated rabies, we aimed to develop a tool to evaluate the programme's performance and generate locally-tailored rabies control programme management guidance to overcome remaining obstacles. METHODS: We developed and validated a robust algorithm to classify progress towards rabies elimination within sub-national administrative units, which we applied to surveillance data from Brazil and Mexico. The method combines criteria that are easy to understand, including logistic regression analysis of case detection time series, assessment of rabies virus variants, and of incursion risk. Subjecting the algorithm to robustness testing, we further employed simulated data sub-sampled at differing levels of case detection to assess the algorithm's performance and sensitivity to surveillance quality. RESULTS: Our tool demonstrated clear epidemiological transitions in Mexico and Brazil: most states progressed rapidly towards elimination, but a few regressed due to incursions and control lapses. In 2015, dog-mediated rabies continued to circulate in the poorest states, with foci remaining in only 1 of 32 states in Mexico, and 2 of 27 in Brazil, posing incursion risks to the wider region. The classification tool was robust in determining epidemiological status irrespective of most levels of surveillance quality. In endemic settings, surveillance would need to detect less than 2.5% of all circulating cases to result in misclassification, whereas in settings where incursions become the main source of cases the threshold detection level for correct classification should not be less than 5%. CONCLUSION: Our tool provides guidance on how to progress effectively towards elimination targets and tailor strategies to local epidemiological situations, while revealing insights into rabies dynamics. Post-campaign assessments of dog vaccination coverage in endemic states, and enhanced surveillance to verify and maintain freedom in states threatened by incursions were identified as priorities to catalyze progress towards elimination. Our finding suggests genomic surveillance should become increasingly valuable during the endgame for discriminating circulating variants and pinpointing sources of incursions.

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper.

An improved mosquito electrocuting trap that safely reproduces epidemiologically relevant metrics of mosquito human-feeding behaviours as determined by human landing catch.

BACKGROUND: Reliable quantification of mosquito host-seeking behaviours is required to determine the efficacy of vector control methods. For malaria, the gold standard approach remains the risky human landing catch (HLC). Here compare the performance of an improved prototype of the mosquito electrocuting grid trap (MET) as a safer alternative with HLC for measuring malaria vector behaviour in Dar es Salaam, Tanzania. METHODS: Mosquito trapping was conducted at three sites within Dar es Salaam representing a range of urbanicity over a 7-month period (December 2012-July 2013, 168 sampling nights). At each site, sampling was conducted in a block of four houses, with two houses being allocated to HLC and the other to MET on each night of study. Sampling was conducted both indoors and outdoors (from 19:00 to 06:00 each night) at all houses, with trapping method (HLC and MET) being exchanged between pairs of houses at each site using a crossover design. RESULTS: The MET caught significantly more Anopheles gambiae sensu lato than the HLC, both indoors (RR [95 % confidence interval (CI)]) = 1.47 [1.23-1.76], P < 0.0001 and outdoors = 1.38 [1.14-1.67], P < 0.0001). The sensitivity of MET compared with HLC did not detectably change over the course of night for either An. gambiae s.l. (OR [CI]) = 1.01 [0.94-1.02], P = 0.27) or Culex spp. (OR [CI]) = 0.99 [0.99-1.0], P = 0.17) indoors and declined only slightly outdoors: An. gambiae s.l. (OR [CI]) = 0.92 [0.86-0.99], P = 0.04), and Culex spp. (OR [CI]) = 0.99 [0.98-0.99], P = 0.03). MET-based estimates of the proportions of mosquitoes caught indoors (P i ) or during sleeping hours (P fl ), as well as the proportion of human exposure to bites that would otherwise occurs indoors (π i ), were statistically indistinguishable from those based on HLC for An. gambiae s.l. (P = 0.43, 0.07 and 0.48, respectively) and Culex spp. (P = 0.76, 0.24 and 0.55, respectively). CONCLUSIONS: This improved MET prototype is highly sensitive tool that accurately quantifies epidemiologically-relevant metrics of mosquito biting densities, behaviours and human exposure distribution.

Erratum to: Development and evaluation of mosquito-electrocuting traps as alternatives to the human landing catch technique for sampling host-seeking malaria vectors.

[This corrects the article DOI: 10.1186/s12936-015-1025-4.].

Modeling HLA associations with EBV-positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis.

HLA genotyping and genome wide association studies provide strong evidence for associations between Human Leukocyte Antigen (HLA) alleles and classical Hodgkin lymphoma (cHL). Analysis of these associations is complicated by the extensive linkage disequilibrium within the major histocompatibility region and recent data suggesting that associations with EBV-positive and EBV-negative cHL are largely distinct. To distinguish independent and therefore potentially causal associations from associations confounded by linkage disequilibrium, we applied a variable selection regression modeling procedure to directly typed HLA class I and II genes and selected SNPs from EBV-stratified patient subgroups. In final models, HLA-A*01:01 and B*37:01 were associated with an increased risk of EBV-positive cHL whereas DRB1*15:01 and DPB1*01:01 were associated with decreased risk. Effects were independent of a prior history of infectious mononucleosis. For EBV-negative cHL the class II SNP rs6903608 remained the strongest predictor of disease risk after adjusting for the effects of common HLA alleles. Associations with "all cHL" and differences by case EBV status reflected the subgroup analysis. In conclusion, this study extends previous findings by identifying novel HLA associations with EBV-stratified subgroups of cHL, highlighting those alleles likely to be biologically relevant and strengthening evidence implicating genetic variation associated with the SNP rs6903608.

Development and evaluation of mosquito-electrocuting traps as alternatives to the human landing catch technique for sampling host-seeking malaria vectors.

BACKGROUND: The human landing catch (HLC) is the gold standard method for sampling host-seeking malaria vectors. However, the HLC is ethically questionable because it requires exposure of humans to potentially infectious mosquito bites. METHODS: Two exposure-free methods for sampling host-seeking mosquitoes were evaluated using electrocuting surfaces as potential replacements for HLC: (1) a previously evaluated, commercially available electrocuting grid (CA-EG) designed for killing flies, and (2) a custom-made mosquito electrocuting trap (MET) designed to kill African malaria vectors. The MET and the CA-EG were evaluated relative to the HLC in a Latin Square experiment conducted in the Kilombero Valley, Tanzania. The sampling consistency of the traps across the night and at varying mosquito densities was investigated. Estimates of the proportion of mosquitoes caught indoors (P(i)), proportion of human exposure occurring indoors (π(i)), and proportion of mosquitoes caught when most people are likely to be indoors (P(fl)) were compared for all traps. RESULTS: Whereas the CA-EG performed poorly (<10% of catch of HLC), sampling efficiency of the MET for sampling Anopheles funestus s.l. was indistinguishable from HLC indoors and outdoors. For Anopheles gambiae s.l., sampling sensitivity of MET was 20.9% (95% CI 10.3-42.2) indoors and 58.5% (95% CI 32.2-106.2) outdoors relative to HLC. There was no evidence of density-dependent sampling by the MET or CA-EG. Similar estimates of P(i) were obtained for An. gambiae s.l. and An. funestus s.l. from all trapping methods. The proportion of mosquitoes caught when people are usually indoors (P(fl)) was underestimated by the CA-EG and MET for An. gambiae s.l., but similar to the HLC for An. funestus. Estimates of the proportion of human exposure occurring indoors (π(i)) obtained from the CA-EG and MET were similar to the HLC for An. gambiae s.l., but overestimated for An. funestus. CONCLUSIONS: The MET showed promise as an outdoor sampling tool for malaria vectors where it achieved >50% sampling sensitivity relative to the HLC. The CA-EG had poor sampling sensitivity outdoors and inside. With further modification, the MET could provide an efficient and safer alternative to the HLC for the surveillance of mosquito vectors outdoors.

Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.

Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

Association between parent-infant interactions in infancy and disruptive behaviour disorders at age seven: a nested, case-control ALSPAC study.

BACKGROUND: Effective early intervention to prevent oppositional/conduct disorders requires early identification of children at risk. Patterns of parent-child interaction may predict oppositional/conduct disorders but large community-based prospective studies are needed to evaluate this possibility. METHODS: We sought to examine whether the Mellow Parenting Observational System (MPOS) used to assess parent-infant interactions at one year was associated with psychopathology at age 7. The MPOS assesses positive and negative interactions between parent and child. It examines six dimensions: anticipation of child's needs, responsiveness, autonomy, cooperation, containment of child distress, and control/conflict; these are summed to produce measures of total positive and negative interactions. We examined videos from the Avon Longitudinal Study of Parents and Children (ALSPAC) sub-cohort who attended the 'Children in Focus' clinic at one year of age. Our sample comprised 180 videos of parent-infant interaction: 60 from infants who received a psychiatric diagnostic categorisation at seven years and 120 randomly selected controls who were group-matched on sex. RESULTS: A negative association between positive interactions and oppositional/conduct disorders was found. With the exception of pervasive developmental disorders (autism), an increase of one positive interaction per minute predicted a 15% (95% CI: 4% to 26%) reduction in the odds of the infant being case diagnosed. There was no statistically significant relationship between negative parenting interactions and oppositional/conduct disorders, although negative interactions were rarely observed in this setting. CONCLUSIONS: The Mellow Parenting Observation System, specifically low scores for positive parenting interactions (such as Responsiveness which encompasses parental warmth towards the infant), predicted later psychiatric diagnostic categorisation of oppositional/conduct disorders.

Predictors of positive and negative parenting behaviours: evidence from the ALSPAC cohort.

BACKGROUND: This study aimed to establish the predictors of positive and negative parenting behaviours in a United Kingdom population. The majority of previous research has focused on specific risk factors and has used a variety of outcome measures. This study used a single assessment of parenting behaviours and started with a wide range of potential pre- and post-natal variables; such an approach might be used to identify families who might benefit from parenting interventions. METHODS: Using a case-control subsample of 160 subjects from the Avon Longitudinal Study of Parents and Children (ALSPAC), regression analysis was undertaken to model parenting behaviours at 12 months as measured by the Mellow Parenting Observational System. RESULTS: Positive parenting increased with maternal age at delivery, levels of education and with prenatal anxiety. More negative interactions were observed among younger mothers, mothers with male infants, with prenatal non-smokers and among mothers who perceived they had a poor support structure. CONCLUSIONS: This study indicates two factors which may be important in identifying families most at risk of negative parenting: younger maternal age at delivery and lack of social support during pregnancy. Such factors could be taken into account when planning provision of services such as parenting interventions. We also established that male children were significantly more likely to be negatively parented, a novel finding which may suggest an area for future research. However the findings have to be accepted cautiously and have to be replicated, as the measures used do not have established psychometric validity and reliability data.

Improving the efficiency of stroke trials: feasibility and efficacy of group adjudication of functional end points.

BACKGROUND AND PURPOSE: Use of the modified Rankin scale (mRS) in multicenter trials may be limited by interobserver variability. We assessed the effect of this on trial power and developed a novel group adjudication approach. METHODS: We generated power and sample size estimates from simulated trials modeled with varying mRS reliability. We conducted a virtual acute stroke trial across 14 UK sites to develop a group adjudication approach. Traditional mRS interviews, performed at local sites, were digitally recorded and scored by adjudication committee. We assessed the effect of translation by comparing scores in translated mRS interviews, originally conducted in English and Mandarin. Agreement was measured using κ and weighted κ (κw) statistics and intraclass correlation coefficient. RESULTS: Statistical simulations suggest that improving mRS reliability from κ=0.25 to κ=0.5 or 0.7 may allow reductions in sample size of n=386 or 490 in a typical n=2000 study. Our virtual acute stroke trial included 370 participants and 563 mRS video assessments. We adjudicated mRS in 538 of 563 (96%) study visits. At 30 and 90 days, 161 of 280 (57.5%) and 131 of 258 (50.8%) clips showed interobserver disagreement. Agreement within the adjudication committee was good (30-day κw=0.85 [95% confidence interval, 0.81-0.86]; 90-day κw=0.86 [95% confidence interval, 0.82-0.88]) without significant or systematic bias in mRS scoring compared with the local mRS. Interobserver reliability of translated mRS assessments was similar to native language clips (native [n=69] κw=0.91 [95% confidence interval, 0.94-0.99]; translated [n=89] κw=0.90 [95% confidence interval, 0.83-0.96]). CONCLUSIONS: Achievable improvements in interobserver reliability may substantially reduce study sample size, with associated financial benefits. Central adjudication of mRS assessments is feasible (including across international centers), valid and reliable despite the challenges of mRS assessment in large clinical trials.

Prediction of 7-year psychopathology from mother-infant joint attention behaviours: a nested case-control study.

BACKGROUND: To investigate whether later diagnosis of psychiatric disorder can be predicted from analysis of mother-infant joint attention (JA) behaviours in social-communicative interaction at 12 months. METHOD: Using data from a large contemporary birth cohort, we examined 159 videos of a mother-infant interaction for joint attention behaviour when children were aged one year, sampled from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Fifty-three of the videos involved infants who were later considered to have a psychiatric disorder at seven years and 106 were same aged controls. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorder, attention-deficit/hyperactivity disorder, pervasive development disorder, anxiety and depressive disorders. Psychiatric diagnoses were obtained using the Development and Wellbeing Assessment when the children were seven years old. RESULTS: None of the three JA behaviours (shared look rate, shared attention rate and shared attention intensity) showed a significant association with the primary outcome of case-control status. Only shared look rate predicted any of the exploratory sub-diagnosis outcomes and was found to be positively associated with later oppositional-conduct disorders (OR [95% CI]: 1.5 [1.0, 2.3]; p = 0.041). CONCLUSIONS: JA behaviours did not, in general, predict later psychopathology. However, shared look was positively associated with later oppositional-conduct disorders. This suggests that some features of JA may be early markers of later psychopathology. Further investigation will be required to determine whether any JA behaviours can be used to screen for families in need of intervention.

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma.

A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.

Does aerobic scope influence geographical distribution of teleost fishes?

Many abiotic and biotic factors are known to shape species' distributions, but we lack understanding of how innate physiological traits, such as aerobic scope (AS), may influence the latitudinal range of species. Based on theoretical assumptions, a positive link between AS and distribution range has been proposed, but there has been no broad comparative study across species to test this hypothesis. We collected metabolic rate data from the literature and performed a phylogenetically informed analysis to investigate the influence of AS on the current geographical distributions of 111 teleost fish species. Contrary to expectations, we found a negative relationship between absolute latitude range and thermal peak AS in temperate fishes. We found no evidence for an association between thermal range of AS and the range of latitudes occupied for 32 species. Our main results therefore contradict the prevailing theory of a positive link between AS and distribution range in fish.

Modeling the effectiveness of targeting Rift Valley fever virus vaccination using imperfect network information.

Livestock movements contribute to the spread of several infectious diseases. Data on livestock movements can therefore be harnessed to guide policy on targeted interventions for controlling infectious livestock diseases, including Rift Valley fever (RVF)-a vaccine-preventable arboviral fever. Detailed livestock movement data are known to be useful for targeting control efforts including vaccination. These data are available in many countries, however, such data are generally lacking in others, including many in East Africa, where multiple RVF outbreaks have been reported in recent years. Available movement data are imperfect, and the impact of this uncertainty in the utility of movement data on informing targeting of vaccination is not fully understood. Here, we used a network simulation model to describe the spread of RVF within and between 398 wards in northern Tanzania connected by cattle movements, on which we evaluated the impact of targeting vaccination using imperfect movement data. We show that pre-emptive vaccination guided by only market movement permit data could prevent large outbreaks. Targeted control (either by the risk of RVF introduction or onward transmission) at any level of imperfect movement information is preferred over random vaccination, and any improvement in information reliability is advantageous to their effectiveness. Our modeling approach demonstrates how targeted interventions can be effectively used to inform animal and public health policies for disease control planning. This is particularly valuable in settings where detailed data on livestock movements are either unavailable or imperfect due to resource limitations in data collection, as well as challenges associated with poor compliance.

Master statistical analysis plan: attractive targeted sugar bait phase III trials in Kenya, Mali, and Zambia.

This manuscript is a master statistical analysis plan for each of three-cluster randomized controlled trials to evaluate the efficacy of attractive targeted sugar baits (ATSB) described in an already published protocol. The master SAP contains an overarching plan for all three trials, which can be adapted to trial-specific circumstances. The primary objective of the trials is to evaluate the efficacy of ATSB in the presence of universal vector control coverage with insecticide-treated nets (ITN) or indoor residual spraying (IRS) after two transmission seasons on clinical malaria incidence as compared with universal vector control coverage with ITN or IRS alone. The primary outcome measure is the incidence rate of clinical malaria, assessed in cohorts aged 12 months to less than 15 years (≥ 5 years to 15 years in Mali) during monthly follow-up visits. The primary unadjusted analysis will be conducted on the intention-to-treat analysis population without adjustment for any anticipated confounding variables. The primary outcome will be analyzed using a multi-level model constructed on a generalized linear model framework with a Poisson likelihood and a log link function. Random intercepts will be included for each study cluster and a fixed effect for study-arm. The analyst will be blinded to study arm assignment. Several secondary outcomes will be analyzed, as well as a pooled analysis (individual patient data meta-analysis) across the three trial sites. Additionally, a standard meta-analysis is expected to be conducted using combined data from all sites.

Integrating contact tracing and whole-genome sequencing to track the elimination of dog-mediated rabies: An observational and genomic study.

Background: Dog-mediated rabies is endemic across Africa causing thousands of human deaths annually. A One Health approach to rabies is advocated, comprising emergency post-exposure vaccination of bite victims and mass dog vaccination to break the transmission cycle. However, the impacts and cost-effectiveness of these components are difficult to disentangle. Methods: We combined contact tracing with whole-genome sequencing to track rabies transmission in the animal reservoir and spillover risk to humans from 2010 to 2020, investigating how the components of a One Health approach reduced the disease burden and eliminated rabies from Pemba Island, Tanzania. With the resulting high-resolution spatiotemporal and genomic data, we inferred transmission chains and estimated case detection. Using a decision tree model, we quantified the public health burden and evaluated the impact and cost-effectiveness of interventions over a 10-year time horizon. Results: We resolved five transmission chains co-circulating on Pemba from 2010 that were all eliminated by May 2014. During this period, rabid dogs, human rabies exposures and deaths all progressively declined following initiation and improved implementation of annual islandwide dog vaccination. We identified two introductions to Pemba in late 2016 that seeded re-emergence after dog vaccination had lapsed. The ensuing outbreak was eliminated in October 2018 through reinstated islandwide dog vaccination. While post-exposure vaccines were projected to be highly cost-effective ($256 per death averted), only dog vaccination interrupts transmission. A combined One Health approach of routine annual dog vaccination together with free post-exposure vaccines for bite victims, rapidly eliminates rabies, is highly cost-effective ($1657 per death averted) and by maintaining rabies freedom prevents over 30 families from suffering traumatic rabid dog bites annually on Pemba island. Conclusions: A One Health approach underpinned by dog vaccination is an efficient, cost-effective, equitable, and feasible approach to rabies elimination, but needs scaling up across connected populations to sustain the benefits of elimination, as seen on Pemba, and for similar progress to be achieved elsewhere. Funding: Wellcome [207569/Z/17/Z, 095787/Z/11/Z, 103270/Z/13/Z], the UBS Optimus Foundation, the Department of Health and Human Services of the National Institutes of Health [R01AI141712] and the DELTAS Africa Initiative [Afrique One-ASPIRE/DEL-15-008] comprising a donor consortium of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA), the New Partnership for Africa's Development Planning and Coordinating (NEPAD) Agency, Wellcome [107753/A/15/Z], Royal Society of Tropical Medicine and Hygiene Small Grant 2017 [GR000892] and the UK government. The rabies elimination demonstration project from 2010-2015 was supported by the Bill & Melinda Gates Foundation [OPP49679]. Whole-genome sequencing was partially supported from APHA by funding from the UK Department for Environment, Food and Rural Affairs (Defra), Scottish government and Welsh government under projects SEV3500 and SE0421.