Nonsecretor Histo-blood Group Antigen Phenotype Is Associated With Reduced Risk of Clinical Rotavirus Vaccine Failure in Malawian Infants

Background Histo–blood group antigen (HBGA) Lewis/secretor phenotypes predict genotype-specific susceptibility to rotavirus gastroenteritis (RVGE). We tested the hypothesis that nonsecretor/Lewis-negative phenotype leads to reduced vaccine take and lower clinical protection following vaccination with G1P[8] rotavirus vaccine (RV1) in Malawian infants Methods A cohort study recruited infants receiving RV1 at age 6 and 10 weeks. HBGA phenotype was determined by salivary enzyme-linked immunosorbent assay (ELISA). RV1 vaccine virus shedding was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in stool collected on alternate days for 10 days post-immunization. Plasma rotavirus–specific immunoglobulin A was determined by ELISA pre- and post-immunization. In a case-control study, HBGA phenotype distribution was compared between RV1-vaccinated infants with RVGE and 1:1 age-matched community controls. Rotavirus genotype was determined by RT-PCR. Results In 202 cohort participants, neither overall vaccine virus fecal shedding nor seroconversion differed by HBGA phenotype. In 238 case-control infants, nonsecretor phenotype was less common in infants with clinical vaccine failure (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.20–0.75). Nonsecretor phenotype was less common in infants with P[8] RVGE (OR, 0.12; 95% CI, 0.03–0.50) and P[4] RVGE (OR, 0.17; 95% CI, 0.04–0.75). Lewis-negative phenotype was more common in infants with P[6] RVGE (OR, 3.2; 95% CI, 1.4–7.2). Conclusions Nonsecretor phenotype was associated with reduced risk of rotavirus vaccine failure. There was no significant association between HBGA phenotype and vaccine take. These data refute the hypothesis that high prevalence of nonsecretor/Lewis-negative phenotypes contributes to lower rotavirus vaccine effectiveness in Malawi

A Spatial and Temporal Risk Assessment of the Impacts of El Niño on the Tropical Forest Carbon Cycle: Theoretical Framework, Scenarios, and Implications

Strong El Niño events alter tropical climates and may lead to a negative carbon balance in tropical forests and consequently a disruption to the global carbon cycle. The complexity of tropical forests and the lack of data from these regions hamper the assessment of the spatial distribution of El Niño impacts on these ecosystems. Typically, maps of climate anomaly are used to detect areas of greater risk, ignoring baseline climate conditions and forest cover. Here, we integrated climate anomalies from the 1982–1983, 1997–1998, and 2015–2016 El Niño events with baseline climate and forest edge extent, using a risk assessment approach to hypothetically assess the spatial and temporal distributions of El Niño risk over tropical forests under several risk scenarios. The drivers of risk varied temporally and spatially. Overall, the relative risk of El Niño has been increasing driven mainly by intensified forest fragmentation that has led to a greater chance of fire ignition and increased mean annual air temperatures. We identified areas of repeated high risk, where conservation efforts and fire control measures should be focused to avoid future forest degradation and negative impacts on the carbon cycle

Karyotype and nuclear DNA content of hexa-, octo-, and duodecaploid lines of Bromus subgen. Ceratochloa

The subgenus Ceratochloa of the genus Bromus includes a number of closely related allopolyploid forms or species that present a difficult taxonomic problem. The present work combines data concerning chromosome length, heterochromatin distribution and nuclear genome size of different 6x, 8x and 12x accessions in this subgenus. Special attention is paid to the karyotype structure and genomic constitution of duodecaploid plants recently found in South America. Hexaploid lineages possess six almost indistinguishable genomes and a nuclear DNA content between 12.72 pg and 15.10 pg (mean 1Cx value = 2.32 pg), whereas octoploid lineages contain the same six genomes (AABBCC) plus two that are characterized by longer chromosomes and a greater DNA content (1Cx = 4.47 pg). Two duodecaploid accessions found in South America resemble each other and apparently differ from the North American duodecaploid B. arizonicus as regards chromosome size and nuclear DNA content (40.00 and 40.50 pg vs. 27.59 pg). These observations suggest that the South American duodecaploids represent a separate evolutionary lineage of the B. subgenus Ceratochloa, unrecognized heretofore

Who should be prioritized for renal transplantation?: Analysis of key stakeholder preferences using discrete choice experiments

Background Policies for allocating deceased donor kidneys have recently shifted from allocation based on Human Leucocyte Antigen (HLA) tissue matching in the UK and USA. Newer allocation algorithms incorporate waiting time as a primary factor, and in the UK, young adults are also favoured. However, there is little contemporary UK research on the views of stakeholders in the transplant process to inform future allocation policy. This research project aimed to address this issue. Methods Discrete Choice Experiment (DCE) questionnaires were used to establish priorities for kidney transplantation among different stakeholder groups in the UK. Questionnaires were targeted at patients, carers, donors / relatives of deceased donors, and healthcare professionals. Attributes considered included: waiting time; donor-recipient HLA match; whether a recipient had dependents; diseases affecting life expectancy; and diseases affecting quality of life. Results Responses were obtained from 908 patients (including 98 ethnic minorities); 41 carers; 48 donors / relatives of deceased donors; and 113 healthcare professionals. The patient group demonstrated statistically different preferences for every attribute (i.e. significantly different from zero) so implying that changes in given attributes affected preferences, except when prioritizing those with no rather than moderate diseases affecting quality of life. The attributes valued highly related to waiting time, tissue match, prioritizing those with dependents, and prioritizing those with moderate rather than severe diseases affecting life expectancy. Some preferences differed between healthcare professionals and patients, and ethnic minority and non-ethnic minority patients. Only non-ethnic minority patients and healthcare professionals clearly prioritized those with better tissue matches. Conclusions Our econometric results are broadly supportive of the 2006 shift in UK transplant policy which emphasized prioritizing the young and long waiters. However, our findings suggest the need for a further review in the light of observed differences in preferences amongst ethnic minorities, and also because those with dependents may be a further priority.</p

Effectiveness of Biosecurity Measures in Preventing Badger Visits to Farm Buildings

This is the final version of the article. Available from Public Library of Science via the DOI in this record.BACKGROUND: Bovine tuberculosis caused by Mycobacterium bovis is a serious and economically important disease of cattle. Badgers have been implicated in the transmission and maintenance of the disease in the UK since the 1970s. Recent studies have provided substantial evidence of widespread and frequent visits by badgers to farm buildings during which there is the potential for close direct contact with cattle and contamination of cattle feed. METHODOLOGY: Here we evaluated the effectiveness of simple exclusion measures in improving farm biosecurity and preventing badger visits to farm buildings. In the first phase of the study, 32 farms were surveyed using motion-triggered infrared cameras on potential entrances to farm buildings to determine the background level of badger visits experienced by each farm. In the second phase, they were divided into four treatment groups; "Control", "Feed Storage", "Cattle Housing" and "Both", whereby no exclusion measures were installed, exclusion measures were installed on feed storage areas only, cattle housing only or both feed storage and cattle housing, respectively. Badger exclusion measures included sheet metal gates, adjustable metal panels for gates, sheet metal fencing, feed bins and electric fencing. Cameras were deployed for at least 365 nights in each phase on each farm. RESULTS: Badger visits to farm buildings occurred on 19 of the 32 farms in phase one. In phase two, the simple exclusion measures were 100% effective in preventing badger entry into farm buildings, as long as they were appropriately deployed. Furthermore, the installation of exclusion measures also reduced the level of badger visits to the rest of the farmyard. The findings of the present study clearly demonstrate how relatively simple practical measures can substantially reduce the likelihood of badger visits to buildings and reduce some of the potential for contact and disease transmission between badgers and cattle.This work was funded by Defra project number SE3119, http://www.defra.gov.uk/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genome-wide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity

Regulation of the Na,K-ATPase Gamma-Subunit FXYD2 by Runx1 and Ret Signaling in Normal and Injured Non-Peptidergic Nociceptive Sensory Neurons

Dorsal root ganglia (DRGs) contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury

Community transmission of rotavirus infection in a vaccinated population in Blantyre, Malawi: a prospective household cohort study.

BACKGROUND: Rotavirus vaccine effectiveness is reduced among children in low-income countries. Indirect (transmission-mediated) effects of rotavirus vaccine might contribute to the total population effect of vaccination. We aimed to examine risk factors for transmission of rotavirus to household contacts in Blantyre, Malawi, and estimated the effectiveness of rotavirus vaccine in preventing transmission of infection to household contacts. METHODS: In this prospective household cohort study, we recruited children born after Sept 17, 2012, and aged at least 6 weeks (vaccine-eligible children) with acute rotavirus gastroenteritis and their household contacts, in four government health facilities in Blantyre, Malawi. Clinical data, a bulk stool sample, and 1-2 mL of serum were collected from case children at presentation. Clinical data and stool samples were also prospectively collected from household contacts over 14 days from presentation. A single stool sample was collected from control households containing asymptomatic children who were frequency age-matched to case children. Samples were tested for rotavirus using semi-quantitative real-time PCR and for anti-rotavirus IgA using a semi-quantitative sandwich ELISA. Risk factors for household transmission of rotavirus infection and clinical disease, including disease severity and faecal shedding density, were identified using mixed effects logistic regression. Vaccine effectiveness against transmission was estimated as 1 minus the ratio of secondary attack rates in vaccinated and counterfactual unvaccinated populations, using vaccine effectiveness estimates from the associated diarrhoeal surveillance platform to estimate the counterfactual secondary attack rate without vaccination. FINDINGS: Between Feb 16, 2015, and Nov 11, 2016, we recruited 196 case households (705 members) and 55 control households (153 members). Household secondary attack rate for rotavirus infection was high (434 [65%] of 665 individuals) and secondary attack rate for clinical disease was much lower (37 [5%] of 698). Asymptomatic infection in control households was common (40 [28%] of 144). Increasing disease severity in an index child (as measured by Vesikari score) was associated with increased risk of transmission of infection (odds ratio 1·17 [95% CI 1·06-1·30) and disease (1·28 [1·08-1·52]) to household contacts. Estimated vaccine effectiveness against transmission was 39% (95% CI 16-57). INTERPRETATION: Rotavirus vaccine has the potential to substantially reduce household rotavirus transmission. This finding should be considered in clinical and health economic assessments of vaccine effectiveness. FUNDING: Wellcome Trust, US National Institutes of Health, and US National Institute of Allergy and Infectious Diseases