Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.

Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.Wellcome Trust (Grant ID: 084716/Z/08/Z)This is the final version of the article. It first appeared from Cell Press/Elsevier via http://dx.doi.org/10.1016/j.ajhg.2016.03.02

Increasing women’s engagement in vector control: a report from Accelerate To Equal project workshops

Abstract Workshops with academic, national and local government, and community stakeholders were held in Kenya (2017) and Indonesia (2018) to understand the role and perceptions of women in vector control and to identify strategies for accelerating involvement of women in sustained support for vector control interventions at multiple levels/sectors

Increasing women’s engagement in vector control: a report from Accelerate To Equal project workshops

Abstract Workshops with academic, national and local government, and community stakeholders were held in Kenya (2017) and Indonesia (2018) to understand the role and perceptions of women in vector control and to identify strategies for accelerating involvement of women in sustained support for vector control interventions at multiple levels/sectors

Monosodium glutamate taste recognition thresholds are not affected by modulation of serotonin or noradrenaline levels in healthy humans

This study was designed to determine the effect of altering serotonin and noradrenaline levels on monosodium glutamate (MSG) taste recognition thresholds in humans. We have previously shown that manipulation of these neurotransmitters lowers taste thresholds of specific taste modalities (Heath et al 2006). A preliminary tongue map for MSG taste was generated in 34 healthy adults (6 male, 28 female, age range 19-71) to determine the most sensitive area of the tongue for further testing. In a further 26 adults (13 male, 13 female, age range 19-48) a series of MSG and sodium chloride solutions were presented either to the back or the tip of the tongue in a pseudorandom order. Recognition thresholds were calculated from psychophysical function curves before and 2 hours after a single acute dose of either paroxetine (serotonin selective reuptake inhibitor), reboxetine (noradrenaline reuptake inhibitor), caffeine (active placebo) or placebo (lactose) in a double blind cross-over design. MSG taste recognition thresholds were significantly lower at the back of the tongue compared to the tip (back 14±3mM, tip, 60±13mM, p<0.01). Comparison of thresholds at either the back or the tip of the tongue showed MSG recognition thresholds were not affected by any drug, or by placebo, in either region. Sodium chloride thresholds were also unaffected by any intervention, as previously shown. Thus, pharmacological modulation of serotonin or noradrenaline levels in humans has no effect on glutamate taste. These findings, together with our previous study showing that the same interventions modulate bitter and sweet taste, support a modality specific neuromodulatory role for serotonin and noradrenaline in human taste perception

Monosodium glutamate taste recognition thresholds are not affected by modulation of serotonin or noradrenaline levels in healthy humans

This study was designed to determine the effect of altering serotonin and noradrenaline levels on monosodium glutamate (MSG) taste recognition thresholds in humans. We have previously shown that manipulation of these neurotransmitters lowers taste thresholds of specific taste modalities (Heath et al 2006). A preliminary tongue map for MSG taste was generated in 34 healthy adults (6 male, 28 female, age range 19-71) to determine the most sensitive area of the tongue for further testing. In a further 26 adults (13 male, 13 female, age range 19-48) a series of MSG and sodium chloride solutions were presented either to the back or the tip of the tongue in a pseudorandom order. Recognition thresholds were calculated from psychophysical function curves before and 2 hours after a single acute dose of either paroxetine (serotonin selective reuptake inhibitor), reboxetine (noradrenaline reuptake inhibitor), caffeine (active placebo) or placebo (lactose) in a double blind cross-over design. MSG taste recognition thresholds were significantly lower at the back of the tongue compared to the tip (back 14±3mM, tip, 60±13mM, p&lt;0.01). Comparison of thresholds at either the back or the tip of the tongue showed MSG recognition thresholds were not affected by any drug, or by placebo, in either region. Sodium chloride thresholds were also unaffected by any intervention, as previously shown. Thus, pharmacological modulation of serotonin or noradrenaline levels in humans has no effect on glutamate taste. These findings, together with our previous study showing that the same interventions modulate bitter and sweet taste, support a modality specific neuromodulatory role for serotonin and noradrenaline in human taste perception

The role of psychology in determining human–predator conflict across southern Kenya

Conflict between people and carnivores can lead to the widespread killing of predators in retaliation for livestock loss and is a major threat to predator populations. In Kenya, a large, rural, pastoralist population comes into regular conflict with predators, which persist across southern Kenya. We explored the social and psychological backdrop to livestock management practices in this area in a process designed to be easy to use and suitable for use across large areas for the study of conflict and transboundary implementation of wildlife conflict reduction measures, focusing on community involvement and needs. We carried out fully structured interviews of livestock managers with a survey tool that examined how social and psychological factors may influence livestock management behavior. We compared survey responses on 3 sites across the study area, resulting in 723 usable responses. Efficacy of individuals’ livestock management varied between and within communities. This variation was partially explained by normative and control beliefs regarding livestock management. Individual livestock managers’ self‐reported management issues were often an accurate reflection of their practical management difficulties. Psychological norms, control beliefs, and attitudes differed among sites, and these differences partially explained patterns associated with conflict (i.e., variation in livestock management behavior). Thus, we conclude that a one‐size‐fits‐all approach to improving livestock management and reducing human–predator conflict is not suitable

The FEED1 trial: protocol for a randomised controlled trial of full milk feeds versus intravenous fluids with gradual feeding for preterm infants (30–33 weeks gestational age)

Background In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units’ workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition. Methods FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30+0 to 32+6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother’s expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births. Discussion This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner. Trial registration ISRCTN ISRCTN89654042. Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included