Mortality following Campylobacter infection: a registry-based linkage study

BACKGROUND: Campylobacteriosis is one of the most commonly identified causes of bacterial diarrheal disease and a common cause of gastroenteritis in travellers from developed nations. Despite the widespread occurrence, there is little information on Campylobacter mortality. METHODS: Mortality among a cohort of Campylobacter cases were compared with the general population 0–1, 1–3, 3–12 and more than 12 month after the onset of the illness. The cases were sub-grouped according to if they had been infected domestically or abroad. RESULTS: The standardized mortality ratio for cases infected domestically was 2.9 (95% CI: 1.9–4.0) within the first month following the illness. The risk then gradually diminished and approached 1.0 after one year or more have passed since the illness. This initial excess risk was not attributable to any particular age group (such as the oldest). In contrast, for those infected abroad, a lower standardized mortality ratio 0.3 (95% CI: 0.04–0.8) was shown for the first month after diagnosis compared to what would be expected in the general population. CONCLUSION: Infection with Campylobacter is associated with an increased short-term risk of death among those who were infected domestically. On the contrary, for those infected abroad a lower than expected risk of death was evident. We suggest that the explanation behind this is a "healthy traveler effect" among imported cases, and effects of a more frail than average population among domestic cases

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype

Background Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. Methods Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. Results We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. Conclusions Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features—particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry—should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations

Contribution of TAT System Translocated PhoX to Campylobacter jejuni Phosphate Metabolism and Resilience to Environmental Stresses

Campylobacter jejuni is a common gastrointestinal pathogen that colonizes food animals; it is transmitted via fecal contamination of food, and infections in immune-compromised people are more likely to result in serious long-term illness. Environmental phosphate is likely an important sensor of environmental fitness and the ability to obtain extracellular phosphate is central to the bacteria's core metabolic responses. PhoX is the sole alkaline phosphatase in C. jejuni, a substrate of the TAT transport system. Alkaline phosphatases mediate the hydrolytic removal of inorganic phosphate (Pi) from phospho-organic compounds and thereby contribute significantly to the polyphosphate kinase 1 (ppk1) mediated formation of poly P, a molecule that regulates bacterial response to stresses and virulence. Similarly, deletion of the tatC gene, a key component of the TAT system, results in diverse phenotypes in C. jejuni including reduced stress tolerance and in vivo colonization. Therefore, here we investigated the contribution of phoX in poly P synthesis and in TAT-system mediated responses. The phoX deletion mutant showed significant decrease (P<0.05) in poly P accumulation in stationary phase compared to the wild-type, suggesting that PhoX is a major contributor to the inorganic phosphate pool in the cell which is essential for poly P synthesis. The phoX deletion is sufficient for a nutrient stress defect similar to the defect previously described for the ΔtatC mutant. Additionally, the phoX deletion mutant has increased resistance to certain antimicrobials. The ΔphoX mutant was also moderately defective in invasion and intracellular survival within human intestinal epithelial cells as well as in chicken colonization. Further, the ΔphoX mutant produced increased biofilm that can be rescued with 1 mM inorganic phosphate. The qRT-PCR of the ΔphoX mutant revealed transcriptional changes that suggest potential mechanisms for the increased biofilm phenotype

Developing a predictive modelling capacity for a climate change-vulnerable blanket bog habitat: Assessing 1961-1990 baseline relationships

Aim: Understanding the spatial distribution of high priority habitats and developing predictive models using climate and environmental variables to replicate these distributions are desirable conservation goals. The aim of this study was to model and elucidate the contributions of climate and topography to the distribution of a priority blanket bog habitat in Ireland, and to examine how this might inform the development of a climate change predictive capacity for peat-lands in Ireland. Methods: Ten climatic and two topographic variables were recorded for grid cells with a spatial resolution of 1010 km, covering 87% of the mainland land surface of Ireland. Presence-absence data were matched to these variables and generalised linear models (GLMs) fitted to identify the main climatic and terrain predictor variables for occurrence of the habitat. Candidate predictor variables were screened for collinearity, and the accuracy of the final fitted GLM was evaluated using fourfold cross-validation based on the area under the curve (AUC) derived from a receiver operating characteristic (ROC) plot. The GLM predicted habitat occurrence probability maps were mapped against the actual distributions using GIS techniques. Results: Despite the apparent parsimony of the initial GLM using only climatic variables, further testing indicated collinearity among temperature and precipitation variables for example. Subsequent elimination of the collinear variables and inclusion of elevation data produced an excellent performance based on the AUC scores of the final GLM. Mean annual temperature and total mean annual precipitation in combination with elevation range were the most powerful explanatory variable group among those explored for the presence of blanket bog habitat. Main conclusions: The results confirm that this habitat distribution in general can be modelled well using the non-collinear climatic and terrain variables tested at the grid resolution used. Mapping the GLM-predicted distribution to the observed distribution produced useful results in replicating the projected occurrence of the habitat distribution over an extensive area. The methods developed will usefully inform future climate change predictive modelling for Irelan

Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) in the Irish paediatric population

Aim  This study aims to investigate the disease frequency of Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) among the Irish population.  Methods  Children ( Results  From 1998 to 2016, 17 children (G mutation accounted for 88% of alleles.  Conclusion  The incidence of MCADD in Ireland is lower than global estimates. The potential for under-ascertainment and late diagnosis of cases exists in Ireland and is of concern for a treatable condition with a significant mortality when undiagnosed. The authors welcome the introduction of MCADD to the National Newborn Bloodspot Screening Program.</p

Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.

Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile-onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconate (3-MGC). Increased urine excretion of methacrylyl-CoA and acryloyl-CoA related metabolites analyzed by LC-MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro-2,3-dihydroxy-2-methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3-MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh-like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3-MGA