Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Understanding the barriers and facilitators of vaccine hesitancy towards the COVID-19 vaccine in healthcare workers and healthcare students worldwide: An Umbrella Review.

BackgroundHealthcare workers (HCWs) and healthcare students display high levels of vaccine hesitancy with impact on healthcare provision, patient safety, and health promotion. The factors related to vaccine hesitancy have been reported in several systematic reviews. However, this evidence needs to be synthesised, as interventions to reduce vaccination hesitancy in this population are needed.MethodsThis Umbrella Review aimed to explore the barriers and facilitators of vaccine hesitancy toward the COVID-19 vaccine for HCWs and healthcare students. The review was performed and reported in accordance with Joanna Briggs Institutes guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A protocol was preregistered on PROSPERO (CRD42022327354). Eight databases were searched from November 2019 to 23rd May 2022 to identify any systematic reviews that explored factors associated with hesitancy towards the COVID-19 vaccine for HCWs or healthcare students.ResultsA total of 31 studies were included in the review. The majority of studies (71%) were appraised as strong or moderate quality and there was a slight degree of overlap (ConclusionThe results from this Umbrella Review have wide-reaching implications for the research area, healthcare systems and institutions and governments worldwide. Designing tailored strategies for specific occupational groups is pivotal to increasing vaccine uptake and securing a safe healthcare provision worldwide

Implications of mild vs moderate trauma childhood distal forearm fractures for peak bone mass acquisition: The two faces of growth

Growth is the most opportune period to modify bone structure. We recently found that children who sustain a distal forearm fracture (DFF) due to mild, but not moderate, trauma have cortical thinning and deficits in bone microarchitecture at the radius and tibia. However, whether these skeletal deficits track into adulthood is unknown. Therefore, we used HRpQCT to examine cortical and trabecular bone parameters at the distal radius and tibia in 150 subjects (75 women; 75 men), age 20–40 yrs, who had a childhood (,18 yrs) DFF and 150 sex- and age-matched non-fracture controls. None used medications, or had diseases, affecting bone metabolism. We used the Landin classification (Acta Orthop Scand 202:1, 1983) to assign trauma levels, blind to the bone imaging results. None had a severe trauma DFF (e.g., traffic accident).Adult women (Fig. A) and men (Fig. B) with a mild trauma (e.g., fall from standing height) DFF in childhood had significant deficits in cortical area (–10.2%and –9.2%, respectively; P,0.05) at the radius as compared to controls. Women with a mild trauma DFF in childhood also had significantly lower cortical volumetric BMD (vBMD, –1.7%; P=0.002), whereas men with a mild trauma DFF in childhood had significantly lower trabecular bone volume fraction (BV/TV, –9.0%; P=0.008)compared to controls. By contrast, adult women and men with a moderate trauma(e.g., sport-related collision) DFF in childhood both had higher radial cortical areas as compared to controls, although only the difference in men was statistically significant (+8.6%; P=0.041). Importantly, skeletal deficits in the mild trauma DFF cases were generalized, as these subjects tended to have similar changes at the tibia, as well as significantly lower DXA-derived areal BMD at the radius, lumbar spine, hip and total body regions as compared to their controls (all P,0.05).In conclusion, a mild trauma DFF during childhood presages deficits in bone structure and density in adulthood. By contrast, as hypothesized by Parfitt (‘‘The Two Faces of Growth: Benefits and Risks to Bone Integrity’’, Osteoporos Int 4:382, 1994),children who suffer a moderate trauma DFF may be paying the price of risk-taking behaviors (e.g., sports) in childhood that optimize cortical bone structure during growth. Therefore, children with a mild trauma DFF should be identified and targeted for lifestyle interventions that encourage achievement of their full skeletal genetic potential

Body composition and physical activity during childhood and adolescence: Relations to biomechanical bone strength

Numerous studies have examined the influences of body composition and physical activity (PA) on bone development, but none have used micro-finite element analysis(mFEA) from HRpQCT scans. Thus, in 150 healthy 8- to 15-yr old boys (n=85) and girls (n=65), we investigated the relations of appendicular skeletal muscle mass(ASM), total body fat mass (TBFM) and PA to distal radius and tibia biomechanical bone strength (failure load), using mFEA. We determined relative ASM and TBFM from whole-body DXA scans. PA strain score (related to mechanical loading) and time spent in vigorous-intensity PA was quantified from a validated questionnaire. Results were similar in analyses stratified by sex; thus, we present analyses from the boys and girls combined. Relative ASM was positively associated with bone strength of the distal radius (r=0.55, P,0.001; Fig. A) and tibia (r=0.61, P,0.001; Fig. B) after adjusting for bone-age, sex, fracture history, relative TBFM and PA. By contrast, after adjustment for the same covariates, substituting relative TBFM for relative ASM, a significant inverse association was observed between relative TBFM and bone strength of the distal radius (r=–0.30, P,0.001), while no correlation was seen at the distal tibia (r=–0.01, P=0.91). In addition, after adjustment for bone-age, sex, fracture history, height and weight, time spent in vigorous-intensity PA was positively associated with bone strength (r=0.28, P,0.01) at the distal tibia only, while PA strain score was significantly associated with greater bone strength of the distal radius(r=0.16, P,0.05) and tibia (r=0.24, P,0.01).These data thus highlight the importance of skeletal muscle mass and PA for optimizing bone strength during growth. Furthermore, fat mass has different ial influences on bone strength at weight-bearing versus non-weight-bearing skeletal sites in children and adolescents. At the distal tibia, fat mass is not associated with bone strength, whereas fat mass is negatively associated with bone strength at the distal radius after adjusting for bone-age, sex, fracture history, skeletal muscle mass and PA. These observations suggest that the strength of the distal radius does not commensurately increase with excess gains in adiposity during growth, which may result in a mismatch between bone strength and the load experienced by the distal forearm during a fall. These findings may, in part, explain why obese children are over-represented in distal forearm fracture cases

Effects of Suppression of Follicle-Stimulating Hormone Secretion on Bone Resorption Markers in Postmenopausal Women

Context: It has recently been proposed that the increase in bone resorption after the menopause may not be due principally to estrogen deficiency but rather to the concomitant increase in circulating FSH levels