Prospecting for new group A streptococcal vaccine candidates

Background & objectives: Most group A streptococcal (GAS) vaccine strategies focused on the surface M protein of the GAS. However, vaccine based on M protein have some drawbacks. In the present study, we used two approaches to identify new proteins and peptides that may have utility as vaccine candidates. Methods: A whole gel elution procedure was used to separate GAS surface antigens into 9 size fractionated pools. Mice were vaccinated with each pool and antibody titre, opsonic ability and protective capacity measured. In an alternative approach BioInformatics was used to identify putative GAS surface proteins. Peptides from within these proteins were then selected on the basis of predicted antigenicity or location. These peptides were conjugated to keyhole lymphocyanin (KLH) and immunogenicity measured in a mouse model. Results: One pool of GAS surface proteins (approximately 29kDa) induced antibodies that were both opsonic and potentially protective. Immunoflourescent microscopy demonstrated that these antibodies bound to the surface of M1 GAS. Amino acid sequencing subsequently identified superoxide dismutase as the major antigen in this pool. A BioInformatic search of the M1 GAS genome and subsequent analysis identified several peptides that fulfilled criteria as potential vaccine candidates. Each peptide when conjugated to KLH was able to induce a strong antibody response. Interpretation & conclusion: Several new antigens were identified that may have potential as vaccine targets. A future GAS vaccine may have multiple peptide epitopes, providing protection against multiple GAS strains

The neuropsychology needs of a hyper-acute stroke unit

BACKGROUND AND AIM: Guidelines recommend routine assessment and management of mood and cognition after stroke, but little is known about the value or feasibility of providing neuropsychology input during the hyper-acute period. We aimed to identify and describe the extent and nature of neuropsychological needs and to investigate the feasibility of providing direct neuropsychology input within a hyper-acute setting. METHODS: Over a 7-month period, Multidisciplinary Team (MDT) members of a central London Hyper-Acute Stroke Unit (HASU) identified stroke patients who they believed would benefit from neuropsychology input, and categorised the nature of neuropsychology intervention required. We examined the demographic and clinical characteristics of the patients identified and the type of intervention required. RESULTS: 23% of patients (101/448) were identified as requiring neuropsychology input. Patients deemed to require input were younger, more likely to be male and more functionally disabled than those not requiring input. Cognitive assessment was the main identified need (93%) followed by mood (29%) and family support (9%). 30% of patients required two types of intervention. During a pilot of neuropsychology provision, 17 patients were seen; 15 completed a full cognitive assessment. All patients assessed presented with cognitive impairment despite three being deemed cognitively intact (> standardised cut-off) using a cognitive screening tool. CONCLUSION: We showed that direct neuropsychology input on a HASU is necessary for complex and varied interventions involving cognition, mood and family support. Furthermore, input is feasible and useful in detecting cognitive impairment not revealed by screening instruments

Whole-brain diffusion tensor imaging predicts 6-month functional outcome in acute intracerebral haemorrhage

Introduction: Small vessel disease (SVD) causes most spontaneous intracerebral haemorrhage (ICH) and is associated with widespread microstructural brain tissue disruption, which can be quantified via diffusion tensor imaging (DTI) metrics: mean diffusivity (MD) and fractional anisotropy (FA). Little is known about the impact of whole-brain microstructural alterations after SVD-related ICH. We aimed to investigate: (1) association between whole-brain DTI metrics and functional outcome after ICH; and (2) predictive ability of these metrics compared to the pre-existing ICH score. Methods: Sixty-eight patients (38.2% lobar) were retrospectively included. We assessed whole-brain DTI metrics (obtained within 5 days after ICH) in cortical and deep grey matter and white matter. We used univariable logistic regression to assess the associations between DTI and clinical-radiological variables and poor outcome (modified Rankin Scale > 2). We determined the optimal predictive variables (via LASSO estimation) in: model 1 (DTI variables only), model 2 (DTI plus non-DTI variables), model 3 (DTI plus ICH score). Optimism-adjusted C-statistics were calculated for each model and compared (likelihood ratio test) against the ICH score. Results: Deep grey matter MD (OR 1.04 [95% CI 1.01–1.07], p = 0.010) and white matter MD (OR 1.11 [95% CI 1.01–1.23], p = 0.044) were associated (univariate analysis) with poor outcome. Discrimination values for model 1 (0.67 [95% CI 0.52–0.83]), model 2 (0.71 [95% CI 0.57–0.85) and model 3 (0.66 [95% CI 0.52–0.82]) were all significantly higher than the ICH score (0.62 [95% CI 0.49–0.75]). Conclusion: Our exploratory study suggests that whole-brain microstructural disruption measured by DTI is associated with poor 6-month functional outcome after SVD-related ICH. Whole-brain DTI metrics performed better at predicting recovery than the existing ICH score

The impact of the UK COVID-19 pandemic on patient-reported health outcomes after stroke: a retrospective sequential comparison

BACKGROUND AND PURPOSE: The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke. METHODS: This retrospective study included adults with acute stroke admitted to the University College Hospital NHS Foundation Trust Hyperacute Stroke Unit. We included two separate cohorts of consecutively enrolled patients from the same geographical population at two time points: 16th March-16th May 2018 (pre-COVID-19 pandemic); and 16th March-16th May 2020 (during the COVID-19 pandemic). Patients in both cohorts completed the validated Patient Reported Outcomes Measurement Information System-29 (PROMIS-29 version 2.0) at 30 days after stroke. RESULTS: We included 205 patients who were alive at 30 days (106 admitted before and 99 admitted during the COVID-19 pandemic), of whom 201/205 (98%) provided patient-reported health outcomes. After adjustment for confounding factors, admission with acute stroke during the COVID-19 pandemic was independently associated with increased anxiety (β = 28.0, p < 0.001), fatigue (β = 9.3, p < 0.001), depression (β = 4.5, p = 0.002), sleep disturbance (β = 2.3, p = 0.018), pain interference (β = 10.8, p < 0.001); and reduced physical function (β = 5.2, p < 0.001) and participation in social roles and activities (β = 6.9, p < 0.001). CONCLUSION: Compared with the pre-pandemic cohort, patients admitted with acute stroke during the first wave of the COVID-19 pandemic reported poorer health outcomes at 30 day follow-up in all domains. Stroke service planning for any future pandemic should include measures to mitigate this major adverse impact on patient health

MRI and CT imaging biomarkers of cerebral amyloid angiopathy in lobar intracerebral hemorrhage

BACKGROUND: Cerebral amyloid angiopathy (CAA), a common cause of intracerebral hemorrhage (ICH), is diagnosed using the Boston criteria including magnetic resonance imaging (MRI) biomarkers (cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS). The simplified Edinburgh criteria include computed tomography (CT) biomarkers (subarachnoid extension (SAE) and finger-like projections (FLPs)). The underlying mechanisms and diagnostic accuracy of CT compared to MRI biomarkers of CAA are unknown. METHODS: We included 140 survivors of spontaneous lobar supratentorial ICH with both acute CT and MRI. We assessed associations between MRI and CT biomarkers and the diagnostic accuracy of CT- compared to MRI-based criteria. RESULTS: FLPs were more common in patients with strictly lobar CMB (44.7% vs 23.5%; p = 0.014) and SAE was more common in patients with cSS (61.3% vs 31.2%; p = 0.002). The high probability of the CAA category of the simplified Edinburgh criteria showed 87.2% (95% confidence interval (CI): 78.3-93.4) specificity, 29.6% (95% CI: 18.0-43.6) sensitivity, 59.3% (95% CI: 38.8-77.6) positive predictive value, and 66.4% (95%: CI 56.9-75.0) negative predictive value, 2.3 (95% CI: 1.2-4.6) positive likelihood ratio and 0.8 (95% CI 0.7-1.0) negative likelihood ratio for probable CAA (vs non-probable CAA), defined by the modified Boston criteria; the area under the receiver operating characteristic curve (AUROC) was 0.62 (95% CI: 0.54-0.71). CONCLUSION: In lobar ICH survivors, we found associations between putative biomarkers of parenchymal CAA (FLP and strictly lobar CMBs) and putative biomarkers of leptomeningeal CAA (SAE and cSS). In a hospital population, CT biomarkers might help rule-in probable CAA (diagnosed using the Boston criteria), but their absence is probably not as useful to rule it out, suggesting an important continued role for MRI in ICH survivors with suspected CAA

Solar-type dynamo behaviour in fully convective stars without a tachocline

In solar-type stars (with radiative cores and convective envelopes), the magnetic field powers star spots, flares and other solar phenomena, as well as chromospheric and coronal emission at ultraviolet to X-ray wavelengths. The dynamo responsible for generating the field depends on the shearing of internal magnetic fields by differential rotation. The shearing has long been thought to take place in a boundary layer known as the tachocline between the radiative core and the convective envelope. Fully convective stars do not have a tachocline and their dynamo mechanism is expected to be very different, although its exact form and physical dependencies are not known. Here we report observations of four fully convective stars whose X-ray emission correlates with their rotation periods in the same way as in Sun-like stars. As the X-ray activity - rotation relationship is a well-established proxy for the behaviour of the magnetic dynamo, these results imply that fully convective stars also operate a solar-type dynamo. The lack of a tachocline in fully convective stars therefore suggests that this is not a critical ingredient in the solar dynamo and supports models in which the dynamo originates throughout the convection zone.Comment: 6 pages, 1 figure. Accepted for publication in Nature (28 July 2016). Author's version, including Method

ParaHaplo 2.0: a program package for haplotype-estimation and haplotype-based whole-genome association study using parallel computing

<p>Abstract</p> <p>Background</p> <p>The use of haplotype-based association tests can improve the power of genome-wide association studies. Since the observed genotypes are unordered pairs of alleles, haplotype phase must be inferred. However, estimating haplotype phase is time consuming. When millions of single-nucleotide polymorphisms (SNPs) are analyzed in genome-wide association study, faster methods for haplotype estimation are required.</p> <p>Methods</p> <p>We developed a program package for parallel computation of haplotype estimation. Our program package, ParaHaplo 2.0, is intended for use in workstation clusters using the Intel Message Passing Interface (MPI). We compared the performance of our algorithm to that of the regular permutation test on both Japanese in Tokyo, Japan and Han Chinese in Beijing, China of the HapMap dataset.</p> <p>Results</p> <p>Parallel version of ParaHaplo 2.0 can estimate haplotypes 100 times faster than a non-parallel version of the ParaHaplo.</p> <p>Conclusion</p> <p>ParaHaplo 2.0 is an invaluable tool for conducting haplotype-based genome-wide association studies (GWAS). The need for fast haplotype estimation using parallel computing will become increasingly important as the data sizes of such projects continue to increase. The executable binaries and program sources of ParaHaplo are available at the following address: <url>http://en.sourceforge.jp/projects/parallelgwas/releases/</url></p

A fast algorithm for genome-wide haplotype pattern mining

<p>Abstract</p> <p>Background</p> <p>Identifying the genetic components of common diseases has long been an important area of research. Recently, genotyping technology has reached the level where it is cost effective to genotype single nucleotide polymorphism (SNP) markers covering the entire genome, in thousands of individuals, and analyse such data for markers associated with a diseases. The statistical power to detect association, however, is limited when markers are analysed one at a time. This can be alleviated by considering multiple markers simultaneously. The <it>Haplotype Pattern Mining </it>(HPM) method is a machine learning approach to do exactly this.</p> <p>Results</p> <p>We present a new, faster algorithm for the HPM method. The new approach use patterns of haplotype diversity in the genome: locally in the genome, the number of observed haplotypes is much smaller than the total number of possible haplotypes. We show that the new approach speeds up the HPM method with a factor of 2 on a genome-wide dataset with 5009 individuals typed in 491208 markers using default parameters and more if the pattern length is increased.</p> <p>Conclusion</p> <p>The new algorithm speeds up the HPM method and we show that it is feasible to apply HPM to whole genome association mapping with thousands of individuals and hundreds of thousands of markers.</p

Jejunal perforation in gallstone ileus – a case series

<p>Abstract</p> <p>Introduction</p> <p>Gallstone ileus is an uncommon complication of cholelithiasis but an established cause of mechanical bowel obstruction in the elderly. Perforation of the small intestine proximal to the obstructing gallstone is rare, and only a handful of cases have been reported. We present two cases of perforation of the jejunum in gallstone ileus, and remarkably in one case, the gallstone ileus caused perforation of a jejunal diverticulum and is to the best of our knowledge the first such case to be described.</p> <p>Case presentations</p> <p><b>Case 1</b></p> <p>A 69 year old man presented with two days of vomiting and central abdominal pain. He underwent laparotomy for small bowel obstruction and was found to have a gallstone obstructing the mid-ileum. There was a 2 mm perforation in the anti-mesenteric border of the dilated proximal jejunum. The gallstone was removed and the perforated segment of jejunum was resected.</p> <p><b>Case 2</b></p> <p>A 68 year old man presented with a four day history of vomiting and central abdominal pain. Chest and abdominal radiography were unremarkable however a subsequent CT scan of the abdomen showed aerobilia. At laparotomy his distal ileum was found to be obstructed by an impacted gallstone and there was a perforated diverticulum on the mesenteric surface of the mid-jejunum. An enterolithotomy and resection of the perforated small bowel was performed.</p> <p>Conclusion</p> <p>Gallstone ileus remains a diagnostic challenge despite advances in imaging techniques, and pre-operative diagnosis is often delayed. Partly due to the elderly population it affects, gallstone ileus continues to have both high morbidity and mortality rates. On reviewing the literature, the most appropriate surgical intervention remains unclear.</p> <p>Jejunal perforation in gallstone ileus is extremely rare. The cases described illustrate two quite different causes of perforation complicating gallstone ileus. In the first case, perforation was probably due to pressure necrosis caused by the gallstone. The second case was complicated by the presence of a perforated jejunal diverticulum, which was likely to have been secondary to the increased intra-luminal pressure proximal to the obstructing gallstone.</p> <p>These cases should raise awareness of the complications associated with both gallstone ileus, and small bowel diverticula.</p