HAPPILEE: HAPPE In Low Electrode Electroencephalography, a standardized pre-processing software for lower density recordings.

Lower-density Electroencephalography (EEG) recordings (from 1 to approximately 32 electrodes) are widely-used in research and clinical practice and enable scalable brain function measurement across a variety of settings and populations. Though a number of automated pipelines have recently been proposed to standardize and optimize EEG pre-processing for high-density systems with state-of-the-art methods, few solutions have emerged that are compatible with lower-density systems. However, lower-density data often include long recording times and/or large sample sizes that would benefit from similar standardization and automation with contemporary methods. To address this need, we propose the HAPPE In Low Electrode Electroencephalography (HAPPILEE) pipeline as a standardized, automated pipeline optimized for EEG recordings with lower density channel layouts of any size. HAPPILEE processes task-free (e.g., resting-state) and task-related EEG (including event-related potential data by interfacing with the HAPPE+ER pipeline), from raw files through a series of processing steps including filtering, line noise reduction, bad channel detection, artifact correction from continuous data, segmentation, and bad segment rejection that have all been optimized for lower density data. HAPPILEE also includes post-processing reports of data and pipeline quality metrics to facilitate the evaluation and reporting of data quality and processing-related changes to the data in a standardized manner. Here the HAPPILEE steps and their optimization with both recorded and simulated EEG data are described. HAPPILEE's performance is then compared relative to other artifact correction and rejection strategies. The HAPPILEE pipeline is freely available as part of HAPPE 2.0 software under the terms of the GNU General Public License at: https://github.com/PINE-Lab/HAPPE.

Pelvic fractures: experience of pelvic ring fractures at a major trauma centre.

In this review, we discuss the imaging classification of pelvic ring fractures in the context of our experience of reporting trauma computed tomography (CT) in a major trauma centre. Pelvic ring fractures are potentially significant injuries with risk of significant haemorrhage and morbidity. This review details the use of classification systems in determining the mechanism and severity of injury, with discussion of the features of the Young and Burgess classification system. We demonstrate the different types of pelvic ring fracture with examples from trauma CT, and with reference to the distribution and frequency of these injuries in trauma patients. This review will allow the reader to assess trauma CT for significant pelvic ring injury and identify features of instability.

Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.

CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.

The use of syndromic surveillance to monitor the incidence of arthropod bites requiring healthcare in England, 2000-2013: a retrospective ecological study.

Climate change experts predict the number of nuisance-biting arthropods in England will increase but there is currently no known surveillance system in place to monitor or assess the public health impact of arthropod bites. This retrospective ecological study utilized arthropod bites requiring healthcare from five national real-time syndromic surveillance systems monitoring general practitioner (GP) consultations (in-hours and out-of-hours), emergency department (ED) attendances and telephone calls to remote advice services to determine baseline incidence in England between 2000 and 2013 and to assess the association between arthropod bites and temperature. During summer months (weeks 20-40) we estimated that arthropod bites contribute a weekly median of ~4000 GP consultations, 750 calls to remote advice services, 700 ED and 1300 GP out-of-hours attendances. In all systems, incidence was highest during summer months compared to the rest of the year. Arthropod bites were positively associated with temperature with incidence rate ratios (IRRs) that ranged between systems from 1·03 [95% confidence interval (CI) 1·01-1·06] to 1·14 (95% CI 1·11-1·16). Using syndromic surveillance systems we have established and described baseline incidence of arthropod bites and this can now be monitored routinely in real time to assess the impact of extreme weather events and climate change.

An analysis of influenza outbreaks in institutions and enclosed societies.

This paper considers the reported attack ratio arising from outbreaks of influenza in enclosed societies. These societies are isolated from the wider community and have greater opportunities for contact between members which would aid the spread of disease. While the particular kind of society (prison, care home, school, barracks, etc.) was not a significant factor in an adjusted model of attack ratio, a person's occupation within the society was. In particular, children and military personnel suffer a greater attack ratio than other occupational types (staff, prisoners, etc.). There was no temporal trend in final attack ratio nor, with the exception of 1918, do pandemic years show abnormal attack ratios. We also observed that as community size increases, the attack ratio undergoes steep nonlinear decline. This statistical analysis draws attention to how the organization of such societies, their size and the occupations of individuals within them affect the final attack ratio.

Using public health scenarios to predict the utility of a national syndromic surveillance programme during the 2012 London Olympic and Paralympic Games.

During 2012 real-time syndromic surveillance formed a key part of the daily public health surveillance for the London Olympic and Paralympic Games. It was vital that these systems were evaluated prior to the Games; in particular what types and scales of incidents could and could not be detected. Different public health scenarios were created covering a range of potential incidents that the Health Protection Agency would require syndromic surveillance to rapidly detect and monitor. For the scenarios considered it is now possible to determine what is likely to be detectable and how incidents are likely to present using the different syndromic systems. Small localized incidents involving food poisoning are most likely to be detected the next day via emergency department surveillance, while a new strain of influenza is more likely to be detected via GP or telephone helpline surveillance, several weeks after the first seed case is introduced.

A case-association cluster detection and visualisation tool with an application to Legionnaires' disease.

Statistical methods used in spatio-temporal surveillance of disease are able to identify abnormal clusters of cases but typically do not provide a measure of the degree of association between one case and another. Such a measure would facilitate the assignment of cases to common groups and be useful in outbreak investigations of diseases that potentially share the same source. This paper presents a model-based approach, which on the basis of available location data, provides a measure of the strength of association between cases in space and time and which is used to designate and visualise the most likely groupings of cases. The method was developed as a prospective surveillance tool to signal potential outbreaks, but it may also be used to explore groupings of cases in outbreak investigations. We demonstrate the method by using a historical case series of Legionnaires' disease amongst residents of England and Wales.

Budd-Chiari-like syndrome in a dog secondary to a gunshot wound treated with balloon angioplasty and endovascular stent placement.

A 6-year-old female spayed Chihuahua mix presented with chronic recurrent ascites. Computed tomographic angiography revealed an isolated stenosis of the caudal vena cava secondary to a metallic foreign body, resulting in Budd-Chiari-like syndrome. Balloon angioplasty and endovascular stent placement successfully resolved the obstruction with long-term resolution of ascites.

Fecal M2-PK in children with Crohn's disease: a preliminary report.

BACKGROUND AND AIMS: Although active inflammatory changes in chronic Crohn's disease (CD) can be detected with serum inflammatory markers, these have low specificity and sensitivity. Stool markers of inflammation, such as M2-pyruvate kinase (M2-PK), permit more direct assessment of mucosal inflammation. The aim of this study was to assess levels of M2-PK in children with active CD and to compare to levels in healthy control children. METHODS: Fecal levels of M2-PK were measured by immunoassay using stored stool samples from children with untreated (active) CD and healthy control children. Correlations between M2-PK levels and disease activity scores and serum inflammatory markers were performed. Comparison was also made between M2PK and a second fecal inflammatory marker, S100A12. RESULTS: Mean fecal M2-PK levels were higher in the 17 patients with active CD than in the 21 healthy controls (p = 0.0007). M2-PK levels did not correlate with disease activity scores or serum inflammatory markers. There was a trend for children with ileocolonic disease to have higher levels of M2-PK in their stool compared to those with colonic disease or isolated ileal disease. Fecal M2PK did not correlate with fecal S100A12 in children with active CD. CONCLUSION: Fecal M2-PK is increased in children with active CD, indicating that this marker may be a useful non-invasive marker for gut inflammation. Further studies of M2PK are required in additional settings with larger cohorts of children with CD and with comparison to other stool markers.

Longer-term outcomes of nutritional management of Crohn's disease in children.

BACKGROUND: While the short-term benefits of exclusive enteral nutrition (EEN) for induction of remission in children with Crohn's disease (CD) are well documented, the longer-term outcomes are less clear. AIM: This retrospective study aimed to ascertain the outcomes for up to 24 months following EEN in a group of children with CD. METHODS: Children treated with EEN as initial therapy for newly diagnosed CD over a 5-year period were identified. Details of disease activity, growth, and drug requirements over the period of follow-up were noted. Outcomes in children managed with EEN were compared to a group of children initially treated with corticosteroids. RESULTS: Over this time period, 31 children were treated with EEN and 26 with corticosteroids. Twenty-six (84 %) of the 31 children treated with EEN entered remission. Children treated with EEN exhibited lower pediatric Crohn's disease activity index (PCDAI) scores at 6 months (p = 0.02) and received lower cumulative doses of steroids over the study period (p < 0.0001) than the group treated with corticosteroids. Height increments over 24 months were greater in the EEN group (p = 0.01). Although the median times to relapse were the same, the EEN group had a lower incidence of relapse in each time interval and survival curve analysis showed lower risk of relapse (p = 0.008). CONCLUSIONS: EEN lead to multiple benefits beyond the initial period of inducing remission for these children, with positive outcomes over 2 years from diagnosis. Of particular clinical relevance to growing children was the reduced exposure to corticosteroids.

The application of geographic information systems and spatial data during Legionnaires disease outbreak responses.

A literature review was conducted to highlight the application and potential benefit of using geographic information systems (GIS) during Legionnaires' disease outbreak investigations. Relatively few published sources were identified, however, certain types of data were found to be important in facilitating the use of GIS, namely: patient data, locations of potential sources (e.g. cooling towers), demographic data relating to the local population and meteorological data. These data were then analysed to gain a better understanding of the spatial relationships between cases and their environment, the cases' proximity to potential outbreak sources, and the modelled dispersion of contaminated aerosols. The use of GIS in an outbreak is not a replacement for traditional outbreak investigation techniques, but it can be a valuable supplement to a response.

Prevalence, geographic distribution, and impact on lifespan of a dilated cardiomyopathy-associated RNA-binding motif protein 20 variant in genotyped dogs.

INTRODUCTION: The study objectives were to determine the prevalence and geographic distribution of a dilated cardiomyopathy (DCM)-associated RNA-binding motif protein 20 (RBM20) variant in canine DNA samples submitted for testing and to evaluate the influence of the genotype on cardiac phenotype and lifespan. ANIMALS: Samples from 2136 dogs including 1834 Standard Schnauzers (SSNZ), 266 Giant Schnauzers (GSNZ), and 36 dogs of other breeds. METHODS: The University of Missouri Canine Genetics Laboratory's sample-accession spreadsheet and Orthopedic Foundation for Animals' database were retrospectively reviewed for samples submitted for RBM20 genotyping from November, 2013, through May, 2018. Data analyzed included breed, date of birth, RBM20 genotype (homozygous wild-type, heterozygous variant [HET], or homozygous variant [HOM]), geographic origin of submission, pedigree, cardiac phenotype, and date of death or current age if alive. RESULTS AND DISCUSSION: The RBM20 variant was only detected in SSNZ and GSNZ. A total of 389 SSNZ were variant-positive (prevalence = 21.2%), with 361 HET (19.7%) and 28 HOM (1.5%). Of the HOM SSNZ, DCM was confirmed in 26 of 28 (92.9%), with the remainder lost to follow-up. The median lifespan of HOM SSNZ (3.06 years) was significantly shorter than that for HET (15.11 years) and wild-type (15.18 years) SSNZ. Twenty-six GSNZ were variant-positive (prevalence = 9.8%), with 23 HET (8.6%) and three HOM (1.1%). Nine GSNZ belonged to one family, including the three HOM GSNZ that all had DCM. CONCLUSIONS: The HOM genotype is associated with DCM and premature death in SSNZ and GSNZ.

An intersectional analysis of sociodemographic disparities in Covid-19 vaccination: A nationwide register-based study in Sweden.

BACKGROUND: Studies on sociodemographic disparities in Covid-19 vaccination uptake in the general population are still limited and mostly focused on older adults. This study examined sociodemographic differences in Covid-19 vaccination uptake in the total Swedish population aged 18-64 years. METHODS: National Swedish register data within the SCIFI-PEARL project were used to cross-sectionally investigate sociodemographic differences in Covid-19 vaccination among Swedish adults aged 18-64 years (n = 5,987,189) by 12 October 2021. Using logistic regression models, analyses were adjusted for sociodemographic factors, region of residence, history of Covid-19, and comorbidities. An intersectional analysis approach including several cross-classified subgroups was used to further address the complexity of sociodemographic disparities in vaccination uptake. FINDINGS: By 12 October 2021, 76·0% of the Swedish population 18-64 years old had received at least two doses of Covid-19 vaccine, an additional 5·5% had received only one dose, and 18·5% were non-vaccinated. Non-vaccinated individuals were, compared to vaccinated, more often younger, male, had a lower income, were not gainfully employed, and/or were born outside Sweden. The social patterning for vaccine dose two was similar, but weaker, than for dose one. After multivariable adjustments, findings remained but were attenuated indicating the need to consider different sociodemographic factors simultaneously. The intersectional analysis showed a large variation in vaccine uptake ranging from 32% to 96% in cross-classified subgroups, reflecting considerable sociodemographic heterogeneity in vaccination coverage. INTERPRETATION: Our study, addressing the entire Swedish population aged 18-64 years, showed broad sociodemographic disparities in Covid-19 vaccine uptake but also wide heterogeneities in coverage. The intersectional analysis approach indicates that focusing on specific sociodemographic factors in isolation and group average risks without considering the heterogeneity within such groups will risk missing the full variability of vaccine coverage. FUNDING: SciLifeLab / Knut & Alice Wallenberg Foundation, Swedish Research Council, Swedish government ALF agreement, FORMAS.

First detection of spotted fever group rickettsiae in Ixodes ricinus and Dermacentor reticulatus ticks in the UK.

A preliminary study was conducted to determine the presence of spotted fever rickettsiae in two species of British tick (Ixodes ricinus and Dermacentor reticulatus). The 16S rRNA gene of Rickettsia spp. was detected in 39/401 (9·7%) of ticks tested, including 22/338 (6·5%) I. ricinus and 17/63 (27%) D. reticulatus. Some positive I. ricinus samples showed 100% homology with Rickettsia helvetica (10/22), and most positive D. reticulatus showed 100% homology with R. raoultii (13/17). Five other Rickettsia spp. were detected exhibiting 96-99% homology. Ticks positive for rickettsiae were collected from various hosts and from vegetation from eight counties across Great Britain. The distribution of R. helvetica in various engorged and unfed stages of I. ricinus suggests that R. helvetica is widespread. R. raoultii was found in questing adult D. reticulatus in Wales and England. This is the first evidence of potentially pathogenic spotted fever rickettsiae in British ticks.

Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response.

OBJECTIVE: To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. METHODS: This was a prospective multicentre cohort study. Stool samples from 101 children (13.3 + or - 3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72 + or - 12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physician's global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. RESULTS: Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 microg/g (2297-8808); lactoferrin 212 microg/g (114-328); M2-pyruvate kinase (M2-PK) 363 U/g (119-3104); and S100A12 469 microg/g (193-1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p<0.001) vs <0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p<0.05). None of the markers was responsive to change (Spearman's rho correlation with change in the PUCAI <0.1; p>0.05, area under the ROC curve <0.65; p>0.05). CONCLUSIONS: The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.

Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Efficacy and safety of a new immunoglobulin G product, Gammaplex(®), in primary immunodeficiency diseases.

This open-label multi-centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21-day and 28 on a 28-day regimen (300-800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrollment. Forty subjects (80·0%) had at least one non-serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product-related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated.

Environmental and ecological potential for enzootic cycles of Puumala hantavirus in Great Britain.

Puumala virus (PUUV) is a zoonotic rodent-borne hantavirus in continental Europe. Its reservoir host, the bank vole (Myodes glareolus), is ubiquitous in Great Britain (GB); however, there has been no reported incidence of virus in either animals or humans. In northwest Europe, increases in bank vole numbers, stimulated by increases in production of beech/oak crops (mast), are associated with outbreaks of nephropathia epidemica (NE) in humans. These so-called 'mast years' are determined by sequential climatic events. This paper investigates the contribution of a number of ecological and environmental factors driving outbreaks of PUUV in northwest Europe and assesses whether such factors might also permit enzootic PUUV circulation in GB. Analysis of GB climate data, using regression models, confirms that mast years in GB are stimulated, and can be predicted, by the same climatic events as mast years in PUUV-endemic regions of northwest Europe. A number of other possible non-climatic constraints on enzootic cycles are discussed.

Nutritional status of children with coeliac disease.

AIMS: The main aim of this study was to assess the nutritional status of children with newly diagnosed Coeliac disease (CD)with comparison to matched controls. A further aim was to assess relationships between presentation patterns and nutrition in childhood CD. METHODS: The nutritional status of newly diagnosed CD was assessed by anthropometry, Bioelectrical Impedance and serum leptin levels, and contrasted to age and gender matched controls. RESULTS: Twenty-five children with CD (mean age of 8.2 +/- 4.5 years) and 25 control children (mean age 8.1 +/- 4.4.) were enrolled. Thirteen (52%) children with CD had gastrointestinal symptoms with 14 having a family history of CD. At presentation 8.7% were wasted, 4.2% were stunted and 20.8% overweight, although none were obese. Mean height and weight for age, other nutritional parameters and serum leptin did not differ between the groups. Serum leptin correlated with BMI in both groups. CONCLUSIONS: Children with CD more commonly present with atypical symptoms than with classical features. Variations in nutrition (under to overnutrition) may be seen at diagnosis, without relationship to the presence of symptoms. Leptin levels were not altered specifically in the setting of CD. Nutritional assessment remains important in the assessment and management of CD in children.

Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: a pilot study.

INTRODUCTION: Canine pulmonary hypertension (PH) is associated with high morbidity and mortality. Tadalafil, a phosphodiesterase-5 inhibitor used commonly in humans with PH, has not been evaluated in a clinical trial in dogs with naturally occurring PH. Our objectives were to compare the efficacy of tadalafil and sildenafil on PH assessed by peak tricuspid regurgitant flow velocity, estimated systolic pulmonary arterial pressure gradient, voluntary activity, quality of life, and safety profiles in dogs with moderate to severe PH. ANIMALS: Twenty-three dogs with echocardiographic evidence of moderate to severe PH were enrolled. METHODS: A prospective short-term, randomized, double-blinded pilot study was carried out. Dogs with PH were randomly allocated to receive sildenafil or tadalafil for 2 weeks and assessed via echocardiography, activity monitors, and owner-reported outcomes. RESULTS: Collectively, phosphodiesterase-5 inhibition significantly decreased (improved) quality of life scores (p = 0.003) and visual analog score (p = 0.024) without significant between-treatment difference of these variables. Phosphodiesterase-5 inhibition did not significantly affect peak tricuspid regurgitant flow velocity (p = 0.056) or voluntary activity (p = 0.27). A total of 33% (7/21) of dogs experienced at least one adverse event during the study (tadalafil, n = 5; sildenafil, n = 2) with no significant difference between treatment type and incidence of adverse events (p = 0.36). DISCUSSION: In this pilot study, phosphodiesterase-5 inhibition led to apparent improvement in quality of life scores without documenting superiority of tadalafil over sildenafil. CONCLUSION: Tadalafil at a dose of 2 mg/kg once daily appears to be a viable alternative to sildenafil in dogs with moderate to severe PH.