Conclusion : four recommendations to improve digital electoral oversight in the UK

To conclude this special section, this article looks at the possible avenues for regulatory reform in the field of digital campaigning. Diagnosing the need for a multi‐layered approach, we argue that action is needed from government, regulators, companies, and civil society. We take each actor in turn and consider the kind of change needed, the prospects for reform, and outline four recommendations for change

Waist-to-Hip Ratio, Cardiovascular Outcomes, and Death in Peritoneal Dialysis Patients

Objectives. The primary objective of this study was to determine the relationship between waist-to-hip ratio (WHR), cardiovascular (CV) events, and mortality in peritoneal dialysis (PD) patients. A secondary objective was to investigate the association between abdominal obesity and systemic inflammatory markers. Methods. This is a prospective study of 22 prevalent PD patients. WHR was measured at baseline. C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured. Main outcomes were first CV event and death from all causes. Survival analysis was used to examine the relationship between anthropomorphic measures and clinical outcomes. Results. Mean follow-up period was 3.1 years. In Kaplan-Meier analysis, survival was lower in those with higher WHR (P = .002). In Cox regression, WHR independently predicted mortality and first CV event after adjustment for known ischemic heart disease (hazard ratio [HR] 1.17, confidence interval [CI] 1.05–1.30 for death; HR 1.13, CI 1.01–1.26 for CV event). WHR correlated with serum TNF-α (r = 0.45; P = .05). Conclusion. The results of this study suggest WHR may be a risk factor for increased CV events and mortality in PD patients. Abdominal obesity is also associated with inflammatory markers. Larger studies are warranted to confirm these findings

Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors

SummaryThe homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor monomers also assemble as heterodimers, the primary ligand-binding sites of which each comprise the first leucine-rich repeat domain (L1) of one receptor type and an α-chain C-terminal segment (αCT) of the second receptor type. We present here crystal structures of IGF-I bound to such a hybrid primary binding site and of a ligand-free version of an IR αCT peptide bound to an IR L1 plus cysteine-rich domain construct (IR310.T). These structures, refined at 3.0-Å resolution, prove congruent to respective existing structures of insulin-complexed IR310.T and the intact apo-IR ectodomain. As such, they provide key missing links in the emerging, but sparse, repertoire of structures defining the receptor family

Fourth ventricle tumors in children: complications and influence of surgical approach

OBJECTIVES: The goal of this study was to characterize the complications and morbidity related to the surgical management of pediatric fourth ventricle tumors. / METHODS: All patients referred to the authors’ institution with posterior fossa tumors from 2002 to 2018 inclusive were screened to include only true fourth ventricle tumors. Preoperative imaging and clinical notes were reviewed to extract data on presenting symptoms; surgical episodes, techniques, and adjuncts; tumor histology; and postoperative complications. / RESULTS: Three hundred fifty-four children with posterior fossa tumors were treated during the study period; of these, 185 tumors were in the fourth ventricle, and 167 fourth ventricle tumors with full data sets were included in this analysis. One hundred patients were male (mean age ± SD, 5.98 ± 4.12 years). The most common presenting symptom was vomiting (63.5%). The most common tumor types, in order, were medulloblastoma (94 cases) > pilocytic astrocytoma (30 cases) > ependymoma (30 cases) > choroid plexus neoplasms (5 cases) > atypical teratoid/rhabdoid tumor (4 cases), with 4 miscellaneous lesions. Of the 67.1% of patients who presented with hydrocephalus, 45.5% had an external ventricular drain inserted (66.7% of these prior to tumor surgery, 56.9% frontal); these patients were more likely to undergo ventriculoperitoneal shunt (VPS) placement at a later date (p = 0.00673). Twenty-two had an endoscopic third ventriculostomy, of whom 8 later underwent VPS placement. Overall, 19.7% of patients had a VPS sited during treatment. Across the whole series, the transvermian approach was more frequent than the telovelar approach (64.1% vs 33.0%); however, the telovelar approach was significantly more common in the latter half of the series (p < 0.001). Gross-total resection was achieved in 70.7%. The most common postoperative deficit was cerebellar mutism syndrome (CMS; 28.7%), followed by new weakness (24.0%), cranial neuropathy (18.0%), and new gait abnormality/ataxia (12.6%). Use of intraoperative ultrasonography significantly reduced the incidence of CMS (p = 0.0365). There was no significant difference in the rate of CMS between telovelar or transvermian approaches (p = 0.745), and multivariate logistic regression modeling did not reveal any statistically significant relationships between CMS and surgical approach. / CONCLUSIONS: Surgical management of pediatric fourth ventricle tumors continues to evolve, and resection is increasingly performed through the telovelar route. CMS is enduringly the major postoperative complication in this patient population

Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy

Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency

Party finance reform as constitutional engineering? The effectiveness and unintended consequences of party finance reform in France and Britain

In both Britain and France, party funding was traditionally characterized by a laissez faire approach and a conspicuous lack of regulation. In France, this was tantamount to a 'legislative vacuum'. In the last two decades, however, both countries have sought to fundamentally reform their political finance regulation regimes. This prompted, in Britain, the Political Parties, Elections and Referendums Act 2000, and in France a bout of 'legislative incontinence' — profoundly transforming the political finance regime between 1988 and 1995. This article seeks to explore and compare the impacts of the reforms in each country in a bid to explain the unintended consequences of the alternative paths taken and the effectiveness of the new party finance regime in each country. It finds that constitutional engineering through party finance reform is a singularly inexact science, largely due to the imperfect nature of information, the limited predictability of cause and effect, and the constraining influence of non-party actors, such as the Constitutional Council in France, and the Electoral Commission in Britain

Clinical T Cell Receptor Repertoire Deep Sequencing and Analysis: An Application to Monitor Immune Reconstitution Following Cord Blood Transplantation

Spectratyping assays are well recognized as the clinical gold standard for assessing the T cell receptor (TCR) repertoire in haematopoietic stem cell transplant (HSCT) recipients. These assays use length distributions of the hyper variable complementarity-determining region 3 (CDR3) to characterize a patient's T cell immune reconstitution post-transplant. However, whilst useful, TCR spectratyping is notably limited by its resolution, with the technique unable to provide data on the individual clonotypes present in a sample. High-resolution clonotype data are necessary to provide quantitative clinical TCR assessments and to better understand clonotype dynamics during clinically relevant events such as viral infections or GvHD. In this study we developed and applied a CDR3 Next Generation Sequencing (NGS) methodology to assess the TCR repertoire in cord blood transplant (CBT) recipients. Using this, we obtained comprehensive TCR data from 16 CBT patients and 5 control cord samples at Great Ormond Street Hospital (GOSH). These were analyzed to provide a quantitative measurement of the TCR repertoire and its constituents in patients post-CBT. We were able to both recreate and quantify inferences typically drawn from spectratyping data. Additionally, we demonstrate that an NGS approach to TCR assessment can provide novel insights into the recovery of the immune system in these patients. We show that NGS can be used to accurately quantify TCR repertoire diversity and to provide valuable inference on clonotypes detected in a sample. We serially assessed the progress of T cell immune reconstitution demonstrating that there is dramatic variation in TCR diversity immediately following transplantation and that the dynamics of T cell immune reconstitution is perturbed by the presence of GvHD. These findings provide a proof of concept for the adoption of NGS TCR sequencing in clinical practice

Using Whole Genome Sequences to Investigate Adenovirus Outbreaks in a Hematopoietic Stem Cell Transplant Unit

A recent surge in human mastadenovirus (HAdV) cases, including five deaths, amongst a haematopoietic stem cell transplant population led us to use whole genome sequencing (WGS) to investigate. We compared sequences from 37 patients collected over a 20-month period with sequences from GenBank and our own database of HAdVs. Maximum likelihood trees and pairwise differences were used to evaluate genotypic relationships, paired with the epidemiological data from routine infection prevention and control (IPC) records and hospital activity data. During this time period, two formal outbreaks had been declared by IPC, while WGS detected nine monophyletic clusters, seven were corroborated by epidemiological evidence and by comparison of single-nucleotide polymorphisms. One of the formal outbreaks was confirmed, and the other was not. Of the five HAdV-associated deaths, three were unlinked and the remaining two considered the source of transmission. Mixed infection was frequent (10%), providing a sentinel source of recombination and superinfection. Immunosuppressed patients harboring a high rate of HAdV positivity require comprehensive surveillance. As a consequence of these findings, HAdV WGS is being incorporated routinely into clinical practice to influence IPC policy contemporaneously

Associations between fruit and vegetable intake, leisure-time physical activity, sitting time and self-rated health among older adults : cross-sectional data from the WELL study

BackgroundLifestyle behaviours, such as healthy diet, physical activity and sedentary behaviour, are key elements of healthy ageing and important modifiable risk factors in the prevention of chronic diseases. Little is known about the relationship between these behaviours in older adults. The purpose of this study was to explore the relationship between fruit and vegetable (F&amp;V) intake, leisure-time physical activity (LTPA) and sitting time (ST), and their association with self-rated health in older adults.MethodsThis cross-sectional study comprised 3,644 older adults (48% men) aged 55-65 years, who participated in the Wellbeing, Eating and Exercise for a Long Life (&quot;WELL&quot;) study. Respondents completed a postal survey about their health and their eating and physical activity behaviours in 2010 (38% response rate). Spearman\u27s coefficient (rho) was used to evaluate the relationship between F&amp;V intake, LTPA and ST. Their individual and shared associations with self-rated health were examined using ordinal logistic regression models, stratified by sex and adjusted for confounders (BMI, smoking, long-term illness and socio-demographic characteristics).ResultsThe correlations between F&amp;V intake, LTPA and ST were low. F&amp;V intake and LTPA were positively associated with self-rated health. Each additional serving of F&amp;V or MET-hour of LTPA were associated with approximately 10% higher likelihood of reporting health as good or better among women and men. The association between ST and self-rated health was not significant in the multivariate analysis. A significant interaction was found (ST*F&amp;V intake). The effect of F&amp;V intake on self-rated health increased with increasing ST in women, whereas the effect decreased with increasing ST in men.ConclusionThis study contributes to the scarce literature related to lifestyle behaviours and their association with health indicators among older adults. The findings suggest that a modest increase in F&amp;V intake, or LTPA could have a marked effect on the health of older adults. Further research is needed to fully understand the correlates and determinants of lifestyle behaviours, particularly sitting time, in this age group

Use of Whole-genome Sequencing of Adenovirus in Immunocompromised Paediatric Patients to Identify Nosocomial Transmission and Mixed-genotype Infection

Background: Adenoviruses are significant pathogens for the immunocompromised, arising from primary infection or reinfection. Serotyping is insufficient to support nosocomial transmission investigations. We investigate whether whole-genome sequencing (WGS) provides clinically relevant information on transmission among patients in a paediatric tertiary hospital. Methods: We developed a target-enriched adenovirus WGS technique for clinical samples and retrospectively sequenced 107 adenovirus-positive residual diagnostic samples, including viraemias (>5x104 copies/ml), from 37 patients collected January 2011 - March 2016. WGS was used to determine genotype and for phylogenetic analysis. Results: Adenovirus sequences were recovered from 105/107 samples. Full genome sequences were recovered from all 20 non-species C samples and from 36/85 species C viruses, with partial genome sequences recovered from the rest. Whole genome phylogenetic analysis suggested linkage of three genotype A31 cases and uncovered an unsuspected epidemiological link to an A31 infection first detected on the same ward four years earlier. In nine samples from one patient who died we identified a mixed genotype adenovirus infection. Conclusions: Adenovirus WGS from clinical samples is possible and useful for genotyping and molecular epidemiology. WGS identified likely nosocomial transmission with greater resolution than conventional genotyping, and distinguished between adenovirus disease due to single or multiple genotypes