Hematocrit and the Risk of Recurrent Venous Thrombosis: A Prospective Cohort Study

BACKGROUND: Venous thromboembolism (VTE) is a multicausal disease which recurs. Hematocrit is associated with a thrombotic risk. We aimed to investigate if hematocrit is associated with the recurrence risk. METHODS: Patients with a first VTE were followed after anticoagulation. Patients with VTE provoked by a transient risk factor, natural inhibitor deficiency, lupus anticoagulant, homozygous or double heterozygous defects, cancer, or long-term antithrombotic treatment were excluded. The study endpoint was recurrent VTE. RESULTS: 150 (23%) of 653 patients had recurrence. Only high hematocrit was significantly associated with recurrence risk [hazard ratio (HR) for 1% hematocrit increase with the third tertile 1.08; 95% CI 1.01-1.15]. No or only a weak association for hematocrits within the first and second tertile was seen (HR 1.03; 95% CI 0.97-1.09, and 1.07; 95% CI 1.00-1.13). Hematocrit was associated with recurrence risk only among women. After five years, the probability of recurrence was 9.9% (95% CI 3.7%-15.7%), 15.6% (95% CI 9.7%-21.2%) and 25.5% (95% CI 15.1%-34.6%) in women, and was 29.2% (95% CI 21.1%-36.5%), 30.1% (95% CI 24.1%-35.7%) and 30.8% (95% CI 22.0%-38.7%) in men for hematocrits in the first, second and third tertile, respectively. Men had a higher recurrence risk (1.9; 95% CI 1.1-2.7; p = 0.03), which dropped by 23.5% after adjustment for hematocrit. Hematocrit was not a significant mediator of the sex-difference in recurrence risk (p = 0.223). CONCLUSIONS: High hematocrit is associated with the recurrence only in women. The different recurrence risk between men and women is possibly partly explained by hematocrit

The efficacy of playing a virtual reality game in modulating pain for children with acute burn injuries: A randomized controlled trial [ISRCTN87413556]

BACKGROUND: The management of burn injuries is reported as painful, distressing and a cause of anxiety in children and their parents. Child's and parents' pain and anxiety, often contributes to extended time required for burns management procedures, in particular the process of changing dressings. The traditional method of pharmacologic analgesia is often insufficient to cover the burnt child's pain, and it can have deleterious side effects [1,2]. Intervention with Virtual Reality (VR) games is based on distraction or interruption in the way current thoughts, including pain, are processed by the brain. Research on adults supports the hypothesis that virtual reality has a positive influence on burns pain modulation. METHODS: This study investigates whether playing a virtual reality game, decreases procedural pain in children aged 5–18 years with acute burn injuries. The paper reports on the findings of a pilot study, a randomised trial, in which seven children acted as their own controls though a series of 11 trials. Outcomes were pain measured using the self-report Faces Scale and findings of interviews with parent/carer and nurses. RESULTS: The average pain scores (from the Faces Scale) for pharmacological analgesia only was, 4.1 (SD 2.9), while VR coupled with pharmacological analgesia, the average pain score was 1.3 (SD 1.8) CONCLUSION: The study provides strong evidence supporting VR based games in providing analgesia with minimal side effects and little impact on the physical hospital environment, as well as its reusability and versatility, suggesting another option in the management of children's acute pain

Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. // Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). // Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. // Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings

Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown</p> <p>Methods</p> <p>To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-β.</p> <p>Results</p> <p>The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-β and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. <it>In vitro</it>, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25^hiCD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-β to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation.</p> <p>Conclusion</p> <p>In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.</p

Population Structure and Gene Flow of the Yellow Anaconda (Eunectes notaeus) in Northern Argentina

Yellow anacondas (Eunectes notaeus) are large, semiaquatic boid snakes found in wetland systems in South America. These snakes are commercially harvested under a sustainable management plan in Argentina, so information regarding population structuring can be helpful for determination of management units. We evaluated genetic structure and migration using partial sequences from the mitochondrial control region and mitochondrial genes cyt-b and ND4 for 183 samples collected within northern Argentina. A group of landscape features and environmental variables including several treatments of temperature and precipitation were explored as potential drivers of observed genetic patterns. We found significant population structure between most putative population comparisons and bidirectional but asymmetric migration in several cases. The configuration of rivers and wetlands was found to be significantly associated with yellow anaconda population structure (IBD), and important for gene flow, although genetic distances were not significantly correlated with the environmental variables used here. More in-depth analyses of environmental data may be needed to fully understand the importance of environmental conditions on population structure and migration. These analyses indicate that our putative populations are demographically distinct and should be treated as such in Argentina's management plan for the harvesting of yellow anacondas

Embryology and bony malformations of the craniovertebral junction

BACKGROUND: The embryology of the bony craniovertebral junction (CVJ) is reviewed with the purpose of explaining the genesis and unusual configurations of the numerous congenital malformations in this region. Functionally, the bony CVJ can be divided into a central pillar consisting of the basiocciput and dental pivot and a two-tiered ring revolving round the central pivot, comprising the foramen magnum rim and occipital condyles above and the atlantal ring below. Embryologically, the central pillar and the surrounding rings descend from different primordia, and accordingly, developmental anomalies at the CVJ can also be segregated into those affecting the central pillar and those affecting the surrounding rings, respectively. DISCUSSION: A logical classification of this seemingly unwieldy group of malformations is thus possible based on their ontogenetic lineage, morbid anatomy, and clinical relevance. Representative examples of the main constituents of this classification scheme are given, and their surgical treatments are selectively discussed

Clinical research without consent in adults in the emergency setting: a review of patient and public views

<p>Abstract</p> <p>Background</p> <p>In emergency research, obtaining informed consent can be problematic. Research to develop and improve treatments for patients admitted to hospital with life-threatening and debilitating conditions is much needed yet the issue of research without consent (RWC) raises concerns about unethical practices and the loss of individual autonomy. Consistent with the policy and practice turn towards greater patient and public involvement in health care decisions, in the US, Canada and EU, guidelines and legislation implemented to protect patients and facilitate acute research with adults who are unable to give consent have been developed with little involvement of the lay public. This paper reviews research examining public opinion regarding RWC for research in emergency situations, and whether the rules and regulations permitting research of this kind are in accordance with the views of those who ultimately may be the most affected.</p> <p>Methods</p> <p>Seven electronic databases were searched: Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews, Philosopher's Index, Age Info, PsychInfo, Sociological Abstracts and Web of Science. Only those articles pertaining to the views of the public in the US, Canada and EU member states were included. Opinion pieces and those not published in English were excluded.</p> <p>Results</p> <p>Considering the wealth of literature on the perspectives of professionals, there was relatively little information about public attitudes. Twelve studies employing a range of research methods were identified. In five of the six questionnaire surveys around half the sample did <it>not </it>agree generally with RWC, though paradoxically, a higher percentage would <it>personally </it>take part in such a study. Unfortunately most of the studies were not designed to investigate individuals' views in any depth. There also appears to be a level of mistrust of medical research and some patients were more likely to accept an experimental treatment 'outside' of a research protocol.</p> <p>Conclusion</p> <p>There are too few data to evaluate whether the rules and regulations permitting RWC protects – or is acceptable to – the public. However, any attempts to engage the public should take place in the context of findings from further basic research to attend to the apparently paradoxical findings of some of the current surveys.</p