The injury mechanism of traumatic amputation

Traumatic amputation has been one of the most defining injuries associated with explosive devices. An understanding of the mechanism of injury is essential in order to reduce its incidence and devastating consequences to the individual and their support network. In this study, traumatic amputation is reproduced using high-velocity environmental debris in an animal cadaveric model. The study findings are combined with previous work to describe fully the mechanism of injury as follows. The shock wave impacts with the casualty, followed by energised projectiles (environmental debris or fragmentation) carried by the blast. These cause skin and soft tissue injury, followed by skeletal trauma which compounds to produce segmental and multifragmental fractures. A critical injury point is reached, whereby the underlying integrity of both skeletal and soft tissues of the limb has been compromised. The blast wind that follows these energised projectiles completes the amputation at the level of the disruption, and traumatic amputation occurs. These findings produce a shift in the understanding of traumatic amputation due to blast from a mechanism predominately thought mediated by primary and tertiary blast, to now include secondary blast mechanisms, and inform change for mitigative strategies

What Is the Magnitude and Long-term Economic Cost of Care of the British Military Afghanistan Amputee Cohort?

Background Personal protection equipment, improved early medical care, and rapid extraction of the casualty have resulted in more injured service members who served in Afghanistan surviving after severe military trauma. Many of those who survive the initial trauma are faced with complex wounds such as multiple amputations. Although costs of care can be high, they have not been well quantified before. This is required to budget for the needs of the injured beyond their service in the armed forces. Question/purposes The purposes of this study were (1) to quantify and describe the extent and nature of traumatic amputations of British service personnel from Afghanistan; and (2) to calculate an estimate of the projected long-term cost of this cohort. Methods A four-stage methodology was used: (1) systematic literature search of previous studies of amputee care cost; (2) retrospective analysis of the UK Joint Theatre Trauma and prosthetic database; (3) Markov economic algorithm for healthcare cost and sensitivity analysis of results; and (4) statistical cost comparison between our cohort and the identified literature. Results From 2003 to 2014, 265 casualties sustained 416 amputations. The average number of limbs lost per casualty was 1.6. The most common type of amputation was a transfemoral amputation (153 patients); the next most common amputation type was unilateral transtibial (143 patients). Using a Markov model of healthcare economics, it is estimated that the total 40-year cost of the UK Afghanistan lower limb amputee cohort is £288 million (USD 444 million); this figure estimates cost of trauma care, rehabilitation, and prosthetic costs. A sensitivity analysis on our model demonstrated a potential ± 6.19% variation in costs. Conclusions The conflict in Afghanistan resulted in high numbers of complex injuries. Our findings suggest that a long-term facility to budget for veterans’ health care is necessary

Knowledge, attitudes and other factors associated with assessment of tobacco smoking among pregnant Aboriginal women by health care providers: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>As with many Indigenous peoples, smoking rates among Aboriginal Australians are considerably higher than those of the non-Indigenous population. Approximately 50% of Indigenous women smoke during pregnancy, a time when women are more motivated to quit. Antenatal care providers are potentially important change agents for reducing the harms associated with smoking, yet little is known about their knowledge, attitudes or skills, or the factors associated with providing smoking cessation advice.</p> <p>Methods</p> <p>This paper aimed to explore the knowledge and attitudes of health care providers caring for pregnant Australian Aboriginal women with regard to smoking risks and cessation; and to identify factors associated with self-reported assessment of smoking. A cross-sectional survey was undertaken with 127 staff providing antenatal care to Aboriginal women from two jurisdictions: the Northern Territory and New South Wales, Australia. Measures included respondents' estimate of the prevalence of smoking among pregnant women; optimal and actual assessment of smoking status; knowledge of risks associated with antenatal smoking; knowledge of smoking cessation; attitudes to providing cessation advice to pregnant women; and perceived barriers and motivators for cessation for pregnant women.</p> <p>Results</p> <p>The median provider estimate of the smoking prevalence was 69% (95%CI: 60,70). The majority of respondents considered assessment of smoking status to be integral to antenatal care and a professional responsibility. Most (79%) indicated that they assess smoking status in 100% of clients. Knowledge of risks was generally good, but knowledge of cessation was poor. Factors independently associated with assessing smoking status among all women were: employer service type (<it>p </it>= 0.025); cessation knowledge score (<it>p </it>= 0.011); and disagreeing with the statement that giving advice is not worth it given the low level of success (<it>p </it>= 0.011).</p> <p>Conclusions</p> <p>Addressing knowledge of smoking risks and cessation counselling is a priority and should improve both confidence and ability, and increase the frequency and effectiveness of counselling. The health system must provide supports to providers through appropriate policy and resourcing, to enable them to address this issue.</p

The Extra Domain A of Fibronectin Increases VEGF-C Expression in Colorectal Carcinoma Involving the PI3K/AKT Signaling Pathway

The extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, is predominantly expressed in various malignancies but not in normal tissues. In the present study, we investigated the potential pro-lymphangiogenesis effects of extra domain A (EDA)-mediated vascular endothelial growth factor-C (VEGF-C) secretion in colorectal carcinoma (CRC). We detected the expressions of EDA and VEGF-C in 52 human colorectal tumor tissues and their surrounding mucosae by immunohistochemical analysis, and further tested the correlation between the expressions of these two proteins in aforementioned CRC tissues. Both EDA and VEGF-C were abundantly expressed in the specimens of human CRC tissues. And VEGF-C was associated with increased expression of EDA in human CRC according to linear regression analysis. Besides, EDA expression was significantly correlated with lymph node metastasis, tumor differentiation and clinical stage by clinicopathological analysis of tissue microarrays containing tumor tissues of 115 CRC patients. Then, human CRC cell SW480 was transfected with lentivectors to elicit expression of shRNA against EDA (shRNA-EDA), and SW620 was transfected with a lentiviral vector to overexpress EDA (pGC-FU-EDA), respectively. We confirmed that VEGF-C was upregulated in EDA-overexpressed cells, and downregulated in shRNA-EDA cells. Moreover, a PI3K-dependent signaling pathway was found to be involved in EDA-mediated VEGF-C secretion. The in vivo result demonstrated that EDA could promote tumor growth and tumor-induced lymphangiogenesis in mouse xenograft models. Our findings provide evidence that EDA could play a role in tumor-induced lymphangiogenesis via upregulating autocrine secretion of VEGF-C in colorectal cancer, which is associated with the PI3K/Akt-dependent pathway

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age

Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders