UK combat-related pelvic junctional vascular injuries 2008-2011: implications for future intervention.

In a recent publication, 297 of 6450 (4.6%) military coalition deaths over ten years were reported to be due to junctional bleeding. The authors suggested that some of these deaths could have been avoided with a junctional haemorrhage control device. Prospectively collected data on all injuries sustained in Afghanistan by UK military personnel from 1 August 2008 to 31 July 2011 period were reviewed, using the UK Joint Theatre Trauma Registry. All fatalities with significant pelvic injuries were identified and analysed, and the cause of death established to assess the potential role for a junctional haemorrhage control device. Significant upper thigh, groin or pelvic injuries were recorded in 124 casualties, of which 93 died. Of these the pelvic injury was the cause of death in 37, but only 1 casualty with potentially survivable injuries was identified where death was due to a vascular injury below the inguinal ligament, not controlled by a CAT. This represents <1% of all deaths in this period, a lower figure than previously published. We further identified 32 casualties where the cause of death was due to a vascular injury between the aortic bifurcation and the inguinal ligament. Eight of these survived to a medical facility but subsequently died of their wounds. These represent a subset in which vascular control proximal to the inguinal ligament could have altered the outcome. Some potentially survivable deaths due to exsanguination may be amenable to proximal vascular control. Our study does not substantiate previous conclusions that this can be achieved through use of a groin junctional tourniquet. We believe there may be a role for more proximal vascular control of pelvic bleeding, and this merits further research.

Case suitability for definitive through knee amputation following lower extremity blast trauma: analysis of 146 combat casualties, 2008-2010.

INTRODUCTION: Analysis of recent UK Armed Forces combat casualty data has highlighted a significant number of through joint traumatic amputations (TAs), most commonly through knee (through knee amputations (TKAs)). Previously, a consensus statement on lower limb amputation from the UK Defence Medical Services reported better outcomes in some patients with TKAs when compared with those with above knee amputations. This study sought to define the proportion of recent combat casualties sustaining severe lower extremity trauma with acute osseous and soft tissue injury anatomy amenable to definitive TKA. METHODS: The UK Joint Theatre Trauma Registry and post mortem CT (PM-CT) databases were used to identify all UK Armed Forces personnel (survivors and fatalities) sustaining a major extremity TA (through/proximal to wrist or ankle joint) between August 2008 and August 2010. Through knee and all below knee TAs were grouped as 'potential TKAs' (pTKAs), that is, possible candidates for definitive TKA. RESULTS: 146 Cases (75 survivors and 71 fatalities) sustaining 271 TAs (130 in survivors, 141 in fatalities) were identified. The through-joint TA rate was 47/271 (17.3%); 34/47 through-joint injuries (72.3%) were TKAs. Overall, 63/130 TAs in survivors and 66/140 TAs in fatalities merited analysis as the pTKA group. Detailed anatomical data on pre-debridement osseous and soft tissue injury levels were only consistently available for fatalities through PM-CT findings. Further analysis of the soft tissue injury profile revealed that a definitive TKA in the pTKA group (all BKAs as well as TKAs) would have been proximal to the zone of injury (ZOI) in only 3/66 cases. CONCLUSIONS: Traumatic TKAs following explosive blast are more common than previously reported. The majority of lower limb TAs are skeletally amenable to a definitive TKA. Maximising residual stump length carries the risks of definitive level amputation within the original ZOI but this study demonstrates that the proximal extent of the soft tissue injury may frequently make this unavoidable. Further work is required to determine the relative merits of definitive below, through and above knee amputations in the short, medium and long term to ensure survivors are subject to minimal complications while maintaining capacity to achieve optimal functional outcomes.

Confirmation of novel type 1 diabetes risk loci in families.

AIMS/HYPOTHESIS: Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. METHODS: We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. RESULTS: Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. CONCLUSIONS/INTERPRETATION: The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.

Functional activity of Pat-1 (Slc26a6) Cl(−)/HCO3(−) exchange in the lower villus epithelium of murine duodenum.

AIMS: The apical membrane anion exchanger putative anion transporter-1 (Pat-1) is expressed at significant levels in the lower villus epithelium of murine duodenum. However, previous studies of Cl(−)/HCO3(−) exchange in the lower villus have failed to demonstrate Pat-1 function. Those studies routinely included luminal glucose which induces Na(+) -coupled glucose transport and acidifies the villus epithelium. Since Pat-1 has been proposed to be an electrogenic 1Cl(−)/2HCO3(−) exchanger, membrane depolarization or cell acidification during glucose transport may obscure Pat-1 activity. Therefore, we investigated the effects of luminal glucose on Cl(−)(IN)/HCO3(−) (OUT) exchange activity in the lower villus epithelium. METHODS: Cl(−)(IN) /HCO (−) (OUT) exchange of villus epithelium in duodenal mucosa from Pat-1 knockout (KO), Slc26a3 [down-regulated in adenoma (Dra)] KO, cystic fibrosis transmembrane conductance regulator (Cftr) KO and wild-type (WT) littermate mice was measured using the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. Short-circuit current (I(sc) ) was measured in Ussing chambers. RESULTS: During glucose absorption, Cl(−)(IN)/HCO3(−) (OUT) exchange in the lower villus epithelium was abolished in the Dra KO and unaffected in the Pat-1 KO relative to WT. However, during electroneutral mannose absorption or electrogenic α-D-methyl glucoside absorption, Cl(−)(IN) /HCO3(−) (OUT) exchange was reduced in both Pat-1 KO and Dra KO villi. Exposure to high [K(+)] abolished Cl(−)(IN) /HCO3(−) (OUT) exchange in the Dra KO but not the Dra/Cftr double KO epithelium, suggesting that Pat-1 activity is little affected by membrane depolarization except in the presence of Cftr. CONCLUSIONS: The metabolic and electrogenic activity of glucose transport obscures Cl(−)(IN) /HCO3(−) (OUT) exchange activity of Pat-1 in the lower villus. The inhibitory effects of membrane depolarization on Pat-1 Cl(−)(IN) /HCO3(−) (OUT) exchange may require concurrent membrane association with Cftr.

Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families.

In recent years the pace of discovery of genetic associations with type I diabetes (T1D) has accelerated, with the total number of confirmed loci, including the major histocompatibility complex (MHC) region, reaching 43. However, much of the deciphering of the associations at these, and the established T1D loci, has yet to be performed in sufficient numbers of samples or with sufficient markers. Here, 257 single-nucleotide polymorphisms (SNPs) have been genotyped in 19 candidate genes (INS, PTPN22, IL2RA, CTLA4, IFIH1, SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21, CAPSL, Q7Z4c4(5Q), FOXP3, EFHB) in 2300 affected sib-pair families and tested for association with T1D as part of the Type I Diabetes Genetics Consortium's candidate gene study. The study had approximately 80% power at alpha=0.002 and a minor allele frequency of 0.2 to detect an effect with a relative risk (RR) of 1.20, which drops to just 40% power for a RR of 1.15. At the INS gene, rs689 (-23 HphI) was the most associated SNP (P=3.8 x 10(-31)), with the estimated RR=0.57 (95% confidence interval, 0.52-0.63). In addition, rs689 was associated with age-at-diagnosis of T1D (P=0.001), with homozygosity for the T1D protective T allele, delaying the onset of T1D by approximately 2 years in these families. At PTPN22, rs2476601 (R620W), in agreement with previous reports, was the most significantly associated SNP (P=6.9 x 10(-17)), with RR=1.55 (1.40-1.72). Evidence for association with T1D was observed for the IFIH1 SNP, rs1990760 (P=7.0 x 10(-4)), with RR=0.88 (0.82-0.95) and the CTLA4 SNP rs1427676 (P=0.0005), with RR=1.14 (1.06-1.23). In contrast, no convincing evidence of association was obtained for SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21 or CAPSL gene regions (http://www.T1DBase.org).

Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families.

The advent of genome-wide association (GWA) studies has revolutionized the detection of disease loci and provided abundant evidence for previously undetected disease loci that can be pooled together in meta-analysis studies or used to design follow-up studies. A total of 1715 SNPs from the Wellcome Trust Case Control Consortium GWA study of type I diabetes (T1D) were selected and a follow-up study was conducted in 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. In addition to the support for previously identified loci (PTPN22/1p13; ERBB3/12q13; SH2B3/12q24; CLEC16A/16p13; UBASH3A/21q22), evidence supporting two new and distinct chromosome locations associated with T1D was observed: FHOD3/18q12 (rs2644261, P=5.9 x 10(-4)) and Xp22 (rs5979785, P=6.8 x 10(-3); http://www.T1DBase.org). There was independent support for both SNPs in a GWA meta-analysis of 7514 cases and 9045 controls (P values=5.0 x 10(-3) and 6.7 x 10(-6), respectively). The chromosome 18q12 region contains four genes, none of which are obvious functional candidate genes. In contrast, the Xp22 SNP is located 30 kb centromeric of the functional candidate genes TLR8 and TLR7 genes. Both TLR8 and TLR7 are functional candidate genes owing to their key roles as pathogen recognition receptors and, in the case of TLR7, overexpression has been associated directly with murine autoimmune disease.

Analysis of 55 autoimmune disease and type II diabetes loci: further confirmation of chromosomes 4q27, 12q13.2 and 12q24.13 as type I diabetes loci, and support for a new locus, 12q13.3-q14.1.

A candidate gene study was conducted on 10 established type II diabetes genes and 45 genes associated with autoimmune diseases, including type I diabetes (T1D), in a maximum of 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. Associations at P values <10(-3) were found for three known T1D regions at chromosomes 4q27, 12q13.2 and 12q24.13 (http://www.T1DBase.org). Support was obtained for a newly identified T1D candidate locus on chromosome 12q13.3-12q14.1 (rs1678536/KIF5A: P=8.1 x 10(-3); relative risk (RR) for minor allele=0.89, 95% CI=0.82-0.97), which has a separate association from the previously reported T1D candidate locus ERBB3/12q13.2-q13.3. Our new evidence adds to that previously published for the same gene region in a T1D case-control study (rs1678542; P=3.0 x 10(-4); odds ratio (OR)=0.92, 95% CI=0.88-0.96). This region, which contains many genes, has also been associated with rheumatoid arthritis.

The effect of pre-operative counselling on smoking patterns in patients undergoing forefoot surgery.

BACKGROUND: Smoking contributes to higher surgical complication rates. Previous studies assessing smoking cessation interventions examined the provision of comprehensive packages. The use of surgery as an incentive to complement brief advice has not been fully evaluated. METHODS: Smokers were counselled and referred to their general practitioners for specific cessation strategies. Smoking status was recorded prior to surgery, on admission and in post-operative clinics. A telephone survey at a mean of 12 months post-operation ascertained long-term behavioural changes. RESULTS: Ninety-seven patients underwent surgery with twenty-five recorded as smokers. Sixteen stopped smoking pre-operatively; a further four reduced their intake, as a direct consequence of counselling. No patients were previously aware of the detrimental effects of smoking associated with foot surgery. CONCLUSIONS: Surgery provides an incentive for smoking cessation, maintained post-operatively. Although forefoot fusions and arthrodeses were used in our study, the results are transferable to other branches of orthopaedic surgery.

No association of multiple type 2 diabetes loci with type 1 diabetes.

AIMS/HYPOTHESIS: We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. METHODS: The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. RESULTS: Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; p (combined) = 1.0 x 10(-4)). No SNPs showed evidence of interaction with any covariate (p > 0.05). CONCLUSIONS/INTERPRETATION: We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.

Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A.

AIM: Until recently, human leucocyte antigen (HLA) class II-independent associations with type 1 diabetes (T1D) in the Major Histocompatibility Complex (MHC) region were not adequately characterized owing to insufficient map coverage, inadequate statistical approaches and strong linkage disequilibrium spanning the entire MHC. Here we test for HLA class II-independent associations in the MHC using fine mapping data generated by the Type 1 Diabetes Genetics Consortium (T1DGC). METHODS: We have applied recursive partitioning to the modelling of the class II loci and used stepwise conditional logistic regression to test approximately 1534 loci between 29 and 34 Mb on chromosome 6p21, typed in 2240 affected sibpair (ASP) families. RESULTS: Preliminary analyses confirm that HLA-B (at 31.4 Mb), HLA-A (at 30.0 Mb) are associated with T1D independently of the class II genes HLA-DRB1 and HLA-DQB1 (P = 6.0 x 10(-17) and 8.8 x 10(-13), respectively). In addition, a second class II region of association containing the single-nucleotide polymorphism (SNP), rs439121, and the class II locus HLA-DPB1, was identified as a T1D susceptibility effect which is independent of HLA-DRB1, HLA-DQB1 and HLA-B (P = 9.2 x 10(-8)). A younger age-at-diagnosis of T1D was found for HLA-B*39 (P = 7.6 x 10(-6)), and HLA-B*38 was protective for T1D. CONCLUSIONS: These analyses in the T1DGC families replicate our results obtained previously in approximately 2000 cases and controls and 850 families. Taking both studies together, there is evidence for four T1D-associated regions at 30.0 Mb (HLA-A), 31.4 Mb (HLA-B), 32.5 Mb (rs9268831/HLA-DRA) and 33.2 Mb (rs439121/HLA-DPB1) that are independent of HLA-DRB1/HLA-DQB1. Neither study found evidence of independent associations at HLA-C, HLA-DQA1 loci nor in the UBD/MAS1L or ITPR3 gene regions. These studies show that to find true class II-independent effects, large, well-powered sample collections are required and be genotyped with a dense map of markers. In addition, a robust statistical methodology that fully models the class II effects is necessary. Recursive partitioning is a useful tool for modelling these multiallelic systems.

CD226 Gly307Ser association with multiple autoimmune diseases.

Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser(307) association with T1D (P=3.46 x 10(-9)) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 x 10(-4)) and rheumatoid arthritis (RA) (P=0.017). The Ser(307) allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus.

As a result of genome-wide association studies in larger sample sets, there has been an increase in identifying genes that influence susceptibility to individual immune-mediated diseases, as well as evidence that some genes are associated with more than one disease. In this study, we tested 17 single nucleotide polymorphisms (SNP) from 16 gene regions that have been reported in several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ankylosing spondylitis (AS) and Crohn's disease (CD) to determine whether the variants are also associated with type 1 diabetes (T1D). In up to 8010 cases and 9733 controls we found some evidence for an association with T1D in the regions containing genes: 2q32/STAT4, 17q21/STAT3, 5p15/ERAP1 (ARTS1), 6q23/TNFAIP3 and 12q13/KIF5A/PIP4K2C with allelic P-values ranging from 3.70 x 10(-3) to 3.20 x 10(-5). These findings extend our knowledge of susceptibility locus sharing across different autoimmune diseases, and provide convincing evidence that the RA/SLE locus 6q23/TNFAIP3 is a newly identified T1D locus.

Fatal fat embolism following femoral head resection in total hip arthroplasty.

We report a rare complication during primary total hip arthroplasty. A fatal fat pulmonary embolism immediately followed removal of the femoral head, prior to further preparation of the acetabulum or femoral shaft. Fat embolism syndrome is a well-known complication during total joint arthroplasty, usually attributed to preparation of the femoral shaft, particularly intramedullary reaming and insertion of the prosthesis. These risk factors have previously been identified in the literature. We believe that this case highlights the need for further research to establish the intramedullary pressures during the processes of dislocation and resection of the femoral neck and the attendant risk.

Hugh Cairns--neurosurgical innovator.

Following in the footsteps of Victor Horsley, the 'father of British neurosurgery', Hugh Cairns continued the tradition ofgreat neurosurgeons associated with the Royal Army Medical Corps. He was a central figure in the acceptance of neurosurgery as a specialty in its own right in Britain, was instrumental in the foundation of Oxford University Medical School, and can legitimately claim to have significantly improved mortality figures in neurosurgical casualties in the Second World War. He was also the driving force in the acceptance of crash helmets for motorcyclists, which have substantially reduced the mortality rates of motorcyclists in those countries in which they have been introduced.

Edward Almroth Wright.

Sixty years ago saw the passing of Edward Almroth Wright, Professor of Pathology at the Army Medical College between 1892 and 1902. Wright secured his place in the medical pantheon, and significant fame, with the discovery of an effective vaccine for typhoid in 1897. This article examine show he earned his place in medical history.

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene.

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C>T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 C>T SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 C>T and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial.

BACKGROUND: Opposing views have been published on the importance of ultrasound screening for abdominal aortic aneurysms. The Multicentre Aneurysm Screening Study was designed to assess whether or not such screening is beneficial. METHODS: A population-based sample of men (n=67800) aged 65-74 years was enrolled, and each individual randomly allocated to either receive an invitation for an abdominal ultrasound scan (invited group, n=33839) or not (control group, n=33961). Men in whom abdominal aortic aneurysms (> or =3 cm in diameter) were detected were followed-up with repeat ultrasound scans for a mean of 4.1 years. Surgery was considered on specific criteria (diameter > or =5.5 cm, expansion > or =1 cm per year, symptoms). Mortality data were obtained from the Office of National Statistics, and an intention-to-treat analysis was based on cause of death. Quality of life was assessed with four standardised scales. The primary outcome measure was mortality related to abdominal aortic aneurysm. FINDINGS: 27147 of 33839 (80%) men in the invited group accepted the invitation to screening, and 1333 aneurysms were detected. There were 65 aneurysm-related deaths (absolute risk 0.19%) in the invited group, and 113 (0.33%) in the control group (risk reduction 42%, 95% CI 22-58; p=0.0002), with a 53% reduction (95% CI 30-64) in those who attended screening. 30-day mortality was 6% (24 of 414) after elective surgery for an aneurysm, and 37% (30 of 81) after emergency surgery. INTERPRETATION: Our results provide reliable evidence of benefit from screening for abdominal aortic aneurysms.

Late results concerning feasibility and compliance from a randomized trial of ultrasonographic screening for abdominal aortic aneurysm.

BACKGROUND: The study was an update at 10 years of a randomized trial of the efficacy of screening for abdominal aortic aneurysm (AAA). The extent of benefit, feasibility and compliance were examined, and reasons why this intervention may fail a proportion of those screened were identified. METHODS: A total of 6058 men aged 65 years and over were randomized to a group invited to attend ultrasonographic screening or to a control group. The mortality rate from AAA in the two arms of the trial was compared using a Poisson model. Analyses were by intention to treat. RESULTS: There was a 21 per cent reduction in mortality rate from AAA over the 10-year follow-up (relative risk 0.79 (95 per cent confidence interval 0.53 to 1.40)). The observed relative mortality reduction peaked at 4 years with a 52 per cent reduction in the study group. Eighteen of 24 AAA deaths in the study group were among those who did not attend the first screen, or failed to comply with the follow-up protocol. CONCLUSION: A greater awareness of the benefits of full participation in a screening programme could provide a larger and sustained mortality reduction.