Open fracture infection following combat trauma : defining the problem and evaluating novel treatments

PhD ThesisThe British military was engaged in combat operations in Iraq and Afghanistan over a 12-year period from 2003 to 2014. It has been asserted that over this time survival after combat injury improved generating a cohort of patients with complex limb injuries, including open fractures, which are prone to infection and challenging to reconstruct. Using an anatomic measure of injury severity I demonstrate an improvement in survival after combat injury. I further tested this finding by devising a military specific version of an anatomic-physiological injury scoring system, which confirmed the survival improvement. The UK military trauma registry was used to determine that the most frequently fractured bone was the Tibia and 65% of these fractures were open. Of these, 23% were surgically treated for infection in the first year and S. aureus bacteria was the causative organism in 60%. Infection was significantly associated with amputation or unplanned revision surgery. To further investigate open fracture infections in a controlled setting, an established rodent model of a stabilised, S. aureus contaminated, femoral defect was refined. This model was used to investigate the relationship between timing of treatment and infection. The results of this study indicate that delaying antibiotics administration has a greater effect on infection rates than delaying surgery and that early antibiotics can reduce the greater infection seen with surgical delay but not negate its effect entirely. Novel treatments with potential to reduce infection in open fractures were then evaluated. Chlorhexidine was found to be similar to saline for wound irrigation with respect to preventing infection. A novel biodegradable antibiotic gel proved to be superior at preventing infection in the model than the existing clinical standard local antibiotic delivery vehicle: bone cement (Polymethylmethacrylate) beads. Finally Bismuth Thiols were demonstrated to potentiate the effect of antibiotics in preventing infection

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

Background: Overall, ~5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. Methods: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. Results: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). Interpretation: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association

Rolling friction of a viscous sphere on a hard plane

A first-principle continuum-mechanics expression for the rolling friction coefficient is obtained for the rolling motion of a viscoelastic sphere on a hard plane. It relates the friction coefficient to the viscous and elastic constants of the sphere material. The relation obtained refers to the case when the deformation of the sphere $\xi$ is small, the velocity of the sphere $V$ is much less than the speed of sound in the material and when the characteristic time $\xi/V$ is much larger than the dissipative relaxation times of the viscoelastic material. To our knowledge this is the first ``first-principle'' expression of the rolling friction coefficient which does not contain empirical parameters.Comment: 6 pages, 2 figure

Evolutionary trait‐based approaches for predicting future global impacts of plant pathogens in the genus Phytophthora

Plant pathogens are introduced to new geographical regions ever more frequently as global connectivity increases. Predicting the threat they pose to plant health can be difficult without in‐depth knowledge of behaviour, distribution and spread. Here, we evaluate the potential for using biological traits and phylogeny to predict global threats from emerging pathogens. We use a species‐level trait database and phylogeny for 179 Phytophthora species: oomycete pathogens impacting natural, agricultural, horticultural and forestry settings. We compile host and distribution reports for Phytophthora species across 178 countries and evaluate the power of traits, phylogeny and time since description (reflecting species‐level knowledge) to explain and predict their international transport, maximum latitude and host breadth using Bayesian phylogenetic generalised linear mixed models. In the best‐performing models, traits, phylogeny and time since description together explained up to 90%, 97% and 87% of variance in number of countries reached, latitudinal limits and host range, respectively. Traits and phylogeny together explained up to 26%, 41% and 34% of variance in the number of countries reached, maximum latitude and host plant families affected, respectively, but time since description had the strongest effect. Root‐attacking species were reported in more countries, and on more host plant families than foliar‐attacking species. Host generalist pathogens had thicker‐walled resting structures (stress‐tolerant oospores) and faster growth rates at their optima. Cold‐tolerant species are reported in more countries and at higher latitudes, though more accurate interspecific empirical data are needed to confirm this finding. Policy implications. We evaluate the potential of an evolutionary trait‐based framework to support horizon‐scanning approaches for identifying pathogens with greater potential for global‐scale impacts. Potential future threats from Phytophthora include Phytophthora x heterohybrida, P. lactucae, P. glovera, P. x incrassata, P. amnicola and P. aquimorbida, which are recently described, possibly under‐reported species, with similar traits and/or phylogenetic proximity to other high‐impact species. Priority traits to measure for emerging species may be thermal minima, oospore wall index and growth rate at optimum temperature. Trait‐based horizon‐scanning approaches would benefit from the development of international and cross‐sectoral collaborations to deliver centralised databases incorporating pathogen distributions, traits and phylogeny

Human Subcutaneous Adipose Tissue Sampling using a Mini-liposuction Technique

Studies on adipose tissue are useful in understanding metabolic and other conditions. Human subcutaneous adipose tissue is accessible. With appropriate training and strict adherence to aseptic technique, subcutaneous adipose samples can be safely and efficiently obtained in a non-clinical setting by researchers. Following the administration of local anesthetic lateral to the umbilicus, a 14 G needle attached to a 5 or 10 mL syringe is inserted through the skin into the subcutaneous tissue. Under suction, the syringe is moved in a reciprocating, slicing motion to isolate fragments of adipose tissue. Withdrawing the plunger is enough to ensure that adipose tissue fragments are aspirated through the needle into the syringe. A single biopsy can collect about 200 mg of tissue. This biopsy technique is very safe for both participants and research staff. Following the biopsy, participants can resume most everyday activities, although they should avoid swimming and overly strenuous activities for 48 h to avoid excessive bleeding. Participants can safely undergo 2 biopsies within a single day, meaning that the technique can be applied in before-after acute intervention studies

Intraoperative fluid irrigation for traumatic wounds (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of intraoperative fluid irrigation in preventing wound infection in traumatic wounds

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Exploring constituency-level estimates for the 2017 British general election

Most opinion polls conducted during British general election campaigns report on each party’s estimated national vote share. Although of considerable interest, these data do not put the spotlight on the marginal seats, the constituencies targeted by the parties for intensive canvassing; these are where the contest for a majority in the House of Commons is won and lost. There have been some polls covering those constituencies as a whole, but very few of individual constituencies so there was very little reporting of the outcome for each party in those individual constituencies. That changed with the 2017 general election, when three analysts published estimates on the internet of each party’s vote share separately for each constituency and with those data predicted which party would win each seat. This paper explores the veracity of those estimates, finding that although in general terms they accurately represented the relative position of each constituency in the share of each party’s votes, nevertheless their estimates of which marginal seats would be won by each were not as accurate. The implications of such polls, especially as their predictive ability is improved, is discussed