Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Report of a Delphi exercise to inform the design of a research programme on screening for thoracic aortic disease.

OBJECTIVES: To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design. METHODS: Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop. RESULTS: Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability. CONCLUSION: A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.

The burden of gunshot wounding of UK military personnel in Iraq and Afghanistan from 2003-14.

INTRODUCTION: Gunshot wounding (GSW) is the second most common mechanism of injury in warfare after explosive injury. The aim of this study was to define the clinical burden of GSW placed on UK forces throughout the recent Iraq and Afghanistan conflicts. METHODS: This study was a retrospective review of data from the UK Military Joint Theatre Trauma Registry (JTTR). A JTTR search identified records within the 12 year period of conflict between 19 Mar 2003 and 27 Oct 2014 of all UK military GSW casualties sustained during the complete timelines of both conflicts. Included cases had their clinical timelines and treatment further examined from time of injury up until discharge from hospital or death. RESULTS: There were 723 casualties identified (177 fatalities, 546 survivors). Median age at the time of injury was 24 years (range 18-46 years), with 99.6% of casualties being male. Most common anatomical locations for injury were the extremities, with 52% of all casualties sustaining extremity GSW, followed by 16% GSW to the head, 15% to the thorax, and 7% to the abdomen. In survivors, the rate of extremity injury was higher at 69%, with head, thorax and abdomen injuries relatively lower at 5%, 11% and 6% respectively. All GSW casualties had a total of 2827 separate injuries catalogued. A total of 545 casualties (523 survivors, 22 fatalities) underwent 2357 recorded surgical procedures, which were carried out over 1455 surgical episodes between admission to a deployed medical facility and subsequent transfer to the Royal Centre for Defence Medicine (RCDM) in the UK. This gave a median of 3 (IQR 2-5) surgical procedures within a median of 2 (IQR 2-3) surgical episodes per casualty. Casualties had a combined length of stay (LoS) of 25 years within a medical facility, with a mean LoS in a deployed facility of 1.9 days and 14 days in RCDM. CONCLUSION: These findings define the massive burden of injury associated with battlefield GSW and underscore the need for further research to both reduce wound incidence and severity of these complex injuries.

Outcomes following limb salvage after combat hindfoot injury are inferior to delayed amputation at five years.

OBJECTIVES: The surgical challenge with severe hindfoot injuries is one of technical feasibility, and whether the limb can be salvaged. There is an additional question of whether these injuries should be managed with limb salvage, or whether patients would achieve a greater quality of life with a transtibial amputation. This study aims to measure functional outcomes in military patients sustaining hindfoot fractures, and identify injury features associated with poor function. METHODS: Follow-up was attempted in all United Kingdom military casualties sustaining hindfoot fractures. All respondents underwent short-form (SF)-12 scoring; those retaining their limb also completed the American Academy of Orthopaedic Surgeons Foot and Ankle (AAOS F&A) outcomes questionnaire. A multivariate regression analysis identified injury features associated with poor functional recovery. RESULTS: In 12 years of conflict, 114 patients sustained 134 fractures. Follow-up consisted of 90 fractures (90/134, 67%), at a median of five years (interquartile range (IQR) 52 to 80 months).The median Short-Form 12 physical component score (PCS) of 62 individuals retaining their limb was 45 (IQR 36 to 53), significantly lower than the median of 51 (IQR 46 to 54) in patients who underwent delayed amputation after attempted reconstruction (p = 0.0351).Regression analysis identified three variables associated with a poor F&A score: negative Bohler's angle on initial radiograph; coexisting talus and calcaneus fracture; and tibial plafond fracture in addition to a hindfoot fracture. The presence of two out of three variables was associated with a significantly lower PCS compared with amputees (medians 29, IQR 27 to 43 vs 51, IQR 46 to 54; p < 0.0001). CONCLUSIONS: At five years, patients with reconstructed hindfoot fractures have inferior outcomes to those who have delayed amputation. It is possible to identify injuries which will go on to have particularly poor outcomes.Cite this article: P. M. Bennett, T. Stevenson, I. D. Sargeant, A. Mountain, J. G. Penn-Barwell. Outcomes following limb salvage after combat hindfoot injury are inferior to delayed amputation at five years. Bone Joint Res 2018;7:131-138. DOI: 10.1302/2046-3758.72.BJR-2017-0217.R2.

Factors influencing infection in 10 years of battlefield open tibia fractures.

The aim of this study was to characterise severe open tibial shaft fractures sustained by the UK military personnel over 10 years of combat in Iraq and Afghanistan. The UK military Joint Theatre Trauma Registry was searched for all such injuries, and clinical records were reviewed for all patients. One hundred Gustilo-Anderson III tibia fractures in 89 patients were identified in the 10 year study period; the majority sustained injuries through explosive weapons (63, 68 %) with the remainder being injured from gunshot wounds. Three fractures were not followed up for 12 months and were therefore excluded. Twenty-two (23 %) of the remaining 97 tibial fractures were complicated by infection, with S. aureus being the causative agent in 13/22 infected fractures (59 %). Neither injury severity, mechanism, the use of an external fixator, the need for vascularised tissue transfer nor smoking status was associated with subsequent infection. Bone loss was significantly associated with subsequent infection (p < 0.0001, Fisher's exact test). This study presents 10 years of open tibial fractures sustained in Iraq and Afghanistan. Most infection in combat open tibia fractures is caused by familiar organisms, i.e. S. aureus. While the overall severity of a casualty's injuries was not associated with infection, the degree of bone loss from the fracture was.

Developing and assessing the utility of a You-Tube based clinical genetics video channel for families affected by inherited tumours.

We have designed and implemented the first worldwide You Tube channel with 22 videos covering common questions asked in familial cancer susceptibility clinics. We discuss the use of the videos including demographics of registered You Tube users, and what lessons have been learnt about how the general public uses medical information online. The most popular video on inheritance patterns has been watched on average 84 times per month. The mostly highly viewed videos include inheritance patterns, breast cancer screening and hereditary non-polyposis colorectal cancer. Registered viewers were more commonly male and the average age of the registered user was 45-54 years; similar to that seen in Genetics Clinics suggesting that age may not be a major barrier to access to this type of information for patients. The videos have been viewed in more than 140 countries confirming that there is clearly an audience for this type of information. Patient feedback questionnaires indicate that these videos provide a useful aide memoir for the clinic appointment, and most people would recommend them to others. In summary, You Tube videos are easy and cost effective to make. They have the ability to disseminate genetics education to a worldwide audience and may be a useful adjunct to clinical appointments.

Died of wounds: a mortality review.

OBJECTIVES: Combat casualty care is a complex system involving multiple clinicians, medical interventions and casualty transfers. Improving the performance of this system requires examination of potential weaknesses. This study reviewed the cause and timing of death of casualties deemed to have died from their injuries after arriving at a medical treatment facility during the recent conflicts in Iraq and Afghanistan, in order to identify potential areas for improving outcomes. METHODS: This was a retrospective review of all casualties who reached medical treatment facilities alive, but subsequently died from injuries sustained during combat operations in Afghanistan and Iraq. It included all deaths from start to completion of combat operations. The UK military joint theatre trauma registry was used to identify cases, and further data were collected from clinical notes, postmortem records and coroner's reports. RESULTS: There were 71 combat-related fatalities who survived to a medical treatment facility; 17 (24%) in Iraq and 54 (76%) in Afghanistan. Thirty eight (54%) died within the first 24 h. Thirty-three (47%) casualties died from isolated head injuries, a further 13 (18%) had unsurvivable head injuries but not in isolation. Haemorrhage following severe lower limb trauma, often in conjunction with abdominal and pelvic injuries, was the cause of a further 15 (21%) deaths. CONCLUSIONS: Severe head injury was the most common cause of death. Irrespective of available medical treatment, none of this group had salvageable injuries. Future emphasis should be placed in preventative strategies to protect the head against battlefield trauma.

Acute shoulder injuries: A clinical review of diagnosis and management in the deployed Naval environment.

Musculoskeletal injuries of the shoulder are a common presentation in primary care. Injuries to this highly mobile region can have a profound impact on the range of movement, resulting in severe functional limitation. The shoulder can also be one of the more complicated regions to examine due to its high mobility, poor localisation of pain and numerous supporting structures. This article aims to review the anatomy of the shoulder, examination technique and the pathology underlying common acute injuries in order to provide guidance to medical personnel deployed with the Royal Navy and Royal Marines.

Combined local and systemic antibiotic delivery improves eradication of wound contamination: An animal experimental model of contaminated fracture.

Systemic antibiotics reduce infection in open fractures. Local delivery of antibiotics can provide higher doses to wounds without toxic systemic effects. This study investigated the effect on infection of combining systemic with local antibiotics via polymethylmethacrylate (PMMA) beads or gel delivery. An established Staphylococcus aureus contaminated fracture model in rats was used. Wounds were debrided and irrigated six hours after contamination and animals assigned to one of three groups, all of which received systemic antibiotics. One group had local delivery via antibiotic gel, another PMMA beads and the control group received no local antibiotics. After two weeks, bacterial levels were quantified. Combined local and systemic antibiotics were superior to systemic antibiotics alone at reducing the quantity of bacteria recoverable from each group (p = 0.002 for gel; p = 0.032 for beads). There was no difference in the bacterial counts between bead and gel delivery (p = 0.62). These results suggest that local antibiotics augment the antimicrobial effect of systemic antibiotics. Although no significant difference was found between vehicles, gel delivery offers technical advantages with its biodegradable nature, ability to conform to wound shape and to deliver increased doses. Further study is required to see if the gel delivery system has a clinical role.

The management and outcome of open fractures of the femur sustained on the battlefield over a ten-year period.

This is a retrospective study of survivors of recent conflicts with an open fracture of the femur. We analysed the records of 48 patients (48 fractures) and assessed the outcome. The median follow up for 47 patients (98%) was 37 months (interquartile range 19 to 53); 31 (66%) achieved union; 16 (34%) had a revision procedure, two of which were transfemoral amputation (4%). The New Injury Severity Score, the method of fixation, infection and the requirement for soft-tissue cover were not associated with a poor outcome. The degree of bone loss was strongly associated with a poor outcome (p = 0.00204). A total of four patients developed an infection; two with S. aureus, one with E. coli and one with A. baumannii. This study shows that, compared with historical experience, outcomes after open fractures of the femur sustained on the battlefield are good, with no mortality and low rates of infection and late amputation. The degree of bone loss is closely associated with a poor outcome.

Medium-term outcomes following limb salvage for severe open tibia fracture are similar to trans-tibial amputation.

Extremity injuries define the surgical burden of recent conflicts. Current literature is inconclusive when assessing the merits of limb salvage over amputation. The aim of this study was to determine medium term functional outcomes in military casualties undergoing limb salvage for severe open tibia fractures, and compare them to equivalent outcomes for unilateral trans-tibial amputees. Cases of severe open diaphyseal tibia fractures sustained in combat between 2006 and 2010, as described in a previously published series, were contacted. Consenting individuals conducted a brief telephone interview and were asked to complete a SF-36 questionnaire. These results were compared to a similar cohort of 18 military patients who sustained a unilateral trans-tibial amputation between 2004 and 2010. Forty-nine patients with 57 severe open tibia fractures met the inclusion criteria. Telephone follow-up and SF-36 questionnaire data was available for 30 patients (61%). The median follow-up was 4 years (49 months, IQR 39-63). Ten of the 30 patients required revision surgery, three of which involved conversion from initial fixation to a circular frame for non- or mal-union. Twenty-two of the 30 patients (73%) recovered sufficiently to complete an age-standardised basic military fitness test. The median physical component score of SF-36 in the limb salvage group was 46 (IQR 35-54) which was similar to the trans-tibial amputation cohort (p=0.3057, Mann-Whitney). Similarly there was no difference in mental component scores between the limb salvage and amputation groups (p=0.1595, Mann-Whitney). There was no significant difference in the proportion of patients in either the amputation or limb salvage group reporting pain (p=0.1157, Fisher's exact test) or with respect to SF-36 physical pain scores (p=0.5258, Mann-Whitney). This study demonstrates that medium term outcomes for military patients are similar following trans-tibial amputation or limb salvage following combat trauma.

The incidence of pelvic fractures with traumatic lower limb amputation in modern warfare due to improvised explosive devices.

AIMS: A frequently-seen injury pattern in current military experience is traumatic lower limb amputation as a result of improvised explosive devices (IEDs). This injury can coexist with fractures involving the pelvic ring. This study aims to assess the frequency of concomitant pelvic fracture in IED-related lower limb amputation. METHODS: A retrospective analysis of the trauma charts, medical notes, and digital imaging was undertaken for all patients arriving at the Emergency Department at the UK military field hospital in Camp Bastion, Afghanistan, with a traumatic lower limb amputation in the six months between September 2009 and April 2010, in order to determine the incidence of associated pelvic ring fractures. RESULTS: Of 77 consecutive patients with traumatic lower limb amputations, 17 (22%) had an associated pelvic fracture (eleven with displaced pelvic ring fractures, five undisplaced fractures and one acetabular fracture). Unilateral amputees (n = 31) had a 10% incidence of associated pelvic fracture, whilst 30 % of bilateral amputees (n = 46) had a concurrent pelvic fracture. However, in bilateral, trans-femoral amputations (n = 28) the incidence of pelvic fracture was 39%. CONCLUSIONS: The study demonstrates a high incidence of pelvic fractures in patients with traumatic lower limb amputations, supporting the routine pre-hospital application of pelvic binders in this patient group.

Mortality, survival and residual injury burden of Royal Navy and Royal Marine combat casualties sustained in 11-years of operations in Iraq and Afghanistan.

We present eleven years of prospectively-gathered data defining the full spectrum of the United Kingdom's (UK) Naval Service (Royal Navy and Royal Marines) casualties, and characterise the injury patterns, recovery and residual functional burden from the conflicts of the last decade. The UK Military Trauma Registry was searched for all Naval Service personnel injured between March 2003 and April 2013. These records were then cross-referenced with the records of the Naval Service Medical Board of Survey (NSMBOS), which evaluates injured Naval Service personnel for medical discharge, continued service in a reduced capacity or Return to Full Duty (RTD). Population at risk data was calculated from service records. There were 277 casualties in the study period: 63 (23%) of these were fatalities. Of the 214 survivors, 63 or 29% (23% of total) were medically discharged; 24 or 11% (9% of total) were placed in a reduced fitness category with medical restrictions placed on their continued military service. A total of 127 individuals (46% of the total and 59% of survivors) RTD without any restriction. The greatest number of casualties was sustained in 2007. There was a 3% casualty risk per year of operational service for Naval Service personnel. The most common reason cited by Naval Service Medical Board of Survey (NSMBOS) for medical downgrading or discharge was injury to the lower limb, with upper limb trauma the next most frequent. This study characterises the spectrum of injuries sustained by the Naval Service during recent conflicts with a very high rate of follow-up. Extremity injuries pose the biggest challenge to reconstructive and rehabilitative services striving to maximise the functional outcomes of injured service personnel.

A versatile model of open-fracture infection : a contaminated segmental rat femur defect.

OBJECTIVES: The purpose of this study was to refine an accepted contaminated rat femur defect model to result in an infection rate of approximately 50%. This threshold will allow examination of treatments aimed at reducing infection in open fractures with less risk of type II error. METHODS: Defects were created in the stablised femurs of anaethetised rats, contaminated with Staphylococcus aureus and then debrided and irrigated six hours later. After 14 days, the bone and implants were harvested for separate microbiological analysis. This basic model was developed in several studies by varying the quantity of bacterial inoculation, introducing various doses of systemic antibiotics with and without local antibiotics. RESULTS: The bacterial inoculation associated with a 50% infection rate was established as 1 × 10(2) colony forming units (CFU). With an initial bacterial inoculum of 1 × 10(5) CFU, the dose of systemic antibiotics associated with 50% infection was 5 mg/Kg of cafazolin injected sub-cutaneously every 12 hours, starting at the time of the first debridment and continuing for 72 hours (seven doses). The systemic dose of cafazolin was lowered to 2 mg/Kg when antibiotic polymethyl methacrylate beads were used concurrently with the same amount of bacterial inoculation. CONCLUSION: This model of open fracture infection has been further refined with potential for local and systemic antibiotics. This is a versatile model and with the concepts presented herein, it can be modified to evaluate various emerging therapies and concepts for open fractures. Cite this article: Bone Joint Res 2014;3:187-92.

Acute bilateral leg amputation following combat injury in UK servicemen.

BACKGROUND: This study aims to characterise the injuries and surgical management of British servicemen sustaining bilateral lower limb amputations. METHODS: The UK Military Trauma Registry was searched for all cases of primary bilateral lower limb amputation sustained between March 2004 and March 2010. Amputations were excluded if they occurred more than 7 days after injury or if they were at the ankle or more distal. RESULTS: There were 1694 UK military patients injured or killed during this six-year study period. Forty-three of these (2.8%) were casualties with bilateral lower limb amputations. All casualties were men with a mean age of 25.1 years (SD 4.3): all were injured in Afghanistan by Improvised Explosive Devices (IEDs). Six casualties were in vehicles when they were injured with the remaining 37 (80%) patrolling on foot. The mean New Injury Severity Score (NISS) was 48.2 (SD 13.2): four patients had a maximum score of 75. The mean TRISS probability of survival was 60% (SD 39.4), with 18 having a survival probability of less than 50% i.e. unexpected survivors. The most common amputation pattern was bilateral trans-femoral (TF) amputations, which was seen in 25 patients (58%). Nine patients also lost an upper limb (triple amputation): no patients survived loss of all four limbs. In retained upper limbs extensive injuries to the hands and forearms were common, including loss of digits. Six patients (14%) sustained an open pelvic fracture. Perineal/genital injury was a feature in 19 (44%) patients, ranging from unilateral orchidectomy to loss of genitalia and permanent requirement for colostomy and urostomy. The mean requirement for blood products was 66 units (SD 41.7). The maximum transfusion was 12 units of platelets, 94 packed red cells, 8 cryoprecipitate, 76 units of fresh frozen plasma and 3 units of fresh whole blood, a total of 193 units of blood products. CONCLUSIONS: Our findings detail the severe nature of these injuries together with the massive surgical and resuscitative efforts required to firstly keep patients alive and secondly reconstruct and prepare them for rehabilitation.

Prospective randomised controlled trial of nanocrystalline silver dressing versus plain gauze as the initial post-debridement management of military wounds on wound microbiology and healing.

INTRODUCTION: Recent conflicts have been characterised by the use of improvised explosive devices causing devastating injuries, including heavily contaminated wounds requiring meticulous surgical debridement. After being rendered surgical clean, these wounds are dressed and the patient transferred back to the UK for on-going treatment. A dressing that would prevent wounds from becoming colonised during transit would be desirable. The aim of this study was to establish whether using nanocrystalline silver dressings, as an adjunct to the initial debridement, would positively affect wound microbiology and wound healing compared to standard plain gauze dressings. METHODS: Patients were prospectively randomised to receive either silver dressings, in a nanocrystalline preparation (Acticoat™), or standard of care dressings (plain gauze) following their initial debridement in the field hospital. On repatriation to the UK microbiological swabs were taken from the dressing and the wound, and an odour score recorded. Wounds were followed prospectively and time to wound healing was recorded. Additionally, patient demographic data were recorded, as well as the mechanism of injury and Injury Severity Score. RESULTS: 76 patients were recruited to the trial between February 2010 and February 2012. 39 received current dressings and 37 received the trial dressings. Eleven patients were not swabbed. There was no difference (p=0.1384, Fishers) in the primary outcome measure of wound colonisation between the treatment arm (14/33) and the control arm (20/32). Similarly time to wound healing was not statistically different (p=0.5009, Mann-Whitney). Wounds in the control group were scored as being significantly more malodorous (p=0.002, Mann-Whitney) than those in the treatment arm. CONCLUSIONS: This is the first randomised controlled trial to report results from an active theatre of war. Performing research under these conditions poses additional challenges to military clinicians. Meticulous debridement of wounds remains the critical determinant in wound healing and infection and this study did not demonstrate a benefit of nanocrystaline silver dressing in respect to preventing wound colonisation or promoting healing, these dressings do however seem to significantly reduce the unpleasant odour commonly associated with battlefield wounds.