Torso body armour coverage defined according to feasibility of haemorrhage control within the prehospital environment: a new paradigm for combat trauma protection.

Developments in military personal armour have aimed to achieve a balance between anatomical coverage, protection and mobility. When death is likely to occur within 60 min of injury to anatomical structures without damage control surgery, then these anatomical structures are defined as 'essential'. However, the medical terminology used to describe coverage is challenging to convey in a Systems Requirements Document (SRD) for acquisition of new armour and to ultimately translate to the correct sizing and fitting of personal armour. Many of those with Ministry of Defence responsible for the procurement of personal armour and thereby using SRDs will likely have limited medical knowledge; therefore, the potentially complex medical terminology used to describe the anatomical boundaries must be translated into easily recognisable and measurable external landmarks. We now propose a complementary classification for ballistic protection coverage, termed threshold and objective, based on the feasibility of haemorrhage control within the prehospital environment.

Immune tolerance of allogeneic haematopoietic cell transplantation supports donor epidermal grafting of recessive dystrophic epidermolysis bullosa chronic wounds.

BACKGROUND: Chronic wounds, a common morbidity in recessive dystrophic epidermolysis bullosa (RDEB), lack definitive therapies. OBJECTIVES: To assess allogeneic epidermal skin grafts in terms of wound healing and durability over time. METHODS: In a prospective, open-label clinical trial for postallogeneic haematopoietic cell transplantation (post-alloHCT) patients with RDEB, up to nine chronic wounds per patient were grafted over 1 year. Epidermal grafts measuring 5 cm2 were obtained from related alloHCT donors in the outpatient setting using the CELLUTOMETM Epidermal Harvesting System. Wounds were photographed and symptom inventories completed at baseline and 6, 12 and 52 weeks after grafting. The trial was registered at ClinicalTrials.gov (NCT02670837). RESULTS: Between August 2016 and January 2019, eight patients with RDEB received a total of 35 epidermal allografts at a median of 1157 days (range 548-2884) post-alloHCT. The median (interquartile range) percentage reductions in wound surface area were 75% (52-94), 95% (72-100) and 100% (97-100) at 6, 12 and 52 weeks postgraft, respectively, each significantly reduced from baseline (P < 0·001). Donor harvest sites healed quickly without scarring. Biopsy evaluation at 1 year of an epidermal allograft site revealed wildtype type VII collagen (immunofluorescence), anchoring fibrils (electron microscopy), and full-thickness skin whole-DNA donor chimerism of 42% (compared with 16% in concurrently biopsied native skin). This strategy subsequently supported release of RDEB pseudosyndactyly. CONCLUSIONS: The immune tolerance established by alloHCT supports successful adoptive transfer of donor epidermal grafts. Persistence of donor grafts in a single patient beyond 1 year and observed migration of donor-grafted cells into adjacent wound suggest that epidermal allografts include nonterminally differentiated cells and/or trigger recruitment of donor bone-marrow-derived cells to mediate wound healing.

Extending existing recommended military casualty evacuation timelines will likely increase morbidity and mortality: a UK consensus statement.

INTRODUCTION: Future conflicts may have limited use of aviation-based prehospital emergency care for evacuation. This will increase the likelihood of extended evacuation timelines and an extended hold at a forward hospital care facility following the completion of damage control surgery or acute medical interventions. METHODS: A three-round Delphi Study was undertaken using a panel comprising 44 experts from the UK armed forces including clinicians, logisticians, medical planners and commanders. The panel was asked to consider the effect of an extended hold at Deployed Hospital Care (Forward) from the current 2-hour timeline to +4, +8, +12 and +24 hours on a broad range of clinical and logistical issues. Where 75% of respondents had the same opinion, consensus was accepted. Areas where consensus could not be achieved were used to identify future research priorities. RESULTS: Consensus was reached that increasing timelines would increase the personnel, logistics and equipment support required to provide clinical care. There is a tipping point with a prolonged hold over 8 hours, after which the greatest number of clinical concerns emerge. Additional specialties of surgeons other than general and orthopaedic surgeons will likely be required with holds over 24 hours, and robust telemedicine would not negate this requirement. CONCLUSIONS: Retaining acute medical emergencies at 4 hours, and head injuries was considered a particular risk. This could potentially be mitigated by an increased forward capacity of some elements of medical care and availability of a CT scanner and intracranial pressure monitoring at over 12 hours. Any efforts to mitigate the effects of prolonged timelines will come at the expense of an increased logistical burden and a reduction in mobility. Ultimately the true effect of prolonged timelines can only be answered by close audit and analysis of clinical outcomes during future operations with an extended hold.

Duplex systems: Top-down or bottom-up approach?

INTRODUCTION: Duplex systems can be complicated by reflux, ureterocele, obstruction (most commonly PUJ in a lower moiety) and wetting secondary to an ectopic ureteric insertion in girls. The decision making algorithm for selection of surgical approach is complex and there is no consensus. The authors described the outcomes following an upper urinary tract approach in 2011(1) and now compare these results in a similar group of patients managed using a lower approach. OBJECTIVES: To assess whether a top-down or bottom-up approach results in different likelihoods for further surgery. STUDY DESIGN: A prospectively database was maintained for consecutive patients undergoing surgery for duplex systems by a single surgeon between 2003 and 2015. Patients were classified into 2 groups; Group 1 initial intention for upper urinary tract approach (heminephroureterectomy-HN) or Group 2 lower urinary tract approach (bladder reconstructive surgery-BRS). The requirement for further surgery was recorded-endoscopic incision (EI), bladder reconstructive surgery (BRS), endoscopic correction of reflux (ECR), heminephroureterectomy (HN). Indications for initial and subsequent surgery included urinary tract infection, VUJ obstruction and incontinence. Endoscopic incision was not performed for patients with an asymptomatic ureterocele. Statistical analysis consisted of Fisher's exact test with a 2 tail p value < 0.05 being statistically significant. RESULTS: 79 patients underwent surgery for duplex systems. 39 patients had HN initially (Group 1) and 40 patients had BRS initially (Group 2). Further surgery was performed in 21% of patients from Group 1 (8 BRS) vs 5% of patients from Group 2 (1 redo BRS, 1 ECR). Significantly less additional surgical procedures were performed after BRS compared to HN (p = 0.048). The presence of both reflux and ureterocele increases the chances of further surgery in those patients who had HN initially compared to BRS (p = 0.01). No patients developed urinary retention or required intermittent catheterisation to improve bladder emptying. CONCLUSIONS: Bladder reconstructive surgery (BRS) reduces the requirement for further surgery compared to heminephroureterectomy (HN) in symptomatic patients with a duplex kidney and either dilating vesicoureteric reflux or ureterocele.

Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life-limiting manifestations. OBJECTIVES: To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy BMT) after reduced-intensity conditioning with infusions of immunomodulatory donor-derived mesenchymal stromal cells (median follow-up 16 months). METHODS: BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre-BMT to 1 year post-BMT. RESULTS: Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)-matched (n = 3), with one HLA-matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno-occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft-versus-host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. CONCLUSIONS: PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor-derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post-transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft-versus-host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen-matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.

Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Revertant mosaicism has been described previously in recessive dystrophic epidermolysis bullosa (RDEB), manifesting as regions of skin with normal mechanical and biological characteristics. Here we report the discovery of revertant dermal fibroblasts, unique in that all other documented cases of revertant mosaicism occur in epidermal keratinocytes. OBJECTIVES: To determine the cause of revertant mosaicism found in a patient with RDEB from isolated epidermal keratinocytes and dermal fibroblasts in blister and mosaic skin regions. METHODS: Skin biopsies were taken from blister and mosaic skin regions of a patient with RDEB. Allele identification was confirmed and the type VII collagen (C7) content and COL7A1 expression profile of isolated keratinocytes and fibroblasts was determined. RESULTS: Keratinocytes isolated from the mosaic area had a slight increase in C7, although overall expression of COL7A1 was unchanged between blister and mosaic fibroblasts. Differential allele expression was identified in blister and mosaic fibroblasts using targeted RNA sequencing (TREx), where the allele harbouring a point mutation was preferentially expressed over that containing a frameshift mutation. A crossing over event was identified in mosaic fibroblasts that was not present in blister fibroblasts, yielding a functional COL7A1 allele in a subset of cells. CONCLUSIONS: In documenting a novel case of revertant mosaicism in RDEB, we have identified dermal fibroblasts as having the capacity to correct blistering functionally. We have also pioneered the use of TREx in quantifying allele-specific expression. Using fibroblasts instead of keratinocytes for RDEB therapies offers advantages in the local and systemic therapy of RDEB. What's already known about this topic? Revertant mosaicism has been previously documented in patients with recessive dystrophic epidermolysis bullosa (RDEB), however, it has only been found in epidermal keratinocytes. What does this study add? We have demonstrated that COL7A1 gene reversion in dermal fibroblasts occurs and is able to form functional skin in a patient with RDEB. Additionally, we have pioneered a new application for targeted RNA sequencing in quantifying allele-specific expression in fibroblasts and keratinocytes. What is the translational message? This opens up possibilities for using fibroblasts as local and systemic therapy for patients with RDEB.

Embryonal tumors in Canadian children less than 36 months of age: results from the Canadian Pediatric Brain Tumor Consortium (CPBTC).

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.

Antegrade sclerotherapy in adolescent varicocele patients.

INTRODUCTION: In the 1970s, Tauber described the antegrade sclerotherapy technique to treat varicoceles, and reported a 10% recurrence rate. The present study aimed to evaluate paediatric success rates and the effect of modifications to the surgical technique. METHODS: A prospective study was performed of all adolescent patients undergoing antegrade sclerotherapy surgery. Each patient had an idiopathic varicocele with spontaneous venous reflux on Doppler examination, and underwent cannulation of a pampiniform plexus vein via a scrotal incision under general anaesthetic. Aethoxysklerol® 3% (2 ml/kg) maximum 3 ml was injected into the pampiniform plexus vein under fluoroscopic monitoring. Success was assessed by clinical examination and Doppler ultrasound 3, 6 and 9 months after surgery. Data were presented as median (interquartile range). Patients were split into three groups: Group A - liquid sclerotherapy with Y connector; Group B - liquid sclerotherapy direct to cannula; and Group C - foam sclerotherapy direct to cannula. Fisher's exact test was used to compare the success rates in each group. RESULTS: A total of 91 patients underwent antegrade sclerotherapy. The median age was 14.8 years (range 13.7-15.5). Eleven persistent varicoceles occurred and were diagnosed by Doppler ultrasound. The success rate of surgery was 58% in Group A, 90% in Group B and 96% in Group C. Success was significantly higher in Group B and Group C compared with Group A. No testicular atrophy occurred; two wound infections, two haematomas and one hydrocele were recorded (Table). CONCLUSION: Introduction of antegrade sclerotherapy in the adolescent population resulted in a safe and cost-effective method for the management of adolescent varicocele. Several modifications to the technique have been introduced to achieve a high success rate (96%) with minimal complications.

Hyperbolic resonances of metasurface cavities.

We propose a new class of optical resonator structures featuring one or two metasurface reflectors or metacavities and predict that such resonators support novel hyperbolic resonances. As an example of such resonances we introduce hyperbolic Tamm plasmons (HTPs) and hyperbolic Fabry-Perot resonances (HFPs). The hyperbolic optical modes feature low-loss incident power re-distribution over TM and TE polarization output channels, clover-leaf anisotropic dispersion, and other unique properties which are tunable and are useful for multiple applications.

Spontaneous emission of electric and magnetic dipoles in the vicinity of thin and thick metal.

Strong modification of spontaneous emission of Eu(3+) ions placed in close vicinity to thin and thick gold and silver films was clearly demonstrated in a microscope setup separately for electric and magnetic dipole transitions. We have shown that the magnetic transition was very sensitive to the thickness of the gold substrate and behaved distinctly different from the electric transition. The observations were described theoretically based on the dyadic Green's function approach for layered media and explained through modified image models for the near and far-field emissions. We established that there exists a "near-field event horizon", which demarcates the distance from the metal at which the dipole emission is taken up exclusively in the near field.

Anti-malarial chemoprophylaxis following evacuation from Afghanistan.

UK forces deployed to Afghanistan between March and November are prescribed anti-malarial chemoprophylaxis (AMC). In 2007 an audit showed poor pre-injury AMC compliance and a prescription rate of 50% amongst those casualties evacuated to Role 4. We re-audited the post-deployment AMC prescribing practice for casualties from Afghanistan for the 2008 and half of the 2009 malaria season. Using the Role 4 prescribing information and communication system (PICS), a retrospective AMC search for Proguanil, Chloroquine, Doxycycline, Mefloquine and Malarone was performed on these casualties. Only five out of 305 (1.64%) inpatients were prescribed appropriate post-deployment AMC medication. Awareness of the need to prescribe AMC following evacuation remains poor, and may be improved by recording AMC compliance in field medical records and modifying the PICS software.

Bipartite anterior extraperitoneal teratoma: evidence for the embryological origins of teratomas?

Teratomas are thought to arise from totipotent primordial germ cells (PGCs) Dehner (1983) which may miss their target destination Moore and Persaud (1984). Teratomas can occur anywhere from the brain to the coccygeal area but are usually in the midline close to the embryological position of the gonadal ridges Bale (1984), Nguyen and Laberge (2000). We report a case of a bipartite anterior extraperitoneal teratoma. This is an unusual position for a teratoma, but one which may support the "missed target" theory of embryology.

Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome.

The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.

Phenotypic characterization of epiphycan-deficient and epiphycan/biglycan double-deficient mice.

OBJECTIVE: To characterize the in vivo role epiphycan (Epn) has in cartilage development and/or maintenance. METHODS: Epn-deficient mice were generated by disrupting the Epn gene in mouse embryonic stem cells. Epn/biglycan (Bgn) double-deficient mice were produced by crossing Epn-deficient mice with Bgn-deficient mice. Whole knee joint histological sections were stained using van Gieson or Fast green/Safranin-O to analyze collagen or proteoglycan content, respectively. Microarray analysis was performed to detect gene expression changes within knee joints. RESULTS: Epn-deficient and Epn/Bgn double-deficient mice appeared normal at birth. No significant difference in body weight or femur length was detected in any animal at 1 month of age. However, 9-month Epn/Bgn double-deficient mice were significantly lighter and had shorter femurs than wild type mice, regardless of gender. Male Epn-deficient mice also had significantly shorter femurs than wild type mice at 9 months. Most of the deficient animals developed osteoarthritis (OA) with age; the onset of OA was observed earliest in Epn/Bgn double-deficient mice. Message RNA isolated from Epn/Bgn double-deficient knee joints displayed increased matrix protein expression compared with wild type mice, including other small leucine-rich proteoglycan (SLRP) members such as asporin, fibromodulin and lumican. CONCLUSION: Similar to other previously studied SLRPs, EPN plays an important role in maintaining joint integrity. However, the severity of the OA phenotype in the Epn/Bgn double-deficient mouse suggests a synergy between these two proteins. These data are the first to show a genetic interaction involving class I and class III SLRPs in vivo.

Brainstem compression: a predictor of postoperative cerebellar mutism.

PURPOSE: Cerebellar mutism is a common complication of posterior fossa tumor resection. We observed marked, preoperative brainstem compression on MR imaging, among patients who developed postoperative mutism. This study was designed to investigate if an association was indeed present. MATERIALS AND METHODS: Patients (18 months-18 years) undergoing resection of a midline, posterior fossa tumor were retrospectively reviewed. Demographic data, tumor pathology, mutism onset and duration, and postoperative complications were obtained from hospital records. Pre- and postoperative MR images were studied to assess tumor size and the severity of pons compression (an estimate of the mechanical and distortional forces imparted by the tumor). RESULTS: Patients with mutism showed greater preoperative pons compression and a greater increase in postoperative pons diameter. CONCLUSION: We predict that brainstem compression may represent white-matter injury from (1) surgical manipulation and traction, and (2) axonal damage caused by the release of the tumor's compressive force and ensuing axon distortion and dysfunction. The results provide support that mutism may be largely caused by white-matter damage disrupted axon integrity and function.

In-vitro fertilization: donor egg sharing for premature ovarian failure.

Premature ovarian failure may be a consequence of gonadotoxic cytotoxic chemotherapy or radiation therapy for malignant or systemic disease often resulting in major quality of life concerns. This is the first reported case in the English-speaking Caribbean using in-vitro fertilization (IVF) donor egg sharing in a patient who experienced premature ovarian failure following chemotherapy and radiation for Hodgkin's disease. The donor's indication was tubal factor infertility. Both patients delivered healthy infants.