Association Between Clozapine Exposure and Risk of Hematologic Malignancies in Veterans With Schizophrenia.

Objective: The objective of this study was to examine the relationship between clozapine use and hematologic malignancies, using national administrative data from the United States Veterans Health Administration (VHA).Methods: This case-control study of veterans with schizophrenia matched cases with incident hematologic malignancy to 10 controls without hematologic malignancy by gender, age, and time since first schizophrenia diagnosis from October 1999, the beginning of VHA data archives, to June 2022. Schizophrenia diagnoses were identified using International Classification of Diseases, Ninth Revision, code 295.x and International Statistical Classification of Diseases, Tenth Revision, codes F20.x and F25.x from inpatient hospitalization and outpatient encounter data. Additional inclusion criteria were age 18-85 years, no prior history of malignancy, and at least 1 year of antipsychotic exposure. Clozapine exposure was assessed using 3 metrics: any exposure, years of exposure, and cumulative defined daily doses (DDD). Conditional multivariable logistic regression was used to adjust for nonmatched confounding variables.Results: A total of 2,306 veterans with schizophrenia were identified with an incident diagnosis of hematologic malignancy and matched to 23,043 controls. Any prior clozapine exposure was more commonly observed among cases (5.3%) than controls (4.1%) and was significantly different after adjustment (odds ratio [OR], 1.31; 95% CI, 1.08-1.60). Risk was dose-dependent, where cumulative clozapine exposures from 3,000 to 4,999 DDD (OR, 1.78; 95% CI, 1.13-2.79) and ≥5,000 DDD (OR, 1.81; 95% CI, 1.24-2.64) were significantly associated with malignancy risk. Similarly, clozapine exposure of 5 or more years was associated with malignancy risk (OR, 1.88; 95% CI, 1.43-2.47).Conclusion: Consistent with prior report, this study observed an increased risk of hematologic malignancy associated with clozapine exposure. These findings suggest patients receiving clozapine use, particularly those with long-term use, should be closely monitored for hematologic malignancy.

Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair.

Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.

Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma.

ABSTRACT: More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.

Exploring Pharmacy Student Experiences with Student Debt and Perspectives on Future Burnout and Loan Relief.

OBJECTIVE: Pharmacy students with substantial educational debt are at risk for excessive workloads, burnout, and clinical errors. During the COVID-19 pandemic, policies addressing economic hardships for all student debt borrowers included temporary suspension of monthly payments and 0% interest during the pause. This study aimed to understand student-level factors regarding student debt from the lived experiences of current pharmacy students and aimed to understand how current pharmacy students view temporary loan relief. METHODS: We used semi-structured interviews of pharmacy students across 4 years of progression in their pharmacy program to better understand student experiences with debt, different factors that may influence the impact of student debt on short-term and long-term outcomes for students, and student perspectives on debt relief policies and potential solutions. Our thematic analysis was grounded in existing evidence and a conceptual framework, while also allowing codes to emerge directly from the data. RESULTS: A total of 20 pharmacy students were interviewed with a median student debt of $77,000, with debt amounts ranging from $0 to $209,000. Students described what mediating factors influenced their experiences, the influence of student debt on clinician burnout, and other outcomes impacted by student debt. Six overarching themes emerged relevant to current students: student debt influences education and career decisions, debt is risky given the saturated pharmacy market, debt is an accepted burden, debt will inhibit starting a life, the COVID-19 loan relief is revealing, and early financial education is needed. CONCLUSION: Pharmacy students burdened with debt described a variety of different experiences and attitudes toward that debt and provided their perspectives on how student debt influences short-term education and career decisions. While students accept the trade-off of debt for their education as an inevitable burden, reported coping mechanisms and strategies shared suggest some solutions may be available to ameliorate this burden.

5-HT1A regulates axon outgrowth in a subpopulation of Drosophila serotonergic neurons.

Serotonergic neurons produce extensively branched axons that fill most of the central nervous system, where they modulate a wide variety of behaviors. Many behavioral disorders have been correlated with defective serotonergic axon morphologies. Proper behavioral output therefore depends on the precise outgrowth and targeting of serotonergic axons during development. To direct outgrowth, serotonergic neurons utilize serotonin as a signaling molecule prior to it assuming its neurotransmitter role. This process, termed serotonin autoregulation, regulates axon outgrowth, branching, and varicosity development of serotonergic neurons. However, the receptor that mediates serotonin autoregulation is unknown. Here we asked if serotonin receptor 5-HT1A plays a role in serotonergic axon outgrowth and branching. Using cultured Drosophila serotonergic neurons, we found that exogenous serotonin reduced axon length and branching only in those expressing 5-HT1A. Pharmacological activation of 5-HT1A led to reduced axon length and branching, whereas the disruption of 5-HT1A rescued outgrowth in the presence of exogenous serotonin. Altogether this suggests that 5-HT1A is a serotonin autoreceptor in a subpopulation of serotonergic neurons and initiates signaling pathways that regulate axon outgrowth and branching during Drosophila development.

A diminutive snake species can maintain regional heterothermy in both homogeneous and heterogeneous thermal environments.

Regional heterothermy is a pattern whereby different body regions are maintained at different temperatures, often to prioritize the function of certain body parts over others, or to maximize the function of organs and tissues that vary in thermal sensitivity. Regional heterothermy is relatively well understood in endotherms, where physiological mechanisms maintain heterogeneity. However, less is known about regional heterothermy in ectotherms, where behavioral mechanisms are more important for generating thermal variation. In particular, whether small and elongate ectotherms with high surface area to volume ratios such as diminutive snakes can maintain regional heterothermy, despite rapid thermal equilibration, is not yet known. We measured regional variation in body temperature and tested whether environmental heterogeneity is used to generate regional heterothermy in the ring-necked snake (Diadophis punctatus) using both field and laboratory studies. We found that ring-necked snakes have robust regional heterothermy in a variety of contexts, despite their small body size and elongate body shape. Temperature variation along the length of their bodies was not detectable when measured externally. However, snakes had higher mouth than cloacal temperatures both in the field and in laboratory thermal gradients. Further, this regional heterothermy was maintained even in ambient laboratory conditions, where the thermal environment was relatively homogeneous. Our results indicate that regional heterothermy in ring-necked snakes is not solely driven by environmental variation but is instead linked to physiological or morphological mechanisms that maintain regional variation in body temperature irrespective of environmental context.

Towards resorbable 3D-printed scaffolds for craniofacial bone regeneration.

This review will briefly examine the development of 3D-printed scaffolds for craniofacial bone regeneration. We will, in particular, highlight our work using Poly(L-lactic acid) (PLLA) and collagen-based bio-inks. This paper is a narrative review of the materials used for scaffold fabrication by 3D printing. We have also reviewed two types of scaffolds that we designed and fabricated. Poly(L-lactic acid) (PLLA) scaffolds were printed using fused deposition modelling technology. Collagen-based scaffolds were printed using a bioprinting technique. These scaffolds were tested for their physical properties and biocompatibility. Work in the emerging field of 3D-printed scaffolds for bone repair is briefly reviewed. Our work provides an example of PLLA scaffolds that were successfully 3D-printed with optimal porosity, pore size and fibre thickness. The compressive modulus was similar to, or better than, the trabecular bone of the mandible. PLLA scaffolds generated an electric potential upon cyclic/repeated loading. The crystallinity was reduced during the 3D printing. The hydrolytic degradation was relatively slow. Osteoblast-like cells did not attach to uncoated scaffolds but attached well and proliferated after coating the scaffold with fibrinogen. Collagen-based bio-ink scaffolds were also printed successfully. Osteoclast-like cells adhered, differentiated, and survived well on the scaffold. Efforts are underway to identify means to improve the structural stability of the collagen-based scaffolds, perhaps through mineralization by the polymer-induced liquid precursor process. 3D-printing technology is promising for constructing next-generation bone regeneration scaffolds. We describe our efforts to test PLLA and collagen scaffolds produced by 3D printing. The 3D-printed PLLA scaffolds showed promising properties akin to natural bone. Collagen scaffolds need further work to improve structural integrity. Ideally, such biological scaffolds will be mineralized to produce true bone biomimetics. These scaffolds warrant further investigation for bone regeneration.

Post-mortem computed tomography in the investigation of conflict and terrorist related deaths: UK military experience of developing a multidisciplinary service.

This paper discusses the introduction, development and utility of post-mortem imaging relating specifically to conflict-related and terrorist-related deaths and considers the use of computed tomography (CT) in the investigations. We demonstrate how a multi-disciplinary approach involving direct communication between forensic pathologist and radiologist can maximise evidential yield, reduce the need for unnecessary dissection and further our understanding of such injuries. This summarises our shared experience of hundreds of cases, each having been individually discussed and reviewed, and has helped shape our understanding of conflict injury as well as contributing to the development of mitigation strategies and adaptations to protective equipment. A series of clinical cases are presented to demonstrate some of the strengths and weaknesses of the process.

Superconducting-qubit readout via low-backaction electro-optic transduction.

Entangling microwave-frequency superconducting quantum processors through optical light at ambient temperature would enable means of secure communication and distributed quantum information processing1. However, transducing quantum signals between these disparate regimes of the electro-magnetic spectrum remains an outstanding goal2-9, and interfacing superconducting qubits, which are constrained to operate at millikelvin temperatures, with electro-optic transducers presents considerable challenges owing to the deleterious effects of optical photons on superconductors9,10. Moreover, many remote entanglement protocols11-14 require multiple qubit gates both preceding and following the upconversion of the quantum state, and thus an ideal transducer should impart minimal backaction15 on the qubit. Here we demonstrate readout of a superconducting transmon qubit through a low-backaction electro-optomechanical transducer. The modular nature of the transducer and circuit quantum electrodynamics system used in this work enable complete isolation of the qubit from optical photons, and the backaction on the qubit from the transducer is less than that imparted by thermal radiation from the environment. Moderate improvements in the transducer bandwidth and the added noise will enable us to leverage the full suite of tools available in circuit quantum electrodynamics to demonstrate transduction of non-classical signals from a superconducting qubit to the optical domain.

A comparison of cine CMR imaging at 0.55 T and 1.5 T.

BACKGROUND: There is a renewed interest in lower field magnetic resonance imaging (MRI) systems for cardiovascular magnetic resonance (CMR), due to their favorable physical properties, reduced costs, and increased accessibility to patients with implants. We sought to assess the diagnostic capabilities of high-performance low-field (0.55 T) CMR imaging for quantification of right and left ventricular volumes and systolic function in both healthy subjects and patients referred for clinical CMR. METHODS: Sixty-five subjects underwent paired exams at 1.5 T using a clinical CMR scanner and using an identical CMR system modified to operate at 0.55 T. Volumetric coverage of the right ventricle (RV) and left ventricles (LV) was obtained using either a breath-held cine balanced steady-state free-precession acquisition or a motion-corrected free-breathing re-binned cine acquisition. Bland-Altman analysis was used to compare LV and RV end-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), and LV mass. Diagnostic confidence was scored on a Likert-type ordinal scale by blinded readers. RESULTS: There were no significant differences in LV and RV EDV between the two scanners (e.g., LVEDV: p = 0.77, bias = 0.40 mL, correlation coefficient = 0.99; RVEDV: p = 0.17, bias = - 1.6 mL, correlation coefficient = 0.98), and regional wall motion abnormality scoring was similar (kappa 0.99). Blood-myocardium contrast-to-noise ratio (CNR) at 0.55 T was 48 ± 7% of the 1.5 T CNR, and contrast was sufficient for endocardial segmentation in all cases. Diagnostic confidence of images was scored as "good" to "excellent" for the two field strengths in the majority of studies. CONCLUSION: A high-performance 0.55 T system offers good bSSFP CMR image quality, and quantification of biventricular volumes and systolic function that is comparable to 1.5 T in patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT03331380, NCT03581318.

Mortality risk among women exposed to violence in Brazil: a population-based exploratory analysis.

OBJECTIVES: The objective of this study was to estimate mortality risk among women exposed to violence in Brazil using population-based data. STUDY DESIGN: This study used a linked database containing nearly 800,000 violence (against women) notifications and 16,500 associated deaths over the period 2011-2016. METHODS: Aggregate age-standardized population-based rates of mortality were built to estimate risk ratios (RRs) at the national and state level, and for different forms of violence and causes of death, as well as type of offender involved, and across various characteristics of the women. RRs compared the rate of mortality among women exposed to violence with that in the general population of women - excess mortality due to violence was also derived from this comparison. The analysis was divided into two time periods (2011-13 and 2014-16). RESULTS: During 2014-16, women exposed to violence had an estimated mortality risk that was 8.3 [95% confidence interval (CI): 8.2-8.5] times higher than that of the general woman population, and an estimated 100 women died on a weekly basis as a direct or indirect consequence of exposure to violence. Higher (all-cause) mortality risk was associated with physical violence and violence that involved repetition and that was self-inflicted. The risk of mortality increased when the cause of death involved external causes (RR: 51.2, 95% CI: 49.6-52.8). When death was attributable to (i) non-communicable diseases and (ii) communicable, maternal, neonatal, and nutritional diseases, the risk was 5.4 [95% CI: 5.3-5.6] and 6.7 [95% CI: 6.1-7.2] times, respectively. Women at greatest (all-cause) mortality risk include white and multiracial (parda) and single women in the age group 10-29 years, who live in the northeast part of the country. When the offender was a partner/ex., women aged 10-19 years showed the greatest (all-cause) mortality risk at 16.9 [95% CI: 13.9-19.8] times. Higher risk was also observed within the age group 30-59 years when death was attributable to external causes (RR: 74.6, 95% CI: 71.3-77.9). For younger women and girls, there was a clear gradient in (all-cause) mortality risk, with those living in the poorest municipalities at greater risk. Age-specific mortality risk also showed significant variation within and across states. CONCLUSIONS: This analysis suggests that most women exposed to violence will likely experience an increased risk of mortality, regardless of her place of residence, age group, racial/ethnic background, marital status situation, and socio-economic status. The estimated RRs are only an approximation given the design of this analysis and should be interpreted with caution.

Measurement of Motion beyond the Quantum Limit by Transient Amplification.

Through simultaneous but unequal electromechanical amplification and cooling processes, we create a method for a nearly noiseless pulsed measurement of mechanical motion. We use transient electromechanical amplification (TEA) to monitor a single motional quadrature with a total added noise -8.5±2.0 dB relative to the zero-point motion of the oscillator, or equivalently the quantum limit for simultaneous measurement of both mechanical quadratures. We demonstrate that TEA can be used to resolve fine structure in the phase space of a mechanical oscillator by tomographically reconstructing the density matrix of a squeezed state of motion. Without any inference or subtraction of noise, we directly observe a squeezed variance 2.8±0.3 dB below the oscillator's zero-point motion.

Opportunities in Interventional and Diagnostic Imaging by Using High-Performance Low-Field-Strength MRI.

Background Commercial low-field-strength MRI systems are generally not equipped with state-of-the-art MRI hardware, and are not suitable for demanding imaging techniques. An MRI system was developed that combines low field strength (0.55 T) with high-performance imaging technology. Purpose To evaluate applications of a high-performance low-field-strength MRI system, specifically MRI-guided cardiovascular catheterizations with metallic devices, diagnostic imaging in high-susceptibility regions, and efficient image acquisition strategies. Materials and Methods A commercial 1.5-T MRI system was modified to operate at 0.55 T while maintaining high-performance hardware, shielded gradients (45 mT/m; 200 T/m/sec), and advanced imaging methods. MRI was performed between January 2018 and April 2019. T1, T2, and T2* were measured at 0.55 T; relaxivity of exogenous contrast agents was measured; and clinical applications advantageous at low field were evaluated. Results There were 83 0.55-T MRI examinations performed in study participants (45 women; mean age, 34 years ± 13). On average, T1 was 32% shorter, T2 was 26% longer, and T2* was 40% longer at 0.55 T compared with 1.5 T. Nine metallic interventional devices were found to be intrinsically safe at 0.55 T (<1°C heating) and MRI-guided right heart catheterization was performed in seven study participants with commercial metallic guidewires. Compared with 1.5 T, reduced image distortion was shown in lungs, upper airway, cranial sinuses, and intestines because of improved field homogeneity. Oxygen inhalation generated lung signal enhancement of 19% ± 11 (standard deviation) at 0.55 T compared with 7.6% ± 6.3 at 1.5 T (P = .02; five participants) because of the increased T1 relaxivity of oxygen (4.7e-4 mmHg-1sec-1). Efficient spiral image acquisitions were amenable to low field strength and generated increased signal-to-noise ratio compared with Cartesian acquisitions (P < .02). Representative imaging of the brain, spine, abdomen, and heart generated good image quality with this system. Conclusion This initial study suggests that high-performance low-field-strength MRI offers advantages for MRI-guided catheterizations with metal devices, MRI in high-susceptibility regions, and efficient imaging. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Grist in this issue.

Blood volume measurement using cardiovascular magnetic resonance and ferumoxytol: preclinical validation.

BACKGROUND: The hallmark of heart failure is increased blood volume. Quantitative blood volume measures are not conveniently available and are not tested in heart failure management. We assess ferumoxytol, a marketed parenteral iron supplement having a long intravascular half-life, to measure the blood volume with cardiovascular magnetic resonance (CMR). METHODS: Swine were administered 0.7 mg/kg ferumoxytol and blood pool T1 was measured repeatedly for an hour to characterize contrast agent extraction and subsequent effect on Vblood estimates. We compared CMR blood volume with a standard carbon monoxide rebreathing method. We then evaluated three abbreviated acquisition protocols for bias and precision. RESULTS: Mean plasma volume estimated by ferumoxytol was 61.9 ± 4.3 ml/kg. After adjustment for hematocrit the resultant mean blood volume was 88.1 ± 9.4 ml/kg, which agreed with carbon monoxide measures (91.1 ± 18.9 ml/kg). Repeated measurements yielded a coefficient of variation of 6.9%, and Bland-Altman repeatability coefficient of 14%. The blood volume estimates with abbreviated protocols yielded small biases (mean differences between 0.01-0.06 L) and strong correlations (r2 between 0.97-0.99) to the reference values indicating clinical feasibility. CONCLUSIONS: In this swine model, ferumoxytol CMR accurately measures plasma volume, and with correction for hematocrit, blood volume. Abbreviated protocols can be added to diagnostic CMR examination for heart failure within 8 min.

Right heart catheterization using metallic guidewires and low SAR cardiovascular magnetic resonance fluoroscopy at 1.5 Tesla: first in human experience.

BACKGROUND: Cardiovascular magnetic resonance (CMR) fluoroscopy allows for simultaneous measurement of cardiac function, flow and chamber pressure during diagnostic heart catheterization. To date, commercial metallic guidewires were considered contraindicated during CMR fluoroscopy due to concerns over radiofrequency (RF)-induced heating. The inability to use metallic guidewires hampers catheter navigation in patients with challenging anatomy. Here we use low specific absorption rate (SAR) imaging from gradient echo spiral acquisitions and a commercial nitinol guidewire for CMR fluoroscopy right heart catheterization in patients. METHODS: The low-SAR imaging protocol used a reduced flip angle gradient echo acquisition (10° vs 45°) and a longer repetition time (TR) spiral readout (10 ms vs 2.98 ms). Temperature was measured in vitro in the ASTM 2182 gel phantom and post-mortem animal experiments to ensure freedom from heating with the selected guidewire (150 cm × 0.035″ angled-tip nitinol Terumo Glidewire). Seven patients underwent CMR fluoroscopy catheterization. Time to enter each chamber (superior vena cava, main pulmonary artery, and each branch pulmonary artery) was recorded and device visibility and confidence in catheter and guidewire position were scored on a Likert-type scale. RESULTS: Negligible heating (< 0.07°C) was observed under all in vitro conditions using this guidewire and imaging approach. In patients, chamber entry was successful in 100% of attempts with a guidewire compared to 94% without a guidewire, with failures to reach the branch pulmonary arteries. Time-to-enter each chamber was similar (p=NS) for  the two approaches. The guidewire imparted useful catheter shaft conspicuity and enabled interactive modification of catheter shaft stiffness, however, the guidewire tip visibility was poor. CONCLUSIONS: Under specific conditions, trained operators can apply low-SAR imaging and using a specific fully-insulated metallic nitinol guidewire (150 cm × 0.035" Terumo Glidewire) to augment clinical CMR fluoroscopy right heart catheterization. TRIAL REGISTRATION: Clinicaltrials.gov NCT03152773 , registered May 15, 2017.

Proposed Criteria for the Use of Low-Dose Vitamin K Supplementation in Patients Using Vitamin K Antagonists: A Literature Review of a Clinical Controversy.

BACKGROUND: Vitamin K antagonists (VKAs) have been used for decades to prevent thromboembolic events, but can be burdensome to patients based on numerous factors impacting anticoagulation control. Low-dose vitamin K supplementation has been theorized to improve anticoagulation control in patients on VKAs that may be vitamin K deficient. The objective of this literature review is to propose criteria for implementing low-dose vitamin K supplementation in patients on VKAs. LITERATURE REVIEW: The CHEST 2012 antithrombotic guidelines recommended against routine use of vitamin K supplementation in patients on VKAs. An observational study and three randomized controlled trials pertaining to this recommendation were evaluated. A literature review was also performed on other studies looking at the impact of low-dose vitamin K supplementation on anticoagulation control through a search in PubMed and the Cochrane Database of Systematic Reviews. One retrospective and two prospective studies were reviewed. Six of the seven studies demonstrated a non-statistically significant trend in data supporting improvement in anticoagulation control with low-dose vitamin K supplementation. CONCLUSION: While many of the studies did not achieve significant results, the majority demonstrated a trend in support of the improvement of anticoagulation control with low-dose vitamin K supplementation in patients on VKAs.

Does preliminary optimisation of an anatomically correct skull-brain model using simple simulants produce clinically realistic ballistic injury fracture patterns?

Ballistic head injury remains a significant threat to military personnel. Studying such injuries requires a model that can be used with a military helmet. This paper describes further work on a skull-brain model using skulls made from three different polyurethane plastics and a series of skull 'fills' to simulate brain (3, 5, 7 and 10% gelatine by mass and PermaGel™). The models were subjected to ballistic impact from 7.62 × 39 mm mild steel core bullets. The first part of the work compares the different polyurethanes (mean bullet muzzle velocity of 708 m/s), and the second part compares the different fills (mean bullet muzzle velocity of 680 m/s). The impact events were filmed using high speed cameras. The resulting fracture patterns in the skulls were reviewed and scored by five clinicians experienced in assessing penetrating head injury. In over half of the models, one or more assessors felt aspects of the fracture pattern were close to real injury. Limitations of the model include the skull being manufactured in two parts and the lack of a realistic skin layer. Further work is ongoing to address these.

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.

Clinical and post mortem analysis of combat neck injury used to inform a novel coverage of armour tool.

INTRODUCTION: There is a requirement in the Ministry of Defence for an objective method of comparing the area of coverage of different body armour designs for future applications. Existing comparisons derived from surface wound mapping are limited in that they can only demonstrate the skin entry wound location. The Coverage of Armour Tool (COAT) is a novel three-dimensional model capable of comparing the coverage provided by body armour designs, but limited information exists as to which anatomical structures require inclusion. The aim of this study was to assess the utility of COAT, in the assessment of neck protection, using clinically relevant injury data. METHOD: Hospital notes and post mortem records of all UK soldiers injured by an explosive fragment to the neck between 01 Jan 2006 and 31 December 2012 from Iraq and Afghanistan were analysed to determine which anatomical structures were responsible for death or functional disability at one year post injury. Using COAT a comparison of three ballistic neck collar designs was undertaken with reference to the percentage of these anatomical structures left exposed. RESULTS: 13/81 (16%) survivors demonstrated complications at one year, most commonly upper limb weakness from brachial plexus injury or a weak voice from laryngeal trauma. In 14/94 (15%) soldiers the neck wound was believed to have been the sole cause of death, primarily from carotid artery damage, spinal cord transection or rupture of the larynx. COAT objectively demonstrated that despite the larger OSPREY collar having almost double the surface area than the two-piece prototype collar, the percentage area of vulnerable cervical structures left exposed only reduced from 16.3% to 14.4%. DISCUSSION: COAT demonstrated its ability to objectively quantify the potential effectiveness of different body armour designs in providing coverage of vulnerable anatomical structures from different shot line orientations. To improve its utility, it is recommended that COAT be further developed to enable weapon and tissue specific information to be modelled, and that clinically significant injuries to other body regions are also incorporated.

Using computerised surface wound mapping to compare the potential medical effectiveness of Enhanced Protection Under Body Armour Combat Shirt collar designs.

INTRODUCTION: Protecting the neck from explosively propelled fragments has traditionally been achieved through a collar attached to the ballistic vest. An Enhanced Protection Under Body Armour Combat Shirt (EP-UBACS) collar has been identified as an additional method of providing neck protection but limited evidence as to its potential medical effectiveness exists to justify its procurement. METHOD: Entry wound locations and resultant medical outcomes were determined using Abbreviated Injury Scale (AIS) for all fragmentation neck wounds sustained by UK soldiers between 01 January 2010 and 31 December 2011. Data were prospectively entered into a novel computerised tool base and comparisons made between three EP-UBACS neck collar designs in terms of predicted reduction in AIS scores. RESULTS: All collars reduced AIS scores, with the greatest reduction provided by designs incorporating increased standoff from the neck and an additional semi-circle of ballistic material underneath the collar at the front and back. DISCUSSION: This technique confirms that reinforcing the neck collar of an EP-UBACS would be expected to reduce injury severity from neck wounds. However, without knowledge of entry wound locations for injuries to other body areas as well as the use of AIS scores without clinical or pathological verification its further use in the future may be limited. The ability to overlay any armour design onto a standardised human was potentially the most useful part of this tool and we would recommend developing this technique using underlying anatomical structures and not just the skin surface.