The ultra-acute steroid response to traumatic injury: a cohort study.

OBJECTIVE: Trauma-induced steroid changes have been studied post-hospital admission, resulting in a lack of understanding of the speed and extent of the immediate endocrine response to injury. The Golden Hour study was designed to capture the ultra-acute response to traumatic injury. DESIGN: We conducted an observational cohort study including adult male trauma patients <60 years, with blood samples drawn ≤1 h of major trauma by pre-hospital emergency responders. METHODS: We recruited 31 adult male trauma patients (mean age 28 [range 19-59] years) with a mean injury severity score (ISS) of 16 (IQR 10-21). The median time to first sample was 35 (range 14-56) min, with follow-up samples collected 4-12 and 48-72 h post-injury. Serum steroids in patients and age- and sex-matched healthy controls (HCs) (n = 34) were analysed by tandem mass spectrometry. RESULTS: Within 1 h of injury, we observed an increase in glucocorticoid and adrenal androgen biosynthesis. Cortisol and 11-hydroxyandrostendione increased rapidly, whilst cortisone and 11-ketoandrostenedione decreased, reflective of increased cortisol and 11-oxygenated androgen precursor biosynthesis by 11ß-hydroxylase and increased cortisol activation by 11ß-hydroxysteroid dehydrogenase type 1. Active classic gonadal androgens testosterone and 5α-dihydrotestosterone decreased, whilst the active 11-oxygenated androgen 11-ketotestosterone maintained pre-injury levels. CONCLUSIONS: Changes in steroid biosynthesis and metabolism occur within minutes of traumatic injury. Studies that address whether ultra-early changes in steroid metabolism are associated with patient outcomes are now required.

Investigating the potential of a prematurely aged immune phenotype in severely injured patients as predictor of risk of sepsis.

BACKGROUND: Traumatic injury elicits a hyperinflammatory response and remodelling of the immune system leading to immuneparesis. This study aimed to evaluate whether traumatic injury results in a state of prematurely aged immune phenotype to relate this to clinical outcomes and a greater risk of developing additional morbidities post-injury. METHODS AND FINDINGS: Blood samples were collected from 57 critically injured patients with a mean Injury Severity Score (ISS) of 26 (range 15-75 years), mean age of 39.67 years (range 20-84 years), and 80.7% males, at days 3, 14, 28 and 60 post-hospital admission. 55 healthy controls (HC), mean age 40.57 years (range 20-85 years), 89.7% males were also recruited. The phenotype and frequency of adaptive immune cells were used to calculate the IMM-AGE score, an indicator of the degree of phenotypic ageing of the immune system. IMM-AGE was elevated in trauma patients at an early timepoint (day 3) in comparison with healthy controls (p < 0.001), driven by an increase in senescent CD8 T cells (p < 0.0001), memory CD8 T cells (p < 0.0001) and regulatory T cells (p < 0.0001) and a reduction in naïve CD8 T cells (p < 0.001) and overall T cell lymphopenia (p < 0 .0001). These changes persisted to day 60. Furthermore, the IMM-AGE scores were significantly higher in trauma patients (mean score 0.72) that developed sepsis (p = 0.05) in comparison with those (mean score 0.61) that did not. CONCLUSIONS: The profoundly altered peripheral adaptive immune compartment after critical injury can be used as a potential biomarker to identify individuals at a high risk of developing sepsis and this state of prematurely aged immune phenotype in biologically young individuals persists for up to two months post-hospitalisation, compromising the host immune response to infections. Reversing this aged immune system is likely to have a beneficial impact on short- and longer-term outcomes of trauma survivors.

Niobium-tantalum oxide as a material platform for linear and nonlinear integrated photonics.

Here we realize the first reported integrated photonic devices fabricated using sputtered niobium-tantalum oxide films. Sputtered niobium-tantalum oxide films are highly promising for integrated photonics as they are scalable to high volume manufacturing, possess high refractive index, and are transparent in the ultraviolet through near infrared wavelength range. At a wavelength near 1550 nm, we observe propagation losses as low as 0.47 dB/cm in waveguides and ring resonators with resonator quality factors as high as 860,000. We also characterize the nonlinear performance of these films and find a Kerr coefficient (n2) of 1.2 ( ± 0.2) × 10-18 m2/W. With this high Kerr coefficient we demonstrate optical parametric oscillation in a ring resonator and supercontinuum generation in a waveguide.

Relieving Pressure on the Emergency Department with a New Treatment Pathway for Hand Trauma Patients - A Three-Year Experience with 15,539 Patients.

Background: Hand injuries are a significant and rising burden on the Emergency Department (ED), often leading to protracted waiting times for patients awaiting specialist input. To combat this, a new treatment pathway for hand trauma was introduced at our institution to reduce waiting times and pressure on the ED. Methods: The treatment pathway performance using waiting times, length of stay and cost metrics was measured prior to and following the introduction of a new treatment pathway. Results: There were 15,539 patients reviewed in total. After the new pathway had been introduced, the number of assessments in ED significantly reduced (Year 1: 907 [19.9%] vs. Year 2: 422 [7.9%]; p < 0.001), and the proportion of patients who had an operation on the same day that they were assessed significantly increased (69 [1.5%] vs. 403 [7.5%] patients; p < 0.001). The median waiting time from assessment to operation and length of stay also significantly reduced following the introduction of the treatment pathway (Year 1: 53 hours and Year 2: 45 hours; p < 0.001). Conclusions: Our data over 3 years shows that these changes have been maintained and, in some cases, have continued to improve since the introduction of the new treatment pathway. We advocate the use of such an approach for all hand trauma centres worldwide to replicate these improvements in patient care. Level of Evidence: Level III.

Time-lens photon Doppler velocimetry (TL-PDV).

We describe a time lens (TL) to expand the dynamic range of photon Doppler velocimetry (PDV) systems. The principle and preliminary design of a TL-PDV system are explained and shown to be feasible through simulations. In a PDV system, an interferometer is used for measuring frequency shifts due to the Doppler effect from the target motion. However, the sampling rate of the electronics could limit the velocity range of a PDV system. A four-wave-mixing (FWM) TL applies a quadratic temporal phase to an optical signal within a nonlinear FWM medium (such as an integrated photonic waveguide or a highly nonlinear optical fiber). By spectrally isolating the mixing product, termed the idler, and with appropriate lengths of dispersion prior to and after this FWM TL, a temporally magnified version of the input signal is generated. Therefore, the frequency shifts of PDV can be "slowed down" with the magnification factor M of the TL. M = 1 corresponds to a regular PDV system without a TL. M = 10 has been shown to be feasible for a TL-PDV system. The use of this effect for PDV can expand the velocity measurement range and allow for the use of lower bandwidth electronics. TL-PDV will open up new avenues for various dynamic material experiments.

A prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its Profile in Trauma: ADaPT.

INTRODUCTION: The improvements in short-term outcome after severe trauma achieved through early resuscitation and acute care can be offset over the following weeks by an acute systemic inflammatory response with immuneparesis leading to infection, multiorgan dysfunction/multiorgan failure (MOF) and death. Serum levels of the androgen precursor dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, steroids with immune-enhancing activity, are low after traumatic injury at a time when patients are catabolic and immunosuppressed. Addressing this deficit and restoring the DHEA(S) ratio to cortisol may provide a range of physiological benefits, including immune modulatory effects. OBJECTIVE: Our primary objective is to establish a dose suitable for DHEA supplementation in patients after acute trauma to raise circulating DHEA levels to at least 15 nmol/L. Secondary objectives are to assess if DHEA supplementation has any effect on neutrophil function, metabolic and cytokine profiles and which route of administration (oral vs sublingual) is more effective in restoring circulating levels of DHEA, DHEAS and downstream androgens. METHODS AND ANALYSIS: A prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its profile in trauma, with a planned recruitment between April 2019 and July 2021, that will investigate DHEA supplementation and its effect on serum DHEA, DHEAS and downstream androgens in trauma. A maximum of 270 patients will receive sublingual or oral DHEA at 50, 100 or 200 mg daily over 3 days. Females aged ≥50 years with neck of femur fracture and male and female major trauma patients, aged 16-50 years with an injury severity score ≥16, will be recruited. ETHICS AND DISSEMINATION: This protocol was approved by the West Midlands - Coventry and Warwickshire Research Ethics Committee (Reference 18/WM/0102) on 8 June 2018. Results will be disseminated via peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION: This trial is registered with the European Medicines Agency (EudraCT: 2016-004250-15) and ISRCTN (12961998). It has also been adopted on the National Institute of Health Research portfolio (CPMS ID:38158). TRIAL PROGRESSION: The study recruited its first patient on 2 April 2019 and held its first data monitoring committee on 8 November 2019. DHEA dosing has increased to 100 mg in both male cohorts and remains on 50 mg in across all female groups.

Integration of Metabolomic and Clinical Data Improves the Prediction of Intensive Care Unit Length of Stay Following Major Traumatic Injury.

Recent advances in emergency medicine and the co-ordinated delivery of trauma care mean more critically-injured patients now reach the hospital alive and survive life-saving operations. Indeed, between 2008 and 2017, the odds of surviving a major traumatic injury in the UK increased by nineteen percent. However, the improved survival rates of severely-injured patients have placed an increased burden on the healthcare system, with major trauma a common cause of intensive care unit (ICU) admissions that last ≥10 days. Improved understanding of the factors influencing patient outcomes is now urgently needed. We investigated the serum metabolomic profile of fifty-five major trauma patients across three post-injury phases: acute (days 0-4), intermediate (days 5-14) and late (days 15-112). Using ICU length of stay (LOS) as a clinical outcome, we aimed to determine whether the serum metabolome measured at days 0-4 post-injury for patients with an extended (≥10 days) ICU LOS differed from that of patients with a short (<10 days) ICU LOS. In addition, we investigated whether combining metabolomic profiles with clinical scoring systems would generate a variable that would identify patients with an extended ICU LOS with a greater degree of accuracy than models built on either variable alone. The number of metabolites unique to and shared across each time segment varied across acute, intermediate and late segments. A one-way ANOVA revealed the most variation in metabolite levels across the different time-points was for the metabolites lactate, glucose, anserine and 3-hydroxybutyrate. A total of eleven features were selected to differentiate between <10 days ICU LOS vs. >10 days ICU LOS. New Injury Severity Score (NISS), testosterone, and the metabolites cadaverine, urea, isoleucine, acetoacetate, dimethyl sulfone, syringate, creatinine, xylitol, and acetone form the integrated biomarker set. Using metabolic enrichment analysis, we found valine, leucine and isoleucine biosynthesis, glutathione metabolism, and glycine, serine and threonine metabolism were the top three pathways differentiating ICU LOS with a p < 0.05. A combined model of NISS and testosterone and all nine selected metabolites achieved an AUROC of 0.824. Differences exist in the serum metabolome of major trauma patients who subsequently experience a short or prolonged ICU LOS in the acute post-injury setting. Combining metabolomic data with anatomical scoring systems allowed us to discriminate between these two groups with a greater degree of accuracy than that of either variable alone.

Kilohertz frame rate snapshot hyperspectral imaging of metal reactive materials.

We demonstrate a kilohertz frame rate snapshot hyperspectral imaging system suitable for high-speed imaging, which we name snapshot hyperspectral imager for emission and reactions (SHEAR). This system splits the sensor of a single high-speed camera to simultaneously capture a conventional image and a spectrally sheared response of the scene under study. Given the small, point-source-like nature of burning metal micro-particles, the spectral response of the species is captured without the need for a slit, as is needed in conventional imaging spectrometers. We pair robust image registration techniques with sparse reconstruction algorithms to computationally disentangle overlapping spectra associated with many burning particles over the course of a combustion experiment. As a proof-of-concept experiment, representative physical vapor deposited Al:Zr composite particles are ignited, and their burn evolution is recorded at a frame rate of 2 kHz using this method. We demonstrate operation over two distinct wavelength ranges spanning hundreds of nanometers in wavelength and with sub-nanometer resolution. We are able to track hundreds of individual Al:Zr particles in a single high-speed video, providing ample statistics of burn time, temperature, and AlO emission timing in a high-throughput method. The demonstrated technology is high-throughput, flexible in wavelength, inexpensive, and relatively easy to implement, and provides a much needed tool for in situ composite metal fuel diagnostics.

Violence-related knife injuries in a UK city; epidemiology and impact on secondary care resources.

BACKGROUND: The incidence of knife-related injuries is rising across the UK. This study aimed to determine the spectrum of knife-related injuries in a major UK city, with regards to patient and injury characteristics. A secondary aim was to quantify their impact on secondary care resources. METHODS: Observational study of patients aged 16+ years admitted to a major trauma centre following knife-related injuries resulting from interpersonal violence (May 2015 to April 2018). Patients were identified using Emergency Department and discharge coding, blood bank and UK national Trauma Audit and Research prospective registries. Patient and injury characteristics, outcome and resource utilisation were collected from ambulance and hospital records. FINDINGS: 532 patients were identified; 93% male, median age 26 years (IQR 20-35). Median injury severity score was 9 (IQR 3-13). 346 (65%) underwent surgery; 133 (25%) required intensive care; 95 (17·9%) received blood transfusion. Median length of stay was 3·3 days (IQR 1·7-6·0). In-hospital mortality was 10/532 (1·9%). 98 patients (18·5%) had previous attendance with violence-related injuries. 24/37 females (64·9%) were injured in a domestic setting. Intoxication with alcohol (19·2%) and illicit drugs (17·6%) was common. Causative weapon was household knife in 9%, knife (other/unspecified) in 38·0%, machete in 13·9%, small folding blade (2·8%) and, unrecorded in 36·3%. INTERPRETATION: Knife injuries constitute 12·9% of trauma team workload. Violence recidivism and intoxication are common, and females are predominantly injured in a domestic setting, presenting opportunities for targeted violence reduction interventions. 13·9% of injuries involved machetes, with implications for law enforcement strategies.

Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery.

CONTEXT: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress. DESIGN AND PARTICIPANTS: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE: We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULTS: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSIONS: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

CONTEXT: Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE: This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN: We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES: We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS: We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION: The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.

Optical coherence tomography using physical domain data compression to achieve MHz A-scan rates.

The three-dimensional volumetric imaging capability of optical coherence tomography (OCT) leads to the generation of large amounts of data, which necessitates high speed acquisition followed by high dimensional image processing and visualization. This signal acquisition and processing pipeline demands high A-scan rates on the front end, which has driven researchers to push A-scan acquisition rates into the MHz regime. To this end, the optical time-stretch approach uses a mode locked laser (MLL) source, dispersion in optical fiber, and a single analog-to-digital converter (ADC) to achieve multi-MHz A-scan rates. While enabling impressive performance this Nyquist sampling approach is ultimately constrained by the sampling rate and bandwidth of the ADC. Additionally such an approach generates massive amounts of data. Here we present a compressed sensing (CS) OCT system that uses a MLL, electro-optic modulation, and optical dispersion to implement data compression in the physical domain and rapidly acquire real-time compressed measurements of the OCT signals. Compression in the analog domain prior to digitization allows for the use of lower bandwidth ADCs, which reduces cost and decreases the required data capacity of the sampling interface. By leveraging a compressive A-scan optical sampling approach and the joint sparsity of C-scan data we demonstrate 14.4-MHz to 144-MHz A-scan acquisition speeds using a sub-Nyquist 1.44 Gsample/sec ADC sampling rate. Furthermore we evaluate the impact of data compression and resulting imaging speed on image quality.

A minimally invasive lens-free computational microendoscope.

Ultra-miniaturized microendoscopes are vital for numerous biomedical applications. Such minimally invasive imagers allow for navigation into hard-to-reach regions and observation of deep brain activity in freely moving animals. Conventional solutions use distal microlenses. However, as lenses become smaller and less invasive, they develop greater aberrations and restricted fields of view. In addition, most of the imagers capable of variable focusing require mechanical actuation of the lens, increasing the distal complexity and weight. Here, we demonstrate a distal lens-free approach to microendoscopy enabled by computational image recovery. Our approach is entirely actuation free and uses a single pseudorandom spatial mask at the distal end of a multicore fiber. Experimentally, this lensless approach increases the space-bandwidth product, i.e., field of view divided by resolution, by threefold over a best-case lens-based system. In addition, the microendoscope demonstrates color resolved imaging and refocusing to 11 distinct depth planes from a single camera frame without any actuated parts.

The cortisol stress response induced by surgery: A systematic review and meta-analysis.

OBJECTIVE: Surgery is a stressor that can be categorized by duration and severity and induces a systemic stress response that includes increased adrenal cortisol production. However, the precise impact of surgical stress on the cortisol response remains to be defined. DESIGN: We performed a systematic review and meta-analysis to assess the cortisol stress response induced by surgery and to stratify this response according to different parameters. METHODS: We conducted a comprehensive search in several databases from 1990 to 2016. Pairs of reviewers independently selected studies, extracted data and evaluated the risk of bias. Cortisol concentrations were standardized, pooled in meta-analysis and plotted over time. RESULTS: We included 71 studies reporting peri-operative serum cortisol measurements in 2953 patients. The cortisol response differed substantially between moderately/highly invasive and minimally invasive surgical procedures. Minimally invasive procedures did not show a peri-operative cortisol peak, whereas more invasive surgeries caused a cortisol surge that was more pronounced in older subjects, women and patients undergoing open surgery and general anaesthesia. The duration of the procedure and the use of etomidate for induction of anaesthesia did not affect the cortisol response. CONCLUSIONS: The peri-operative cortisol stress response is dynamic and influenced by patient-specific, surgical and anaesthetic features. However, the available evidence is derived from highly heterogeneous studies, with only two of 71 studies measuring cortisol by mass spectrometry, which currently prevents a precise and reproducible definition of this response.

Widefield compressive multiphoton microscopy.

A single-pixel compressively sensed architecture is exploited to simultaneously achieve a 10× reduction in acquired data compared with the Nyquist rate, while alleviating limitations faced by conventional widefield temporal focusing microscopes due to scattering of the fluorescence signal. Additionally, we demonstrate an adaptive sampling scheme that further improves the compression and speed of our approach.

Secure communications using nonlinear silicon photonic keys.

We present a secure communication system constructed using pairs of nonlinear photonic physical unclonable functions (PUFs) that harness physical chaos in integrated silicon micro-cavities. Compared to a large, electronically stored one-time pad, our method provisions large amounts of information within the intrinsically complex nanostructure of the micro-cavities. By probing a micro-cavity with a rapid sequence of spectrally-encoded ultrafast optical pulses and measuring the lightwave responses, we experimentally demonstrate the ability to extract 2.4 Gb of key material from a single micro-cavity device. Subsequently, in a secure communication experiment with pairs of devices, we achieve bit error rates below 10-5 at code rates of up to 0.1. The PUFs' responses are never transmitted over the channel or stored in digital memory, thus enhancing the security of the system. Additionally, the micro-cavity PUFs are extremely small, inexpensive, robust, and fully compatible with telecommunications infrastructure, components, and electronic fabrication. This approach can serve one-time pad or public key exchange applications where high security is required.

Silicon photonic physical unclonable function.

Physical unclonable functions (PUFs) serve as a hardware source of private information that cannot be duplicated and have applications in hardware integrity and information security. Here we demonstrate a photonic PUF based on ultrafast nonlinear optical interactions in a chaotic silicon micro-cavity. The device is probed with a spectrally-encoded ultrashort optical pulse, which nonlinearly interacts with the micro-cavity. This interaction produces a highly complex and unpredictable, yet deterministic, ultrafast response that can serve as a unique "fingerprint" of the cavity and as a source of private information for the device's holder. Experimentally, we extract 17.1-kbit binary keys from six different photonic PUF designs and demonstrate the uniqueness and reproducibility of these keys. Furthermore, we experimentally test exact copies of the six photonic PUFs and demonstrate their unclonability due to unavoidable fabrication variations.

High-speed all-optical Haar wavelet transform for real-time image compression.

We present a high-speed single pixel flow imager based on an all-optical Haar wavelet transform of moving objects. Spectrally-encoded wavelet measurement patterns are produced by chirp processing of broad-bandwidth mode-locked laser pulses. A complete wavelet pattern set serially illuminates the object via a spectral disperser. This high-rate structured illumination transforms the scene into a set of sparse coefficients. We show that complex scenes can be compressed to less than 30% of their Nyquist rate by thresholding and storing the most significant wavelet coefficients. Moreover by employing temporal multiplexing of the patterns we are able to achieve pixel rates in excess of 360 MPixels/s.