Transfer of bovine embryos into a uterus primed with high progesterone concentrations positively impacts fetal development at 42 days of gestation.

Elevated circulating progesterone (P4) concentrations in the first week after conception have been associated with accelerated post-hatching conceptus elongation. However, the consequences, if any, on the development of the fetus are unknown. The objective of this study was to determine the relationship between early circulating P4 and fetal and placental morphometric characteristics at 42 days of gestation. A previously validated model of asynchronous embryo transfer (ET), known to alter uterine exposure to P4, was used in 107 heifers divided in two replicates (replicate 1: n = 51, replicate 2: n = 56). Heifers were randomly assigned to one of the two following groups: those receiving a Day 7 embryo on Day 7 of the cycle (synchronous; ET_D7, n = 49) and those transferred a Day 7 embryo on Day 9 of the cycle (asynchronous; ET_D9, n = 58). The synchronization protocol was started two days earlier for heifers in the ET_D9 group such that ET was done on the same day for both groups. P4 concentrations were determined from Day 3 after estrus to the day of ET. Pregnant heifers were slaughtered at Day 42 of gestation for fetal and placental morphometric measurements. The effects of the group, replicate, fetal sex, and interactions between these variables on fetal and placental characteristics were determined by ANOVA, while Pearson correlation was employed to assess the linear relationship between P4 concentrations two days before and on the day of ET on the fetal parameters. The uteri of heifers in the ET_D9 group were exposed to higher concentrations (P < 0.0001) of P4 from four days before ET, than heifers in the ET_D7 group. Both group and fetal sex variables impacted on fetal crown-rump length (CRL) (group: P < 0.0001, sex: P = 0.001) and fetal weight (group: P = 0.006, sex: P = 0.003). Fetal sex influenced the amniotic sac area (P = 0.003) and amniotic sac weight (P = 0.004); while the group affected the number of cotyledons (P = 0.0009), and the fetal heart weight (P = 0.018). All these parameters were larger in the ET_D9 group compared with ET_D7, and in males compared with females. There was a positive correlation between P4 concentrations two days before ET and fetal weight and CRL, for each sex or considering all fetuses (R2 ∼0.4, p < 0.05). In conclusion, bovine embryos transferred into a uterus primed with higher P4 concentrations underwent enhanced development reflected in higher weight and size at the beginning of the fetal period.

Improvements in National Code Red transfusion practice in Scotland after adoption of recommendations from the Scottish National Code Red 2015 review.

AIMS: The Scottish Transfusion and Laboratory Support in Trauma Group (TLSTG) previously reviewed all National Code Red activations between June 1st 2013 and October 31st 2015, generating a number of recommendations to be adopted to optimise the transfusion support given to patients following major trauma in Scotland. A repeat National survey was undertaken for all patients for whom Code Red was activated between 1st November 2015 and 31st December 2017. METHODS: A clinical and transfusion lead for each centre entered anonymised data onto a secure electronic database (REDCap). RESULTS: During the study period there were 66 activations (24 South-East of Scotland, 32 West, 10 East). Mean age was 45 years and 88% were male. Mean Injury Severity Score (ISS) was 28 with 75% blunt trauma. 93% (62/66) of Code Red patients received blood components with a 300% increase in pre-hospital transfusion (48 vs 16 patients; p<0.001). Median time from 999 call to Code Red activation reduced significantly to 37 min from 70 min (p = 0.01) giving the hospital more time to prepare transfusion components. 78% patients received pre-hospital tranexamic acid (TXA; improved from 70%, p = 0.67, ns). Concentrated Red Cell (CRC): Fresh Frozen Plasma (FFP) ratio was always less than 2:1 and below 1.4:1 at 90 min, compared to 2013-15 when CRC: FFP ratios did not drop to below 2:1 until 150 min after arrival in the ED. Mean time for Full Blood Count (FBC; 46 mins versus 81; p = 0.004) and clotting (53 mins versus 119; p<0.001) result was reduced. Survival to hospital discharge was unchanged (66% versus 63%; p = 1.00 ns). CONCLUSIONS: Code Red practice has improved in several ways since our last survey with earlier Code Red activation, more patients receiving pre-hospital transfusion and improved CRC:FFP ratios. Interventions such as earlier on scene Code Red activation, provision of pre-hospital TXA, Emergency Department (ED) resuscitation room pre-thawed FFP and point-of-care viscoelastic coagulation testing have all contributed to these improvements in transfusion practice in Scotland.

Prehospital critical care is associated with increased survival in adult trauma patients in Scotland.

BACKGROUND: Scotland has three prehospital critical care teams (PHCCTs) providing enhanced care support to a usually paramedic-delivered ambulance service. The effect of the PHCCTs on patient survival following trauma in Scotland is not currently known nationally. METHODS: National registry-based retrospective cohort study using 2011-2016 data from the Scottish Trauma Audit Group. 30-day mortality was compared between groups after multivariate analysis to account for confounding variables. RESULTS: Our data set comprised 17 157 patients, with a mean age of 54.7 years and 8206 (57.5%) of male gender. 2877 patients in the registry were excluded due to incomplete data on their level of prehospital care, leaving an eligible group of 14 280. 13 504 injured adults who received care from ambulance clinicians (paramedics or technicians) were compared with 776 whose care included input from a PHCCT. The median Injury Severity Score (ISS) across all eligible patients was 9; 3076 patients (21.5%) met the ISS>15 criterion for major trauma. Patients in the PHCCT cohort were statistically significantly (all p<0.01) more likely to be male; be transported to a prospective Major Trauma Centre; have suffered major trauma; have suffered a severe head injury; be transported by air and be intubated prior to arrival in hospital. Following multivariate analysis, the OR for 30-day mortality for patients seen by a PHCCT was 0.56 (95% CI 0.36 to 0.86, p=0.01). CONCLUSION: Prehospital care provided by a physician-led critical care team was associated with an increased chance of survival at 30 days when compared with care provided by ambulance clinicians.

Evaluation of the provision of helicopter emergency medical services in Europe.

BACKGROUND: Helicopter emergency medical services (HEMS) are a useful means of reducing inequity of access to specialist emergency care. The aim of this study was to evaluate the variations in HEMS provision across Europe, in order to inform the further development of emergency care systems. METHODS: This is a survey of primary HEMS in the 32 countries of the European Economic Area and Switzerland. Information was gathered through internet searches (May to September 2016), and by emailing service providers, requesting verification and completion of data (September 2016 to July 2017). HEMS provision was calculated as helicopters per million population and per 1000 km2 land area, by day and by night, and per US$10 billion of gross domestic product (GDP), for each country. RESULTS: In 2016, the smallest and least prosperous countries had no dedicated HEMS provision. Luxembourg had the highest number of helicopters by area and population, day and night. Alpine countries had high daytime HEMS coverage and Scandinavia had good night-time coverage. Most helicopters carried a doctor. Funding of services varied from public to charitable and private. Most services performed both primary (from the scene) and secondary (interfacility) missions. CONCLUSIONS: Within Europe, there is a large variation in the number of helicopters available for emergency care, regardless of whether assessed with reference to population, land area or GDP. Funding of services varied, and did not seem to be clearly related to the availability of HEMS.

Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse.

PROBLEM: Crry is a widely expressed type 1 transmembrane complement regulatory protein in rodents which protects self-tissue by downregulating C3 activation. Crry-/- concepti produced by Crry+/-  × Crry+/- matings are attacked by maternal complement system leading to loss before day 10. The membrane attack complex is not the mediator of this death. We hypothesized that the ability of C3b to engage the alternative pathway's feedback loop relatively unchecked on placental membranes induces the lesion yielding the demise of the Crry-/- mouse. METHOD OF STUDY: We investigated the basis of Crry-/- conceptus demise by depleting maternal complement with cobra venom factor and blocking antibodies. We monitored their effects primarily by genotyping and histologic analyses. RESULTS: We narrowed the critical period of the complement effect from 6.5 to 8.5 days post-coitus (dpc), which is immediately after the conceptus is exposed to maternal blood. Deposition by 5.5 dpc of maternal C3b on the placental vasculature lacking Crry-/- yielded loss of the conceptus by 8.5 dpc. Fusion of the allantois to the chorion during placental assembly did not occur, fetal vessels originating in the allantois did not infiltrate the chorioallantoic placenta, the chorionic plate failed to develop, and the labyrinthine component of the placenta did not mature. CONCLUSION: Our data are most consistent with the deposition of C3b being responsible for the failure of the allantois to fuse to the chorion leading to subsequent conceptus demise.

Clinician tasking in ambulance control improves the identification of major trauma patients and pre-hospital critical care team tasking.

INTRODUCTION: Trauma remains the fourth leading cause of death in western countries and is the leading cause of death in the first four decades of life. NICE guidance in 2016 advocated the attendance of pre-hospital critical care trauma team (PHCCT) in the pre-hospital stage of the care of patients with major trauma. Previous publications support dispatch by clinicians who are also actively involved in the delivery of the PHCCT service; however there is a lack of objective outcome measures across the current reviewed evidence base. In this study, we aimed to assess the accuracy of PHCCT clinician led dispatch, when measured by Injury Severity Score (ISS). METHODS: A retrospective cohort study over a 2 year period pre and post implementation of a PHCCT clinician led dispatch of PHCCT for potential major trauma patients, using national ambulance data combined with national trauma registry data. RESULTS: A total of 99,702 trauma related calls were made to SAS including 495 major trauma patients with an ISS >15, and a total of 454 dispatches of a PHCCT. Following the introduction of a PHCCT clinician staffed trauma desk, the sensitivity for major trauma was increased from 11.3% to 25.9%. The difference in sensitivity between the pre and post trauma desk group was significant at 14.6% (95% CI 7.4%-21.4%, p < .001). DISCUSSION: The results from the study support the results from other studies recommending that a PHCCT clinician should be located in ambulance control to identify major trauma patients as early as possible and co-ordinate the response.

Three- versus four-factor prothrombin complex concentrates for "factor-based" resuscitation in a porcine hemorrhagic shock model.

BACKGROUND: Bleeding is a leading cause of preventable death after severe injury. Prothrombin complex concentrates (PCC) treat inborn coagulation disorders and reverse oral anticoagulants, but are proposed for use in "factor-based" resuscitation strategies. Few studies exist for this indication in acidosis, or that compare 3-factor PCC (3PCC) versus 4-factor PCC (4PCC) products. We aimed to assess and compare their safety and efficacy in a porcine model of severe hemorrhagic shock and coagulopathy. METHODS: Twenty-five adult Yorkshire swine underwent 35% volume hemorrhage, ischemia-reperfusion injury, and protocolized crystalloid resuscitation. Seventeen animals were randomized at 4 hours after model creation to receive a 45-IU/kg dose of either 3PCC or 4PCC. An additional eight animals received autologous plasma transfusion before 4PCC to better characterize response to PCC. Individual factor levels were drawn at 4 hours and 6 hours. RESULTS: The model created significant acidosis with mean pH of 7.21 and lactate of 9.6 mmol/L. After PCC, 66.7% of 3PCC animals and 25% of 4PCC animals (regardless of plasma administration) developed consumptive coagulopathy. The animals that developed consumptive coagulopathy had manifested the "lethal triad" with lower temperatures (36.3°C vs. 37.8°C), increased acidosis (pH, 7.14 vs. 7.27; base excess, -12.1 vs. -6.5 mEq/L), and worse coagulopathy (prothrombin time, 17.1 vs. 14.6 seconds; fibrinogen, 87.9 vs. 124.1 mg/dL) (all p < 0.05). In the absence of a consumptive coagulopathy, 3PCC and 4PCC improved individual clotting factors with transient improvement of prothrombin time, but there was significant depletion of fibrinogen and platelets with no lasting improvement of coagulopathy. CONCLUSION: PCC failed to correct coagulopathy and was associated with fibrinogen and platelet depletion. Of greater concern, PCC administration resulted in consumptive coagulopathy in the more severely ill animals. The incidence of consumptive coagulopathy was markedly increased with 3PCC versus 4PCC, and these products should be used with caution in this setting.

Experience of implementing a National pre-hospital Code Red bleeding protocol in Scotland.

INTRODUCTION: The Scottish Transfusion and Laboratory Support in Trauma Group (TLSTG) have introduced a unified National pre-hospital Code Red protocol. This paper reports the results of a study aiming to establish whether current pre-hospital Code Red activation criteria for trauma patients successfully predict need for in hospital transfusion or haemorrhagic death, the current admission coagulation profile and Concentrated Red Cell (CRC): Fresh Frozen Plasma (FFP) ratio being used, and whether use of the protocol leads to increased blood component discards? METHODS: Prospective cohort study. Clinical and transfusion leads for each of Scotland's pre-hospital services and their receiving hospitals agreed to enter data into the study for all trauma patients for whom a pre-hospital Code Red was activated. Outcome data collected included survival 24h after Code Red activation, survival to hospital discharge, death in the Emergency Department and death in hospital. RESULTS: Between June 1st 2013 and October 31st 2015 there were 53 pre-hospital Code Red activations. Median Injury Severity Score (ISS) was 24 (IQR 14-37) and mortality 38%. 16 patients received pre-hospital blood. The pre-hospital Code Red protocol was sensitive for predicting transfusion or haemorrhagic death (89%). Sensitivity, specificity, positive and negative predictive values of the pre-hospital SBP <90mmHg component were 63%, 33%, 86% and 12%. 19% had an admission prothrombin time >14s and 27% had a fibrinogen <1.5g/L. CRC: FFP ratios did not drop to below 2:1 until 150min after arrival in the ED. 16 red cell units, 33 FFP and 6 platelets were discarded. This was not significantly increased compared to historical data. CONCLUSIONS: A National pre-hospital Code Red protocol is sensitive for predicting transfusion requirement in bleeding trauma patients and does not lead to increased blood component discards. A significant number of patients are coagulopathic and there is a need to improve CRC: FFP ratios and time to transfusion support especially FFP provision. Training clinicians to activate pre-hospital Code Red earlier during the pre-hospital phase may give blood bank more time to thaw and prepare FFP and may improve FFP administration times and ratios so long as components are used upon their availability.

Paediatric workload of an adult retrieval service in Scotland.

The Emergency Medical Retrieval Service (EMRS) provides adults with life-threatening conditions in remote areas with timely interventions and rapid access to definitive medical care, including a primary response service. Paediatric patients are managed under a separate network. Despite this, there has been an increase in paediatric retrievals by EMRS. We aim to inform future service development and ascertain how EMRS can serve the needs of this cohort. This is a retrospective, observational study. Raw data were retrieved from the database of paediatric patients retrieved by EMRS for 9 years. A total of 112 paediatric patients were retrieved; 46% were primary retrievals. The most common injuries were head injuries (n=29) and orthopaedic injuries (n=16). Common interventions include fluid resuscitation (n=34), ventilation (n=22) and sedation/paralysis (n=22).This study describes the evolution of an adult retrieval service to cover paediatric patients in Scotland outside the remit of the paediatric retrieval service.

Seeking Sepsis in the Emergency Department- Identifying Barriers to Delivery of the Sepsis 6.

The Sepsis 6 is an internationally accepted management bundle that, when initiated within one hour of identifying sepsis, can reduce morbidity and mortality. This management bundle was advocated by the Scottish Patient Safety Programme as part of its Acute Adult campaign launched in 2008 and adopted by NHS Tayside in 2012. Despite this, the Emergency Department (ED) of Ninewells Hospital, a tertiary referral centre and major teaching hospital in Scotland, was displaying poor success in the Sepsis 6. We therefore set out to improve compliance by evaluating the application of all aspects of the NHS Tayside Sepsis 6 bundle within one hour of ED triage time, to identify what human factors may influence achieving the one hour The Sepsis 6 bundle. This allowed us to tailor a number of specific interventions including educational sessions, regular audit and personal feedback and check list Sepsis 6 sticker. These interventions promoted a steady increase in compliance from an initial rate of 51.0% to 74.3%. The project highlighted that undifferentiated patients create a challenge in initiating the Sepsis 6. Pyrexia is a key human factor-trigger for recognising sepsis with initial nursing assessment being vital in recognition and identifying the best area (resus) of the department to manage severely septic patients. EDs need to recognise these challenges and develop educational and feedback plans for staff and utilise available resources to maximise the Sepsis 6 compliance.

Modeling and measurement of geometrically nonlinear damping in a microcantilever-nanotube system.

Nonlinear mechanical systems promise broadband resonance and instantaneous hysteretic switching that can be used for high sensitivity sensing. However, to introduce nonlinear resonances in widely used microcantilever systems, such as AFM probes, requires driving the cantilever to an amplitude that is too large for any practical applications. We introduce a novel design for a microcantilever with a strong nonlinearity at small cantilever oscillation amplitude arising from the geometrical integration of a single BN nanotube. The dynamics of the system was modeled theoretically and confirmed experimentally. The system, besides providing a practical design of a nonlinear microcantilever-based probe, demonstrates also an effective method of studying the nonlinear damping properties of the attached nanotube. Beyond the typical linear mechanical damping, the nonlinear damping contribution from the attached nanotube was found to be essential for understanding the dynamical behavior of the designed system. Experimental results obtained through laser microvibrometry validated the developed model incorporating the nonlinear damping contribution.

Capability of Scottish emergency departments to provide physician-based prehospital critical care teams: a national survey.

OBJECTIVE: The aim of this study was to establish the current capabilities of emergency departments in Scotland to provide a prehospital medical team at the request of the ambulance service. METHODS: A prospective telephone survey of all major emergency departments in Scotland was conducted, requesting information on their ability to provide a prehospital team, the configuration of the team and the equipment, transport, training and governance arrangements for this service. RESULTS: All 25 major emergency departments in Scotland responded to the survey (100% response). Eighteen departments (72%) were able to provide a prehospital team, with 15 (60%) able to provide a team 24 h/day. Team composition was variable and only one-third of teams were able to deploy within 15 min. In total, 50% of departments able to respond had received no requests in the preceding 12 months and only two departments had each received more than 50 requests. Less than half of the departments checked prehospital equipment on a weekly or a more frequent basis and only three departments provided ongoing training in prehospital care. CONCLUSION: The majority of emergency departments in Scotland are able to provide a prehospital team on the request of the ambulance service. There is high variability in the composition and seniority of the team, with less ability to provide a team out of hours. With two notable exceptions, the overall activation of these prehospital teams is infrequent, and there are significant improvements required with regard to the clinical governance surrounding the provision of these teams.

7-Substituted 8-aza-7-deazaadenosines for modification of the siRNA major groove.

Here we describe the synthesis of new 7-substituted 8-aza-7-deazaadenosine ribonucleoside phosphoramidites and their use in generating major groove-modified duplex RNAs. A 7-ethynyl analog leads to further structural diversification of the RNA via post-automated RNA synthesis azide-alkyne cycloaddition reactions. In addition, we report preliminary studies on the effects of eight different purine 7-position modifications on RNA duplex stability and pairing specificity. Finally, the effect on RNAi activity of this type of modification at eight different positions in an siRNA guide strand has been explored. Analogs were identified with large 7-position substituents that maintain adenosine pairing specificity and are well-tolerated at specific positions in an siRNA guide strand.

Click-based synthesis of triazolobithiazole ΔF508-CFTR correctors for cystic fibrosis.

Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1H-1,2,3-triazol-1-yl)-4,5'-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared to the benchmark bithiazole CF corrector corr-4a, improved logP values (4.5 vs 5.96).

Nucleophilic substitution of oxazino-/oxazolino-/benzoxazin [3,2-b]indazoles: an effective route to 1H-indazolones.

A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these indazoles is further demonstrated by ANRORC (addition of the nucleophile, ring-opening, and ring closure) reactions to yield isomeric pyrazoloindazolones by a process wherein iodide acts first as a nucleophile and subsequently as a leaving group.

The eye at altitude.

High altitude retinopathy (HAR) was first described in 1969 as engorgement of retinal veins with occasional papilloedema and vitreous hemorrhage. Since then various studies have attempted to define the incidence, etiology and significance of this phenomenon, usually with small numbers of subjects. Recently studies on relatively large groups of subjects in Nepal, Bolivia and Tibet have confirmed that the retinal vasculature becomes engorged and tortuous in all lowlanders ascending above 2500m. Sometimes this leads to hemorrhages, cotton wool spots and papilloedema, which is the pathological state better known as high altitude retinopathy. These studies have also shown a significant change in both corneal thickness and intraocular pressure at altitude. The retinal blood vessels are the only directly observable vascular system in the human body and also supply some of the most oxygen-demanding tissue, the photoreceptors of the retina. New techniques are being applied in both hypobaric chamber and field expeditions to observe changes in retinal function during conditions of hypobaric hypoxia. This work allows better advice to be given to lowlanders traveling to altitude either if they have pre-existing ocular conditions or if they suffer from visual problems whilst at altitude. This especially applies to the effect of altitude on refractive eye surgery and results of recent studies will be discussed so that physicians can advise their patients using the latest evidence. Retinal hypoxia at sea level accounts for the developed world's largest cause of blindness, diabetic retinopathy. The investigation of retinal response to hypobaric hypoxia in healthy subjects may open new avenues for treatment of this debilitating disease.

Nitric oxide involves in carnosine-induced hyperactivity in chicks.

Carnosine has been characterized as a putative neurotransmitter and implicated as having a possible role in neuron-glia cell interactions. We previously confirmed that central administration of carnosine induced hyperactivity in chicks. In the present study, we investigated the effects of nitric oxide (NO) synthase (NOS) inhibitors on carnosine-induced hyperactivity in chicks. Carnosine-induced (3.2 micromol) hyperactivity was attenuated by intracerebroventricular (i.c.v.) co-administration with a non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester HCl (200 and 400 nmol) in a dose-dependent manner, while the hyperactivity was not attenuated by the inactive isomer of the NOS inhibitor N(G)-nitro-D-arginine methyl ester HCl (400 nmol). The i.c.v. injection of a selective inhibitor of inducible NOS (iNOS) L-N(6)-(1-iminoethyl) lysine HCl (400 nmol) did not affect carnosine-induced hyperactivity. These results suggest that carnosine-induced hyperactivity may be linked to the constitutive NOS (cNOS), rather than iNOS, in the brain. Central carnosine may regulate brain function and/or behaviors by NO generation via cNOS in chicks.

Tooth in the perioral tissues: a complication of craniofacial trauma.

Dental examination is very important in any patient presenting with craniofacial trauma. Avulsed teeth must be accounted for as they can be found in distant anatomical sites with potential life-threatening complications.

Comparison of brain arginine-vasotocin and corticotrophin-releasing factor for physiological responses in chicks.

Arginine-vasotocin (AVT), a non-mammalian homologue of mammalian arginine-vasopressin, is a stress-related peptide in the brain of birds. The aim of the present study was to determine the effects of intracerebroventricular (ICV) injection of AVT on feeding behavior, body temperature, corticosterone release and several behavioral parameters in chicks. These effects were compared with those of corticotrophin-releasing factor (CRF), another stress-related peptide. The ICV injection of AVT inhibited feeding behavior, increased rectal temperature, and increased plasma corticosterone concentrations, but these effects were weaker than those of CRF. AVT induced hypoactivity as evidenced by decreased vocalization and stepping while CRF induced hyperactivity. The present results demonstrate that some functions of brain AVT are similar to those of CRF, although these effects are weaker than those induced by CRF. However, some AVT-induced behaviors were different from CRF, indicating that the physiological roles of AVT in the regulation of stress behavior are different from those of CRF in chicks.