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Introduction: Tranexamic acid (TXA) reduces bleeding and mortality. Recent trials have demonstrated improved survival with shorter intervals to TXA administration. The aims of this service evaluation were to assess the interval from injury to TXA administration and describe the characteristics of patients who received TXA pre-hospital and in-hospital.Methods: We reviewed Trauma and Audit Research Network records and local trauma registries to identify patients of any age that received TXA at all London Major Trauma Centres and Queen's Medical Centre, Nottingham, during 2017. We used the 2016 NICE Guidelines (NG39) which state that TXA should be given within 3 hours of injury.Results: We identified 1018 patients who received TXA, of whom 661 (65%) had sufficient data to assess the time from injury to TXA administration. The median interval was 74 min (IQR: 47-116). 92% of patients received TXA within 3 hours from injury, and 59% within 1 hour. Half of the patients (54%) received prehospital TXA. The median time to TXA administration when given prehospital was 51 min (IQR: 39-72), and 112 min (IQR: 84-160) if given in-hospital (p<0.001). In-hospital TXA patients had less haemodynamic derangement and lower base deficit on admission compared with patients given prehospital TXA.Conclusion: Prehospital administration of TXA is associated with a shorter interval from injury to drug delivery. Identifying a proportion of patients at risk of haemorrhage remains a challenge. However, further reinforcement is needed to empower pre-hospital clinicians to administer TXA to trauma patients without overt signs of shock. [ABSTRACT FROM AUTHOR]

A pilot study of an external quality assessment scheme was run between February 1985 and September 1986 to (i) assess the feasibility of running one from a district general hospital; (ii) to estimate the time required to organise and run it with a computer; (iii) to provide sound statistical results with which future schemes could be compared. Seven laboratories participated, and the 20 smears selected from each laboratory were circulated in three rounds in batches of seven, seven, and six according to a prearranged order. Results analysed using the kappa statistic showed moderate levels of interlaboratory agreement, with complete agreement emerging only on a small proportion of cases. [ABSTRACT FROM PUBLISHER]

The variation between two observers in grading 100 biopsies and the corresponding main specimens of rectal carcinomas has been examined. Using kappa statistics, which take account of chance agreement, we found a highly significant level of agreement. As expected, higher levels were obtained for intraobserver agreement. However, disagreements between observers were in many instances "haphazard" and there were differences in bias between them. Fifty paired biopsies and main tumours were graded by five observers and the results analysed for bias and by kappa statistics for overall and conditional agreement. These methods revealed significant overall agreement but the levels for some observer pairs did not differ significantly from chance. Examination for observer bias indicated differing standards of grading, and haphazard disagreements reached high levels for some observer pairs. The intraobserver agreement between the grade of the biopsy and the corresponding main tumour varied from 56-69% but only 52% of the poorly differentiated tumours were diagnosed as such in the preoperative biopsy by the "specialist" observer. The poor predictive value was not improved by taking multiple biopsies. We conclude that the grade of a rectal carcinoma cannot be accurately assessed on a preoperative biopsy and that this has serious implications for the management of low rectal cancers. Furthermore the wide discrepancies in diagnostic standards between some pathologists mean that studies on the treatment and prognosis of rectal cancer which utilise histological grade for comparison purposes must be viewed with considerable skepticism. [ABSTRACT FROM PUBLISHER]

Fourteen previously reported cases of atresia of the coronary sinus ostium, in which the coronary venous flow entered the right atrium by a persistent left superior vena cava, the innominate vein, and the right superior vena cava, are reviewed and two new cases reported. The first new case was in a 43 year old woman with atypical chest pains in whom investigations for suspected ischaemic heart disease, including coronary arteriography, yielded normal results. She died suddenly from massive myocardial infarction due to extensive old thrombotic occlusion of a major coronary artery without any appreciable underlying disease of the vessel wall. Exercise testing is considered to be advisable in symptomatic patients with normal coronary angiograms and attention to the venous phase might be informative. The second new case occurred in a child with an atrial septal defect and complete transposition of the great arteries, who died aged 1 month. [ABSTRACT FROM PUBLISHER]

Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95–0.99, P=4.6 × \(10^{−3}\)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96–1.01, P=0.139). Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Introduction International guidelines for the management Primary spontaneous pneumothorax (PSP) vary on the definition of size, and treatment of PSP. The American consensus based ACCP guidelines recommend removal of air via an intercostal drain (ICD) in large PSP, and the BTS guidance suggest needle aspiration (NA) first, with quoted success rates of 30%-80%. In 2005/6 there were 5954 finished consultant episodes for PSP in England. Methods We performed a retrospective audit of PSP presenting to the Emergency Department (ED) over a 24-month period. Electronic patient records (ED and inpatient) were keyword searched for "pneumothorax" and x-rays were interrogated. We used HRG code DZ26B ("Pneumothorax without complications"), with a tariff of £1840.83 per episode to calculate cost implications. Measure of agreement of PSP size was assessed with Cohen's κ. Results 43 confirmed pneumothorax cases were identified, 37 PSP. Of those with PSP: mean (SD) age was 28 (6.9) years, 31 (84%) were male, 23 (62%) were right sided. See Abstract P35 table 1 for assessment of PSP size. 21 (56.8%) had NA, successfully in 8 (38%). 17 (46%) patients had an ICD placed; 12 (70.6%) with <14F drains. Median length of stay following ICD was 5 (IQR 2 12) days. 28 e (75.6%) had appropriate adherence to BTS guidelines (4 (10.8%) were not aspirated, 5 (13.5%) had a large, rather than small, ICD). 14 (37.8%) patients were sent for thoracoscopic surgery (on site), 4 (9.2%) PSP not resolving, 10 due to ipsi-, or contralateral, reoccurrence of PSP. If Nationally 10% of patients do not have NA as first line treatment, then (assuming a 40% success rate), this may be costing the NHS in England up to £438 412 a year in preventable admissions. Adherence to ACCP guidance would cost the NHS in England an extra £3.9 million in additional ICDs and hospital admissions. Conclusions ACCP and BTS guidance on PSP size have only poor-fair agreement. Local practice to increase NA rates and use of small drains should be adopted. Adherence to appropriate National guidelines has large healthcare economic implications. [ABSTRACT FROM AUTHOR]

Introduction: Tranexamic acid (TXA) reduces bleeding and mortality. Recent trials have demonstrated improved survival with shorter intervals to TXA administration. The aims of this service evaluation were to assess the interval from injury to TXA administration and describe the characteristics of patients who received TXA pre-hospital and in-hospital., Methods: We reviewed Trauma and Audit Research Network records and local trauma registries to identify patients of any age that received TXA at all London Major Trauma Centres and Queen's Medical Centre, Nottingham, during 2017. We used the 2016 NICE Guidelines (NG39) which state that TXA should be given within 3 hours of injury., Results: We identified 1018 patients who received TXA, of whom 661 (65%) had sufficient data to assess the time from injury to TXA administration. The median interval was 74 min (IQR: 47-116). 92% of patients received TXA within 3 hours from injury, and 59% within 1 hour. Half of the patients (54%) received prehospital TXA. The median time to TXA administration when given prehospital was 51 min (IQR: 39-72), and 112 min (IQR: 84-160) if given in-hospital (p<0.001). In-hospital TXA patients had less haemodynamic derangement and lower base deficit on admission compared with patients given prehospital TXA., Conclusion: Prehospital administration of TXA is associated with a shorter interval from injury to drug delivery. Identifying a proportion of patients at risk of haemorrhage remains a challenge. However, further reinforcement is needed to empower pre-hospital clinicians to administer TXA to trauma patients without overt signs of shock., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Skeletal muscle perfusion during exercise is impaired in heart failure, but the underlying mechanisms are poorly understood. One possibility is that sympathetic vasoconstriction is enhanced in exercising muscle in heart failure as a result of impaired counterregulatory mechanisms that normally act to attenuate vasoconstrictor responses. In healthy animals, sympathetic vasoconstriction in contracting skeletal muscle is attenuated by endogenously produced nitric oxide (NO). Because the NO pathway may be dysfunctional in heart failure, we hypothesized that reduced NO in contracting muscle would result in enhanced sympathetic vasoconstriction. In sham rats and rats with chronic myocardial infarctions (MIs) produced by coronary artery ligation, we measured arterial pressure and femoral artery blood flow responses to sympathetic nerve stimulation (1, 2.5, and 5 Hz) in resting and contracting hindlimb. In resting hindlimb, sympathetic stimulation decreased femoral vascular conductance similarly in sham and MI rats. In contracting hindlimb, these vasoconstrictor responses were attenuated to a greater extent in sham than in MI rats. NO synthase inhibition enhanced sympathetic vasoconstriction in contracting hindlimb of sham, but not MI, rats. Conversely, infusion of L-arginine or a superoxide scavenger, tempol or tiron, attenuated sympathetic vasoconstriction in contracting hindlimb of MI rats. NO synthase expression was similar, but malondialdehyde (a marker of free radical damage) was greater in skeletal muscle from MI than from sham rats. These data suggest that impaired metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle of MI rats is a consequence of superoxide-mediated disruption of the NO pathway.

Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to alpha-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD.

Sympathetically evoked vasoconstriction is modulated by skeletal muscle contraction, but the underlying events are incompletely understood. During contraction, intramuscular oxygenation decreases with increasing exercise intensity. We therefore hypothesized that tissue hypoxia plays a crucial role in the attenuation of sympathetic vasoconstriction in contracting skeletal muscle. In 19 subjects, near-infrared spectroscopy was used to measure decreases in muscle oxygenation (DeltatHbO2+MbO2) as an estimate of the vasoconstrictor response to reflex sympathetic activation with lower body negative pressure (LBNP) in the microcirculation of resting and contracting forearm muscles. Oxygen delivery to the muscles was reduced by decreasing (a) arterial O2 content by breathing 10 % O2, or (b) muscle perfusion by applying forearm positive pressure (FPP, +40 mmHg). In resting forearm, reflex sympathetic activation decreased muscle oxygenation by 11 +/- 1 %. Handgrip alone at 5 and 20 % of maximal voluntary contraction (MVC) decreased muscle oxygenation by 4 +/- 1 and 28 +/- 4 %, respectively. When superimposed on handgrip, LBNP-induced decreases in muscle oxygenation were preserved during handgrip at 5 % MVC, but were abolished during handgrip at 20 % MVC. Oral administration of aspirin (1 g) did not restore the latter response. When the decrease in forearm muscle oxygenation elicited by handgrip at 20 % MVC was mimicked by either (a) systemic hypoxia plus 5 % handgrip (DeltatHbO2+MbO2, -32 +/- 3 %), or (b) hypoperfusion of resting muscle by FPP (DeltatHbO2+MbO2, -26 +/- 6 %), LBNP-induced decreases in muscle oxygenation were greatly attenuated. These data suggest that local tissue hypoxia is involved in the metabolic attenuation of sympathetic vasoconstriction in the microcirculation of exercising human skeletal muscle. The specific underlying mechanism remains to be determined, although products of the cyclo-oxygenase pathway do not appear to be involved.