What drives junior doctors to use clinical practice guidelines? A national cross-sectional survey of foundation doctors in England & Wales.

BACKGROUND: Clinical practice guidelines (CPGs) aim to improve patient care, but their use remains variable. We explored attitudes that influence CPG use amongst newly qualified doctors. METHODS: A self-completed, anonymous questionnaire was sent to all Foundation Doctors in England and Wales between December 2012 and May 2013. We included questions designed to measure the 11 domains of the validated Theoretical Domains Framework (TDF). We correlated these responses to questions assessing current and future intention to use CPGs. RESULTS: A total of 13,138 doctors were invited of which 1693 [corrected] (13 %) responded. 1,035 (62.5 %) reported regular CPG use with 575 (34.4 %) applying CPGs 2-3 times per week. A significant minority of 606 (36.6 %) declared an inability to critically appraise evidence. Despite efforts to design a questionnaire that captured the domains of the TDF, the domain scales created had low internal reliability. Using previously published studies and input from an expert statistical group, an alternative model was sought using exploratory factor analysis. Five alternative domains were identified. These were judged to represent: "confidence", "familiarity", "commitment and duty", "time" and "perceived benefits". Using regression analyses, the first three were noted as consistent predictors of both current and future intentions to use CPGs in decreasing strength order. CONCLUSIONS: In this large survey of newly qualified doctors, "confidence", "familiarity" and "commitment and duty" were identified as domains that influence use of CPGs in frontline practice. Additionally, a significant minority were not confident in critically appraising evidence. Our findings suggest a number of approaches that may be taken to improve junior doctors' commitment to CPGs through processes that increase their confidence and familiarity in using CPGs. Despite limitations of a self-reported survey and potential non-response bias, these findings are from a large representative sample and a review of existing implementation strategies may be warranted based on these findings.

Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide.

AIMS/HYPOTHESIS: Plasma ceramide concentrations correlate with insulin sensitivity, inflammation and atherosclerotic risk. We hypothesised that plasma ceramide concentrations are increased in the presence of elevated fatty acid levels and are regulated by increased liver serine C-palmitoyltransferase (SPT) activity. METHODS: Lean humans and rats underwent an acute lipid infusion and plasma ceramide levels were determined. One group of lipid-infused rats was administered myriocin to inhibit SPT activity. Liver SPT activity was determined in lipid-infused rats, and obese, insulin resistant mice. The time and palmitate dose-dependent synthesis of intracellular and secreted ceramide was determined in HepG2 liver cells. RESULTS: Plasma ceramide levels were increased during lipid infusion in humans and rats, and in obese, insulin-resistant mice. The increase in plasma ceramide was not associated with changes in liver SPT activity, and inhibiting SPT activity by ~50% did not alter plasma ceramide levels in lipid-infused rats. In HepG2 liver cells, palmitate incorporation into extracellular ceramide was both dose- and time-dependent, suggesting the liver cells rapidly secreted the newly synthesised ceramide. CONCLUSIONS/INTERPRETATION: Elevated systemic fatty acid availability increased plasma ceramide but this was not associated with changes in hepatic SPT activity, suggesting that liver ceramide synthesis is driven by substrate availability rather than increased SPT activity. This report also provides evidence that the liver is sensitive to the intracellular ceramide concentration, and an increase in liver ceramide secretion may help protect the liver from the deleterious effects of intracellular ceramide accumulation.

Should warfarin or aspirin be stopped prior to prostate biopsy? An analysis of bleeding complications related to increasing sample number regimes.

AIM: To determine whether patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy with increased sampling numbers are more likely to experience bleeding complications and whether warfarin or low-dose aspirin are independent risk factors. MATERIALS AND METHODS: 930 consecutive patients with suspected prostatic cancer were followed up after biopsy. Warfarin/low-dose aspirin was not stopped prior to the procedure. An eight to 10 sample regime TRUS-guided prostate biopsy was performed and patients were offered a questionnaire to complete 10 days after the procedure, to determine any immediate or delayed bleeding complications. RESULTS: 902 patients returned completed questionnaires. 579 (64.2%) underwent eight core biopsies, 47 (5.2%) underwent nine, and 276 (30.6%) underwent 10. 68 were taking warfarin [mean international normalized ratio (INR) = 2.5], 216 were taking low-dose aspirin, one was taking both, and 617 were taking neither. 27.9% of those on warfarin and 33.8% of those on aspirin experienced haematuria. 37% of those on no blood-thinning medication experienced haematuria. 13.2% of those on warfarin and 14.4% of those on aspirin experienced rectal bleeding. 11.5% of those on no blood-thinning medication experienced rectal bleeding. 7.4% of those on warfarin and 12% of those on aspirin experienced haematospermia. 13.8% of those on neither experienced haematospermia. Regression analysis showed a significant association between increasing sampling number and occurrence of all bleeding complication types. There was no significant association between minor bleeding complications and warfarin use; however, there was a significant association between minor bleeding complications and low-dose aspirin use. There was no severe bleeding complication. CONCLUSION: There is an increased risk of bleeding complications following TRUS-guided prostate biopsy with increased sampling numbers but these are minor. There is also an increased risk with low-dose aspirin use; however, there is no increased risk of bleeding complications with warfarin use. These results suggest that up to 10 cores during prostate biopsy remains acceptable safe practice and cessation of warfarin and low-dose aspirin is usually not necessary.

Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice.

AIMS/HYPOTHESIS: Hepatic steatosis is characterised by excessive triacylglycerol accumulation and is strongly associated with insulin resistance. An inability to efficiently mobilise liver triacylglycerol may be a key event mediating hepatic steatosis. Adipose triacylglycerol lipase (ATGL) is a key triacylglycerol lipase in the liver and we hypothesised that liver-specific overproduction of ATGL would reduce steatosis and enhance insulin action in obese rodents. METHODS: Studies of fatty acid metabolism were conducted in primary hepatocytes isolated from wild-type and Atgl (also known as Pnpla2)⁻(/)⁻ mice. An ATGL adenovirus was utilised to overproduce ATGL in the livers of obese insulin-resistant C57Bl/6 mice (Ad-ATGL). Blood chemistry, hepatic lipid content and insulin sensitivity were assessed in mice. RESULTS: Triacylglycerol content was increased in Atgl⁻(/)⁻ hepatocytes and was associated with increased fatty acid uptake and impaired fatty acid oxidation. ATGL adenovirus administration in obese mice increased the production of hepatic ATGL protein and reduced triacylglycerol, diacylglycerol and ceramide content in the liver. Overproduction of ATGL improved insulin signal transduction in the liver but did not affect fasting glycaemia or insulinaemia. Inflammatory signalling was not suppressed by ATGL overproduction. While ATGL overproduction increased plasma non-esterified fatty acids, neither lipid deposition nor insulin-stimulated glucose uptake were affected in skeletal muscle. CONCLUSIONS/INTERPRETATION: Liver ATGL overproduction decreases hepatic steatosis and mildly enhances liver insulin sensitivity. These effects are not sufficient to improve fasting glycaemia or insulinaemia in rodent obesity.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1ß involves reductions in long-chain acyl-CoA levels and oxidative stress.

AIMS/HYPOTHESIS: To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1ß [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance. METHODS: Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1ß in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1ß on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. RESULTS: Pgc-1ß gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1ß. In rats fed a HFD, increasing the levels of Pgc-1ß partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. CONCLUSIONS: Our data show that an increase in Pgc-1ß expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

Effect of Teflon Transmittance on Sensitivity of Thermoluminescence Dosimeter Cards.

Thermoluminescence dosimeter cards purchased by the US Navy in recent years have different radiation sensitivities, e.g., they exhibit a different amount of light per dose unit. Presented tests indicate that the optical transparency of the Teflon encapsulation is partially responsible for the significant variation of the DT-702/PD radiation sensitivity. It was confirmed also that the Teflon transparency is in fact a primary cause of the radiation sensitivity increase in the most recently produced dosimetric cards. This conclusion is based on the correlation found between the calibrated radiation sensitivity of the dosimeter card element and the optical transparency of its Teflon encapsulation. The transparency measurements were performed at the wavelength of 400 nm within a 10 nm spectral interval effectively covering the spectral range of the thermoluminescence. It is anticipated that the experimentally determined correlation will help to approve the acceptance of new thermoluminescence dosimeter cards in the Naval Dosimetry Center inventory as well as improve the production process.

Serum myeloperoxidase concentration in a healthy population: biological variations, familial resemblance and new genetic polymorphisms.

Myeloperoxidase (MPO) has been involved in the pathogenesis of several diseases through excessive production of reactive oxygen species (ROS) as well as through its genetic polymorphism. The aims of this study were to identify the factors affecting MPO serum concentration, to study the familial resemblance of MPO levels and to investigate the association between newly described MPO polymorphisms as well as the G-463A one and MPO levels in a healthy population. MPO serum concentrations were measured by an enzymatic immuno-assay (EIA) in 82 healthy families of the STANISLAS Cohort and MPO genotype, determination was performed using PCR-restriction fragment length polymorphism or allele specific oligonucleotide assay. MPO concentrations were significantly higher in parents than in offspring. The factors affecting MPO levels were age, the number of white cells, smoking in fathers and oral contraceptive intake in mothers. They explain from 12.4% up to 35.9% of MPO variability in men and women, respectively. Family correlations of MPO concentrations were of similar magnitude. The -129A allele of a newly described G-129A substitution was significantly associated with decreased MPO levels, whereas the -463A allele was suggested to be associated with increased levels of lipid variables. In this study, we identified factors affecting MPO serum concentrations and showed that molecular variations of the gene have only a weak influence on MPO variability. In contrast, the association between the G-463A polymorphism and lipid levels would suggest a possible implication of MPO in the risk of cardiovascular diseases. These results have to be confirmed and further investigations will be conducted in that way.

Effect of a smooth muscle relaxant from the stonefish, Synanceia trachynis, on KCl-induced responses in the guinea-pig vas deferens.

Stonefish skin secretion contains a smooth muscle relaxant, synancein II, that selectively inhibits tonic responses of KCl-induced contractions of the guinea-pig vas deferens. Synancein II (5-50 micrograms/ml) and nifedipine (10(-8)-10(-7) M) reduced tonic responses equally. Over these concentrations, synancein II inhibited phasic responses more than did nifedipine. Rapid inhibition of phasic responses by synancein II (low concentrations) but its inability to block this response at high concentrations suggests that more than one extracellular and/or intracellular Ca2+ source may contribute to the generation of the phasic response. Some calcium antagonists selectively inhibit tonic responses induced by KCl in many different organs, whilst others inhibit phasic responses. Whereas we previously reported that synancein II selectively inhibits phasic rather than tonic responses in the guinea-pig ileum, the present results reveals a reversal of this selectivity.

Effect of apolipoprotein E on cell viability in a human neuroblastoma cell line: influence of oxidation and lipid-association.

Apolipoprotein E (apoE) whose polymorphic expression is widely associated with Alzheimer's disease (AD) is one of the most studied protein present in cerebral amyloid deposits. Native or fragments of apoE are known to exert neurotoxic effects. We evaluated the effects of apoE oxidation and lipid-association on the viability of human neuroblastoma IMR32 cells. We show that apoE affects cell viability only when it is lipid-associated and applied at a concentration near to that found in plasma, and this whatever the isoform. Oxidized phospholipid-associated apoE has a similar impact on cell viability. These findings show the necessity of including apoE into phospholipids when studying its effect on cell metabolism and underline the probable intervention of surface heparan sulfate proteoglycans (HSPG). It also warrants further studies in order to delineate the pathophysiological importance of apoE.

Comparative action of three major ciguatoxins on guinea-pig atria and ilea.

The actions of pure ciguatoxin-1, ciguatoxin-2 and ciguatoxin-3 were assessed on the contractile activity of isolated guinea-pig left atria and ilea. Low concentrations of each ciguatoxin caused transient positive inotropy, whereas moderate concentrations induced transient and sustained positive inotropic phases. The transient positive inotropic phase was inhibited by tetrodotoxin or atenolol, indicating this phase stems from indirect effects of the ciguatoxins via the stimulation of intrinsic adrenergic nerves. On atria pretreated with atropine and alpha- and beta-adrenoceptor antagonists to block neural actions of the ciguatoxins, moderate concentrations of each ciguatoxin induced only slowly developing, sustained positive inotropy. ED50s for the indirect positive inotropic phase were 2.7 x 10(-11), 1.6 x 10(-10) and 1.4 x 10(-11) M and for the direct positive inotropic phase were 1.6 x 10(-10), 1.4 x 10(-9) and 1.5 x 10(-9) M for ciguatoxin-1, -2 and -3, respectively, indicating that their effects on neurons are 10-fold (ciguatoxin-1 and -2) to 100-fold (ciguatoxin-3) more potent than those directly on the myocardium. High concentrations of each ciguatoxin additionally induced sustained negative inotropy which could be reversed by lidocaine. On guinea-pig ilea, each ciguatoxin induced a transient contracture which could be abolished by atropine. Each ciguatoxin significantly reduced the contractile response of ilea to nicotine, without affecting the contractile response to acetylcholine. We conclude that ciguatoxin-1, -2 and -3 activate similarly the voltage-dependent Na+ channels in neuronal and myocardial tissues, but vary in their relative affinity for the Na+ channels in these tissues.

Ciguatera and mannitol: in vivo and in vitro assessment in mice.

Mannitol (1 g/kg i.v.) is currently the treatment of choice for acute ciguatera, but confirmation of this treatment's apparent efficacy awaits further experimental or controlled clinical evidence. In mice, mannitol (1 g/kg i.v.) administered before or after i.p. ciguatoxin did not influence the signs of intoxication or the time to death. The effects of oral ciguatoxin differed from those following i.p. ciguatoxin, but again i.v. mannitol provided no detectable benefit. Development of hypothermia was rapid in mice receiving i.p. or oral ciguatoxin and was unaffected by i.v. mannitol. A sublethal i.p. dose of ciguatoxin initially retarded (day 0-4) but then accelerated (day 4-12) the growth of mice. Mannitol (i.v.) had no influence on these effects of ciguatoxin on the growth of mice. Ciguatoxin inhibited responses of isolated diaphragms to nerve stimulation (ED50 = 9 x 10(-11) M), while directly stimulated diaphragms were inhibited by five-fold higher concentrations. Mannitol (50 mM) added to the organ bath did not influence the ciguatoxin-induced inhibition of diaphragm responses to nerve stimulation in vitro. Responses of isolated diaphragm to nerve stimulation were normal in preparations removed from ciguatoxin-treated mice displaying pronounced dyspnoea (gasping). However, responses to nerve stimulation were reduced in preparations removed from mice immediately following death from ciguatoxin. Mannitol (i.v.) partially protected the phrenic nerve-diaphragm from this effect of ciguatoxin in vivo. We conclude that the lethal effects of ciguatoxin in mice probably stem from a central action, and suggest that species differences may account for the absence of any marked beneficial effect of i.v. mannitol in the mouse model for ciguatera in humans.

Action of ciguatoxin on human atrial trabeculae.

This report describes the action of ciguatoxin-1, the major ciguatoxin present in fishes that cause ciguatera, on the contractile activity of human cardiac musculature. Ciguatoxin-1 caused a large, sustained and concentration-dependent positive inotropy in human atrial trabeculae that were obtained during coronary artery bypass surgery from otherwise healthy hearts. Atenolol (a beta 1-adrenoceptor selective antagonist without local anaesthetic-type activity) or low concentrations of tetrodotoxin abolished the positive inotropy caused by ciguatoxin-1, indicating that ciguatoxin-1 stimulated neural elements present in this tissue to release noradrenaline. The positive inotropic action of ciguatoxin-1 did not stem from a significant direct action on myocardial voltage-dependent sodium channels, nor did it stem from significant alpha 1- or beta 2-adrenoreceptor stimulation. Ciguatoxin-1 caused positive inotropy in preparations stimulated at between 0.02 and 2.0 Hz. Mannitol, currently the treatment of choice for ciguatera, did not significantly reverse the positive inotropy induced by ciguatoxin-1 in human atrial trabeculae.

Prefabricated functional braces for the treatment of fractures of the tibial diaphysis.

We have reviewed our experiences with prefabricated functional braces in the treatment of diaphyseal tibial fractures. The braces were developed in an attempt to reduce the occasional technical difficulties encountered with the use of custom-made braces. Between January 1979 and July 1983 we treated 625 diaphyseal tibial fractures. One hundred and eighty-six patients (29.8 per cent) were lost to follow-up, the braces had to be discontinued in thirty-eight (9.2 per cent), and ten fractures (2.5 per cent) failed to unite. We conducted careful radiographic and clinical analyses of the remaining 391 patients. Two hundred and fifty-seven (65.7 per cent) of the fractures were closed and 134 (34.3 per cent) were open. Three hundred and fifty-seven (91.2 per cent) of the patients had ten millimeters of final shortening or less, and 306 (78.3 per cent) had a final angulation of 5 degrees or less. The average time from injury to bracing was 3.9 weeks (range, one to twelve weeks) for the closed fractures and 5.0 weeks (range, one to twelve weeks) for the open fractures. These findings appear to support our concept that function of the extremity is beneficial to osteogenesis and that many diaphyseal tibial fractures can be satisfactorily stabilized in prefabricated functional braces. These braces also have the advantage of not immobilizing the adjacent joints and they permit the gradual restoration of weight-bearing.

["Linguistitis" of medical terminology (I)]. / Lingvistitis terminologiae medicinae (I).

A 1994/95 survey on language and terminology in emergency wards revealed a number of contradictory tendencies within today's Danish medical terminology. On the one hand, an increasing number of medical terms are nationalized. This tendency is reflected not only in intercollegial language, but also in the Danish version of the ICD-10 where a number of official diagnostic terms are casually translated into Danish or undergo various degrees of nationalization to appear as hybrids. On the other hand, knowledge of English becomes increasingly important: good passive command of the language is a must for medical students, and doctors committed to research need a good active command as well. This situation raises a number of questions: is there a need for setting up criteria for the terminology used in Danish medical literature and encyclopedia in order to avoid confusion, and for defining a language policy for future medical doctors?

["Linguistitis" of medical terminology (II). Language-policy and questions from a perspective of younger physicians]. / Lingvistitis terminologiae medicinae (II). Sprogpolitiske spørgsmål set i lyset af nogle yngre laegers holdninger.

In a previous article in the Journal of the Danish Medical Association, "Medical Terminology Linguistitis (I)", the author pointed out the importance of involving the users in connection with the definition of a language policy concerning Danish medical terminology and future medical doctors' need for language proficiency. A recent inquiry, involving 11 medical doctors (Ph.D. students), suggests that there is in fact a need for a language policy. Also, the respondents expressed strong antipathy against a full nationalization of the terms which can in some cases be observed in the Danish version of ICD-10. On the basis of this survey, the following questions are discussed in this article: Future medical doctors' need for knowledge of Latin and English, medical doctors' opinions concerning a terminology based on Latin, or Danish, and some important aspects concerning the definition of a language policy in the medical area.