Unintended consequences of policy change to watchful waiting for asymptomatic inguinal hernias.

INTRODUCTION: In 2009 the Department of Health instructed McKinsey & Company to provide advice on how commissioners might achieve world class National Health Service productivity. Asymptomatic inguinal hernia repair was identified as a potentially cosmetic procedure, with limited clinical benefit. The Birmingham and Solihull primary care trust cluster introduced a policy of watchful waiting for asymptomatic inguinal hernia, which was implemented across the health economy in December 2010. This retrospective cohort study aimed to examine the effect of a change in clinical commissioning policy concerning elective surgical repair of asymptomatic inguinal hernias. METHODS: A total of 1,032 patients undergoing inguinal hernia repair in the 16 months after the policy change were compared with 978 patients in the 16 months before. The main outcome measure was relative proportion of emergency repair in groups before and after the policy change. Multivariate binary logistic regression was used to adjust the main outcome for age, sex and hernia type. RESULTS: The period after the policy change was associated with 59% higher odds of emergency repair (3.6% vs 5.5%, adjusted odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.03-2.47). In turn, emergency repair was associated with higher odds of adverse events (4.7% vs 18.5%, adjusted OR: 3.68, 95% CI: 2.04-6.63) and mortality (0.1% vs 5.4%, p<0.001, Fisher's exact test). CONCLUSIONS: Introduction of a watchful waiting policy for asymptomatic inguinal hernias was associated with a significant increase in need for emergency repair, which was in turn associated with an increased risk of adverse events. Current policies may be placing patients at risk.

Blast injury to the perineum.

Recent military operations have resulted in a small but significant number of military personnel suffering severe perineal injuries. In association with lower limb amputation and pelvic fracture, this complex is described as the 'signature injury' of the current conflict in Afghanistan. There are significant consequences of surviving severe perineal injury but the experience of managing these casualties is limited. This article gives an overview of the processes developed to meet these challenges and introduces a series of articles which examine the subject in finer detail.

Minimum energy structure of hydridotris(pyrazolyl)borato iridium(V) tetrahydride is not a C(3upsilon) capped octahedron.

Recent synthesis and NMR spectroscopy of neutral Ir(V) complexes hydridotris(3,5-dimethylpyrazol-1-yl)borato tetrahydride (Tp*IrH(4)) and hydridotris(pyrazol-1-yl)borato tetrahydride (TpIrH(4)) have been interpreted as supporting face-capped octahedral structures (C(3upsilon)) with each of three Ir-H bonds trans to an Ir-N bond and the fourth hydride capping the IrH(3) face. Here, density functional geometry optimizations and coupled cluster calculations on hydridotris(pyrazol-1-yl)borato iridium tetrahydrogen find that a C(s) edge-bridged octahedral tetrahydride structure and a C(1) eta(2)-dihydrogen, dihydride structure are local minima and find that the C(3upsilon) structure is a local maximum (second-order saddle point). Several low energy transition states connecting the local minima have been located, and these minima can be used to simulate the experimental NMR spectra. A comparison of the experimental infrared spectrum of Tp*IrH(4) and the harmonic frequency calculations on the C(s), C(1), and C(3upsilon) structures also supports the assignment of the C(s)and C(1) structures as the observed ones.

Exploring surfaces and cavities in lipoxygenase and other proteins by hyperpolarized xenon-129 NMR.

This paper presents an exploratory study of the binding interactions of xenon with the surface of several different proteins in the solution and solid states using both conventional and hyperpolarized (129)Xe NMR. The generation of hyperpolarized (129)Xe by spin exchange optical pumping affords an enhancement by 3-4 orders of magnitude of its NMR signal. As a result, it is possible to observe Xe directly bound to the surface of micromolar quantities of lyophilized protein. The highly sensitive nature of the (129)Xe line shape and chemical shift are used as indicators for the conditions most likely to yield maximal dipolar contact between (129)Xe nuclei and nuclear spins situated on the protein. This is an intermediate step toward achieving the ultimate goal of NMR enhancement of the binding-site nuclei by polarization transfer from hyperpolarized (129)Xe. The hyperpolarized (129)Xe spectra resulting from exposure of four different proteins in the lyophilized, powdered form have been examined for evidence of binding. Each of the proteins, namely, metmyoglobin, methemoglobin, hen egg white lysozyme, and soybean lipoxygenase, yielded a distinctly different NMR line shape. With the exception of lysozyme, the proteins all possess a paramagnetic iron center which can be expected to rapidly relax the (129)Xe and produce a net shift in its resonance position if the noble gas atom occupies specific binding sites near the iron. At temperatures from 223 to 183 K, NMR signals were observed in the 0-40 ppm chemical shift range, relative to Xe in the gas phase. The signals broadened and shifted downfield as the temperature was reduced, indicating that Xe is exchanging between the gas phase and internal or external binding sites of the proteins. Additionally, conventional (129)Xe NMR studies of metmyoglobin and lipoxygenase in the solution state are presented. The temperature dependence of the chemical shift and line shape indicate exchange of Xe between adsorption sites on lipoxygenase and Xe in the solvent on the slow to intermediate exchange time scale. The NMR results are compared with N(2), Xe, and CH(4) gas adsorption isotherms. It is found that lipoxygenase is unique among the proteins studied in possessing a relatively high affinity for gas molecules, and in addition, demonstrating the most clearly resolved adsorbed (129)Xe NMR peak in the lyophilized state.

Candida species and C. albicans biotypes in women attending clinics in genitourinary medicine.

Yeasts were isolated from two or more anatomical sites in 198 women attending genitourinary clinics on at least two occasions. The yeast biotypes isolated concurrently from the vagina and urethra were the same in 138 (99%) of 140 instances, and 94% of 124 concurrent genital and anal isolates were of matching types, whereas only 75% of concurrent genital and oral isolates were of the same type. Mixtures of Candida spp. or C. albicans biotypes were encountered only five times among 545 yeast-positive samples. In instances where Candida spp. were isolated at successive times from the same site in a patient, the same yeast type was encountered on 97 (87%) of 112 occasions when the interval between samples was less than 15 weeks, and on 19 (66%) of 29 occasions when the interval was 15 weeks or more. These data indicate a tendency to carriage of phenotypically consistent types of Candida among most women attending genitourinary clinics.

Effects of azole antifungals in vitro on host/parasite interactions relevant to Candida infections.

Clotrimazole, fluconazole, itraconazole and ketoconazole were tested for their influence on three aspects of host/parasite interactions in the context of Candida infections. None of clotrimazole, itraconazole or ketoconazole had any effect on the adherence of C. albicans to vaginal epithelial cells, in vitro, regardless of whether the drugs were used to pretreat the fungi or the vaginal cells or were added to the fungus/vaginal cell mixture. Clotrimazole pretreatment of polymorphonuclear leucocytes led to a marked suppression of their ability to phagocytose and kill C. albicans, but fluconazole and ketoconazole had no similar effect. None of these three antifungals affected phagocytosis or killing when they were added to the leucocyte candida mixture or when used to pretreat the fungi. Clotrimazole and ketoconazole both reduced proliferative responses of lymphocyte suspensions to mitogens but fluconazole showed no anti-lymphocyte effect. This difference in action against lymphocytes may help to explain the known disparity between the antifungal effects of fluconazole and ketoconazole against C. albicans in vivo and against experimental candida infections in vitro. Clotrimazole effected a suppression of ATP concentrations in lymphocytes but fluconazole and ketoconazole had no similar effects.

Candida concentrations in the vagina and their association with signs and symptoms of vaginal candidosis.

Among 106 women harbouring yeasts in the vagina and with other causes of genital pathology excluded, there was a statistically significant association between numbers of yeasts recovered semi-quantitatively from vaginal swabs and symptoms of pruritus and signs of abnormal vaginal discharge but no association between yeast numbers and other individual symptoms or signs of vaginal candidosis, including patients' own subjective assessment of abnormal vaginal discharge. The presence of yeasts detectable by direct microscopic examination was statistically associated with pruritus, discharge and vaginitis. There was no relationship between numbers of vaginal yeasts and histories of antibiotic or oral contraceptive usage or the stage of the menstrual cycle. Distributions of Candida species and Candida albicans biotypes were not statistically related to any symptoms, signs or other factors. The results of this study suggest that vaginal pathology caused by Candida species may be related to the quantity of the fungus in the vagina and that only pruritus and objectively assessed vaginal discharge are firm clinical indicators of Candida infection.

Epidemiology of vaginal Candida infection: significance of numbers of vaginal yeasts and their biotypes.

The prevalence, quantity and biotypes of vaginal yeasts were determined for 1082 randomly selected nonpregnant patients attending two genitourinary medicine clinics. The overall yeast prevalence was 22.1% with a geometric mean of 40 and a median of 75 yeast colonies per positive isolate (on 5-cm Petri dishes). There was no statistically significant variation in prevalence, quantity or biotype of yeasts with the patients' age, season of the year, stage of the menstrual cycle, recent antibiotic history, contraceptive use or main diagnosis (excluding candidosis). A clinical score for Candida infection, based on symptoms of pruritus and signs of Candida vulvovaginitis, showed significant variation with the prevalence and quantity of yeast isolates. Unequivocal clinical evidence of candidosis was strongly associated with high concentrations of vaginal yeasts. There was also some association between certain groups of Candida albicans biotypes and the clinical score. These observations reemphasize the need for consideration of both clinical and mycological factors in establishing a diagnosis of vulvovaginal Candida infection. It is suggested that isolation of fewer than 10 yeast colonies from a vaginal swab is usually unlikely to indicate an infection requiring treatment.

Growth of pathogenic Candida isolates anaerobically and under elevated concentrations of CO2 in air.

Individual isolates of seven potentially pathogenic yeast species in the genus Candida all grew to some extent in Eagle's minimal essential medium including serum under elevated concentrations of CO2 and in anaerobic gas jars. The C. glabrata and C. tropicalis isolates had the highest anaerobic growth rates and yields, the C. guilliermondii and C. parapsilosis isolates had the lowest, and the C. albicans, C. krusei and C. pseudotropicalis isolates gave intermediate growth rates and yields. The same relative abilities to grow anaerobically were seen when the seven isolates were cultured in liquid and on agar formulations of a peptone-glucose broth and two media containing Yeast Nitrogen Base.

Antifungal relative inhibition factors: BAY l-9139, bifonazole, butoconazole, isoconazole, itraconazole (R 51211), oxiconazole, Ro 14-4767/002, sulconazole, terconazole and vibunazole (BAY n-7133) compared in vitro with nine established antifungal agents.

Nine new antifungal agents were tested for their activity in vitro in terms of relative inhibition factors (RIFs) against 26 isolates of Candida species, eight isolates of Aspergillus species and six isolates of dermatophyte fungi. Eight of the new compounds were azole antifungals, the ninth was a phenylmorpholine derivative. Against Candida species, all the novel compounds gave RIFs that were of a similar order to RIFs for established imidazole compounds. Two topical antifungals, butoconazole and terconazole, and two systemic antifungals, itraconazole and vibunazole, gave mean RIFs less than 60% in tests with Candida species, and therefore matched clotrimazole, ketoconazole and tioconazole in terms of RIF. However, none of the new compounds gave RIFs as low as amphotericin B against the Candida isolates. Against Aspergillus isolates, itraconazole, with a mean RIF of 25%, was even more active in vitro than amphotericin B. Vibunazole was as active as ketoconazole against Aspergillus isolates. All the new antifungals except Bay l-9139 gave very low RIFs against dermatophyte isolates, and thus matched established imidazole antifungals for inhibitory effects in vitro. In terms of RIF data, all the nine new compounds tested appear to offer reasonable potential for antifungal chemotherapy in vivo. A similar conclusion would not have been drawn from minimal inhibitory concentration data, which tended to show most of the new antifungals in a very poor light. Tests with amphotericin B, 5-fluorocytosine and ketoconazole showed that RIF can vary substantially with the pH of the test medium. For amphotericin B and ketoconazole the best activity was seen at neutral pH values; for 5-fluorocytosine the greatest inhibitory activity was found at lower pH values.

Effect of oxygen and storage temperature on intermediate moisture meat products.

During storage of glycerol desorbed intermediate moisture meats at 38°C it was found that, for both protein crosslinking and loss of haemoprotein character to occur, oxygen must be present. However, collagen degradation, as monitored by the formation of water-soluble hydroxyproline containing fragments, still occurred in the absence of oxygen although the rate of degradation was slower than that observed in aerobically stored samples. The rates of the various deteriorative reactions also varied with storage temperature, there being the expected decrease in rate with temperature for both the crosslinking and haemoprotein breakdown reactions. However, the temperature dependence of the collagen breakdown reaction was apparently more complex as there was no measurable breakdown, even during several months of storage, at temperatures of 17°C and below.

The role of lipids and glycerol in determining the shelf-life of glycerol desorbed intermediate moisture meat products.

During storage of glycerol desorbed intermediate moisture beef at 38°C the marked loss of eating quality, demonstrated by increasing loss of nitrogen solubility in sodium dodecyl sulphate (SDS) plus ß-mercaptoethanol, loss of haemoprotein character, decrease in pH and the formation of water-soluble hydroxyproline containing fragments, is not markedly affected by the presence of oleic acid and/or butylated hydroxytoluene. In addition, gas-liquid chromatographic analysis of the lipid fractions suggests that, in these meats, the relative composition of the neutral phospholipid fractions does not change to any marked extent during storage. However, the TBA and peroxide values, which are very high in the freshly prepared meats, do decrease quite markedly during storage. Consideration of these results suggests that, in glycerol desorbed meats, glycerol oxidation products are the major reactants leading to loss of eating quality.

Prediction of water activity, a(w), in cook-soak equilibrated intermediate moisture meats.

The relationship between the moisture content and water activity, a(w), of several meat samples adjusted to intermediate moisture water activities by cook-soak equilibration in glycerol solutions containing 9·5% sodium chloride was determined. Within experimental error the relationship was found to be unique for all the lean meats studied. It was also found that a modification of the Grover method (Grover, 1947) in which a(w) is determined from the well established relationship between a(w) and sucrose equivalent, E(s), was an excellent predictor of the final a(w) of the ssystem. E(s) was calculated from E(s) = E(1)X(1) + E(1)X(2) + … etc. where E(1) are specific constants for each humectant and X(1) and X(2) are given as weight of humectant in the system/weight of water in the system. E values of 9·0 and 2·2 for sodium chloride and glycerol were applicable for initial salt concentrations of 0 to 20 (w/w)_and glycerol concentrations of 0 to 90% (w/w) The method was equally applicable to propylene glycol (E value 3·2)/salt systems and sorbitol (E value 1·0)/salt systems.