Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Surgical Management of Stuttering Ischemic Priapism: A Case Report and Concise Clinical Review.

Stuttering priapism is an extremely rare and poorly understood entity. We present a rare case of a 47-year-old Afro-Caribbean gentleman who required proximal shunt procedure to treat his ischemic stuttering priapism after he had failed medical management. We provided a concise review of the literature on the surgical management of ischemic priapism. This case highlighted the importance of prompt surgical intervention in prolonged stuttering priapism to avoid serious psychological and functional complications.

Methanol-based fixation is superior to buffered formalin for next-generation sequencing of DNA from clinical cancer samples.

BACKGROUND: Next-generation sequencing (NGS) of tumour samples is a critical component of personalised cancer treatment, but it requires high-quality DNA samples. Routine neutral-buffered formalin (NBF) fixation has detrimental effects on nucleic acids, causing low yields, as well as fragmentation and DNA base changes, leading to significant artefacts. PATIENTS AND METHODS: We have carried out a detailed comparison of DNA quality from matched samples isolated from high-grade serous ovarian cancers from 16 patients fixed in methanol and NBF. These experiments use tumour fragments and mock biopsies to simulate routine practice, ensuring that results are applicable to standard clinical biopsies. RESULTS: Using matched snap-frozen tissue as gold standard comparator, we show that methanol-based fixation has significant benefits over NBF, with greater DNA yield, longer fragment size and more accurate copy-number calling using shallow whole-genome sequencing (WGS). These data also provide a new approach to understand and quantify artefactual effects of fixation using non-negative matrix factorisation to analyse mutational spectra from targeted and WGS data. CONCLUSION: We strongly recommend the adoption of methanol fixation for sample collection strategies in new clinical trials. This approach is immediately available, is logistically simple and can offer cheaper and more reliable mutation calling than traditional NBF fixation.

Acute paraspinal compartment syndrome as a rare cause of loin pain.

A significant proportion of emergency urological admissions are comprised of ureteric colic presenting as loin pain. A variety of alternative pathologies present in this manner and should be considered during systematic assessment. We report the case of a patient admitted with severe unilateral back and flank pain after strenuous deadlift exercise. Clinical examination and subsequent investigation following a significant delay demonstrated acute paraspinal compartment syndrome (PCS) after an initial misdiagnosis of ureteric colic. The patient was managed conservatively. We review the current literature surrounding the rare diagnosis of PCS and discuss the management options.

Delirium affects length of hospital stay after lung transplantation.

BACKGROUND: Delirium is relatively common after lung transplantation, although its prevalence and prognostic significance have not been systematically studied. The purpose of the present study was to examine pretransplant predictors of delirium and the short-term impact of delirium on clinical outcomes among lung transplant recipients. METHODS: Participants underwent pretransplant cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test. After transplant, delirium was assessed using the Confusion Assessment Method until discharge. RESULTS: Sixty-three patients were transplanted between March and November 2013, of which 23 (37%) developed delirium. Among transplanted patients, 48 patients completed pretransplant cognitive testing. Better pretransplant cognitive function was associated with lower risk of delirium (odds ratio, 0.69 [95% confidence interval 0.48, 0.99], P = .043); and demographic and clinical features including native disease (P = .236), the Charlson comorbidity index (P = .581), and the lung allocation score (P = .871) were unrelated to risk of delirium, although there was a trend for women to experience delirium less frequently (P = .071). The presence (P = .006) and duration (P = .027) of delirium were both associated with longer hospital stays. CONCLUSION: Delirium occurs in more than one-third of patients after lung transplantation. Delirium was associated with poorer pretransplant cognitive functioning and longer hospital stays, after accounting for other medical and demographic factors.

The impact of increased dispersal in response to disease control in patchy environments.

This paper uses a mathematical framework to investigate the impact of increased movement in response to disturbance caused by disease control strategies. Implementation of invasive disease control strategies such as culling may cause species to disperse beyond their natural range, thus aiding the spread of infection to otherwise infection free areas. Both linear and non-linear dispersal functions are compared with constant per capita dispersal in a coupled two patch SI model. For highly virulent or infrequently transmitted pathogens, it is found that an increase of dispersal due to control requires a higher level of disease control than in the constant dispersal model. Patches which may be sources or reservoirs of infection are investigated and it is found that if dispersal increases in response to control, then all patches, reservoir or not, must be targeted. The single host two patch model is then extended to a two host wildlife/livestock system with one species 'wildlife' free to move between patches and the other 'livestock' confined. In the two host case, control of one species alone will only achieve successful pathogen exclusion if that species is a reservoir for infection.

Stocking methods and parasite-induced reductions in capture: modelling Argulus foliaceus in trout fisheries.

Argulus foliaceus is a macroparasite which can have a significant impact on yield in recreational trout fisheries, partly by increasing fish mortalities but also by reducing the appetite of infected fish, making them less likely to respond to bait. The aim of this paper is to determine the impact of four commonly used fish stocking methods both on the parasite dynamics, and on fisheries' yields. The wider consequences of the resultant reduction in host feeding are also of interest. To this end four different stocking methods were incorporated into Anderson and May's macroparasite model, which comprises three differential equations representing the host, attached parasite and free-living parasite populations. To each of these a reduction in the fish capture rate, inversely linked to the mean parasite burden, is added and the effects interpreted. Results show that (1) the common practise of increasing the stocking rate as catches drop may be counterproductive; (2) in the absence of any wild population of reservoir hosts, the parasite will be unable to survive if the stocking rate does not exceed the rate of capture; (3) compensatory stocking to account for fish mortalities can have disastrous consequences on yield; and (4) the parasite can, under certain circumstances, maintain the host population by preventing their capture.

Pathogen exclusion from eco-epidemiological systems.

Increasing concerns about the changing environment and the emergence of pathogens that cross species boundaries have added to the urgency of understanding the dynamics of complex ecological systems infected by pathogens. Of particular interest is the often counterintuitive way in which infection and predation interact and the consequent difficulties in designing control strategies to manage the system. To understand the mechanisms involved, we focus on the pathogen exclusion problem, using control maps (on which the network of exclusion thresholds are plotted) in order to readily identify which exclusion strategies will work and why others will not. We apply this approach to the analysis of parasite exclusion in two game bird ecologies. For higher dimensions, we propose a computational scheme that will generate the optimal exclusion strategy, taking into account all operational constraints on the pathogen invasion matrix, populations, and controls. The situation is further complicated when external forcing distorts pathogen thresholds. This distortion is highly sensitive to the lags between forcing components, a sensitivity that can be exploited by management using correctly lagged cyclically varying controls to reduce the effort involved in pathogen exclusion.

Sexually antagonistic co-evolution: a model and an empirical test.

Models reveal that sexually antagonistic co-evolution exaggerates female resistance and male persistence traits. Here we adapt an established model by including directional sexual selection acting against persistence. We find similar equilibria to previous models showing that sexually antagonistic co-evolution can be limited by counteracting sexual, as well as, natural selection. We tested the model using empirical data for the seaweed fly, Coelopa ursina, in which body size acts as a persistence and a resistance trait. Our model can generate continuous co-evolutionary cycles and stable equilibria, however, all simulations using empirically derived parameter estimates reach stable equilibria. Thus, stable equilibria might be more common in nature than continuous co-evolutionary cycles, suggesting that sexual conflict is unlikely to promote speciation. The model predicts male biased sexual size dimorphism for C. ursina, comparable with empirically observed values. Male persistence is shown to be more sensitive than female resistance to changes in model parameters.

Spoilage and safety characteristics of ground beef treated with lactic acid bacteria.

Lactic acid bacteria (LAB) can decrease numbers of Escherichia coli O157:H7 and Salmonella in ground beef during storage. Two dose-titration studies were conducted in ground beef to determine dose levels of LAB needed to inhibit the pathogens. A second study evaluated whether LAB masked changes typically associated with the spoilage of ground beef displayed under refrigerated (0 degrees C) or abusive (10 degrees C) temperatures packaged in both traditional overwrap (TOP) and modified atmosphere packaging (MAP; 80% O(2)-20% CO(2)). Microbial analyses were conducted to determine spoilage endpoints and pathogen reduction. In the dose-titration study, Salmonella was reduced by 3 log cycles at all doses (10(6), 10(7), and 10(8) LAB per g) after 3 days of storage and was eliminated after 5 days of storage. E. coli O157:H7 was reduced by 2 log cycles at all dosages after 3 days of storage and by 3 log cycles after 5 days of storage. In the spoilage studies, as expected, total aerobic plate counts and LAB populations in LAB-inoculated samples were higher than the controls initially, but the counts were similar near the end of the study. While total spoilage bacteria generally increased over time, very few differences existed between treatments stored at 0 degrees C and 10 degrees C in coliforms, Brochothrix thermosphacta, yeasts and molds, and Pseudomonas spp. counts for both the TOP and MAP samples. We conclude that LAB could potentially be added to ground beef in TOP and MAP as a processing intervention for E. coli O157:H7 and Salmonella without masking microbial spoilage characteristics.

Exclusion of generalist pathogens in multihost communities.

Knowing how to control a pathogen that infects more than one host species is of increasing importance because the incidence of such infections grows with continuing environmental change. Of concern are infections transmitted from wildlife to humans or livestock. To determine which options are available to control a pathogen in these circumstances, we analyze the pathogen invasion matrix for the multihost susceptible-infected-susceptible model. We highlight the importance of both community structure and the column sum or row sum index, an indicator of both force of infection and community stability. We derive a set of guidelines for constructing culling strategies and suggest a hybrid strategy that has the advantages of both the bottom-up and the top-down approaches, which we study in some detail. The analysis holds for an arbitrary number of host species, enabling the analysis of large-scale ecological systems and systems with spatial dimensions. We test the robustness of our methods by making two changes in the structure of the underlying dynamic model, adding direct competition and introducing frequency-dependent infection transmission. In particular, we show that the introduction of an additional host can eliminate the pathogen rather than eliminate the resident host. The discussion is illustrated with a reference to bovine tuberculosis.

Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival, recidivism, and risk factors predisposing to recidivism.

The aim of this study performed at the Liver Unit at the Queen Elizabeth Hospital, Birmingham, UK, is to assess posttransplantation alcohol consumption and identify risk factors associated with recidivism. This retrospective case-control study used a self-report questionnaire to assess pretransplantation and posttransplantation drinking, and a retrospective cohort study used patient notes to analyze risk factors for recidivism. Of 64 patients who underwent transplantation for alcoholic liver disease (ALD) between May 1996 and November 1999, a total of 49 surviving patients (40 men, 9 women) were available for study. The comparison group consisted of 49 patients matched for age, sex, and date of transplantation who underwent transplantation for non-alcohol-induced chronic liver disease. Two-year patient survival rates were 82% in both study groups. The questionnaire response rate was 69.3% and 75.5% in patients with and without ALD, respectively. Data on recidivism (defined as any alcohol consumption after transplantation) were available in 46 of the 49 patients with ALD. Of these, 45.6% were drinking; 21.7% reported only occasionally drinking; 17.3%, moderate drinking; and 6.5%, heavy drinking. Information on alcohol consumption was available from 41 of the 49 controls. Of these, 52.5% consumed alcohol; 22.0% reported drinking only on special occasions; 24.4%, moderate drinking; and 4.9%, a return to heavy drinking. However, these differences were not statistically significant, and log-rank analysis found no significant difference in time to resumption of drinking. In the ALD cohort, no significant risk factors were identified to predict recidivism. No pretransplantation risk factors (including period of abstinence before transplantation) correlated with recidivism. Survival after transplantation for ALD is similar to that in other forms of chronic liver disease. Recidivism rates for patients with ALD are high, but patients with ALD do not drink more than their control counterparts posttransplantation. In most instances, alcohol consumption posttransplantation is minimal to moderate (<20 units/wk) and seems to be controlled.

RNA polymerase inhibitors with activity against rifampin-resistant mutants of Staphylococcus aureus.

A collection of rifampin-resistant mutants of Staphylococcus aureus with characterized RNA polymerase beta-subunit (rpoB) gene mutations was cross-screened against a number of other RNA polymerase inhibitors to correlate susceptibility with specific rpoB genotypes. The rpoB mutants were cross-resistant to streptolydigin and sorangicin A. In contrast, thiolutin, holomycin, corallopyronin A, and ripostatin A retained activity against the rpoB mutants. The second group of inhibitors may be of interest as drug development candidates.

The development of removable appliances in the United Kingdom.

The evolution since 1900 of the removable orthodontic appliance is described. The effects upon this evolution of political and economic events, the introduction of new materials and the British approach to orthodontic treatment are discussed. Present opinion favours the increased use of fixed appliances but it seems likely that removable appliances will still be suitable in about half those cases requiring active treatment.