Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Potentially Harmful Ionizing Radiation Exposure from Diagnostic Tests and Medical Procedures in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) may have significant potentially harmful ionizing radiation exposure (PHIRE) from diagnostic tests and medical procedures (DTMP) during their initial hospitalization. METHODS: In this single-center, retrospective, observational study, we evaluated the incidence of PHIRE using all patients with radiographically proven aSAH who survived hospitalization over a 6-year period. Patient data were then used to fit a full logistic regression model, a reduced-variable logistic regression model with least absolute shrinkage and selection operator penalty, and a nonparametric tree-based model. Testing data were then used to calculate each predictive model's accuracy. RESULTS: Of 192 patients included in this study, 69 (35.9%) met criteria for PHIRE. Patients with PHIRE were more likely to have a poor Hunt-Hess Score (40.6% vs. 12.2%, P < 0.0001), a poor modified Fischer Grading Scale score (30.4% vs. 16.3%, P = 0.03), ventriculostomy (91.3% vs. 47.2%, P < 0.0001), vasospasm (81.2% vs. 34.1%, P < 0.0001), and ventriculoperitoneal shunt (31.9% vs. 10.6%, P < 0.001). Parametric PHIRE prediction modeling with a full logistic regression model and reduced-logistic regression modeling with least absolute shrinkage and selection operator penalty demonstrated PHIRE prediction accuracy of 67% and 78% accuracy, respectively. Nonparametric tree-based PHIRE modeling demonstrated a prediction accuracy of 58%. CONCLUSIONS: On the basis of our data, PHIRE occurs in approximately 35% of aSAH patients. The reduced-variable logistic regression model had the greatest predictive accuracy for PHIRE. Future studies should validate our findings and predictive models and, if our conclusions hold, further clarification of the risks of PHIRE and methods to reduce PHIRE should be investigated.

Hazard Group 3 agent decontamination using hydrogen peroxide vapour in a class III microbiological safety cabinet.

AIMS: This study investigated the efficacy of hydrogen peroxide vapour (HPV) at inactivating hazard group 3 bacteria that have been presented dried from their growth medium to present a realistic challenge. METHODS AND RESULTS: Hydrogen peroxide vapour technology (Bioquell) was used to decontaminate a class III microbiological safety cabinet containing biological indicators (BIs) made by drying standard working suspensions of the following agents: Bacillus anthracis (Ames) spores, Brucella abortus (strain S99), Burkholderia pseudomallei (NCTC 12939), Escherichia coli O157 ST11 (NCTC 12079), Mycobacterium tuberculosis (strain H37Rv) and Yersinia pestis (strain CO92) on stainless steel coupons. Extended cycles were used to expose the agents for 90 min. The HPV cycle completely inactivated B. anthracis spores, B. abortus, B. pseudomallei, E. coli O157 and Y. pestis when BIs were processed using quantitative and qualitative methods. Whilst M. tuberculosis was not completely inactivated, it was reduced by 4 log10 from a starting concentration of 106 colony-forming units. CONCLUSIONS: This study demonstrates that HPV is able to inactivate a range of HG3 agents at high concentrations with associated organic matter, but M. tuberculosis showed increased resistance to the process. SIGNIFICANCE AND IMPACT OF THE STUDY: This publication demonstrates that HPV can inactivate HG3 agents that have an organic load associated with them. It also shows that M. tuberculosis has higher resistance to HPV than other agents. This shows that an appropriate BI to represent the agent of interest should be chosen to demonstrate a decontamination is successful.

A Novel Tool to Guide Reintegration of Anesthesiologists Into Clinical and Academic Work After Concussion.

Concussion is a common form of mild traumatic brain injury that can cause somatic, cognitive, and behavioral impairments lasting days to weeks. There are no published guidelines or recommendations to facilitate the safe and successful reintegration of anesthesiologist clinicians and trainees into clinical and academic work after concussion. We developed a simple 4-phase postconcussion recovery protocol for anesthesiologists who have suffered concussion and describe the successful use of this postconcussion recovery protocol to support reintegration of an Anesthesiology Critical Care Medicine fellow who developed mild concussion during vacation leave.

Late diagnosis, delayed presentation and late presentation among persons enrolled in a clinical HIV cohort in Ontario, Canada (1999-2013).

OBJECTIVES: Timely HIV diagnosis and presentation to medical care are important for treatment and prevention. Our objective was to measure late diagnosis, delayed presentation and late presentation among individuals in the Ontario HIV Treatment Network Cohort Study (OCS) who were newly diagnosed in Ontario. METHODS: The OCS is a multi-site clinical cohort study of people living with HIV in Ontario, Canada. We measured prevalence of late diagnosis [CD4 count < 350 cells/µL or an AIDS-defining condition (ADC) within 3 months of HIV diagnosis], delayed presentation (≥ 3 months from HIV diagnosis to presentation to care), and late presentation (CD4 count < 350 cells/µL or ADC within 3 months of presentation). We identified characteristics associated with these outcomes and explored their overlap. RESULTS: A total of 1819 OCS participants were newly diagnosed in Ontario from 1999 to 2013. Late diagnosis (53.0%) and presentation (54.0%) were common, and a quarter (23.1%) of participants were delayed presenters. In multivariable models, the participants of delayed presentation decreased over calendar time, but that of late diagnosis/presentation did not. Late diagnosis contributed to the majority (> 87%) of late presentation, and the prevalence of delayed presentation was similar among those diagnosed late versus early (13.4 versus 13.4%, respectively; P = 0.99). Characteristics associated with higher odds of late diagnosis/presentation in multivariable analyses included older age at diagnosis/presentation; African, Caribbean and Black race/ethnicity; Indigenous race/ethnicity; female sex; and being a male who did not report sex with men. There were lower odds of late diagnosis/presentation among participants who had ever injected drugs. In contrast, delayed presentation risk factors included younger age at diagnosis and having ever injected drugs. CONCLUSIONS: Late presentation is common in Ontario, as it is in other high-income countries. Our findings suggest that efforts to reduce late presentation should focus on facilitating earlier diagnosis for the populations identified in this analysis.

Imaging the dome of Santa Maria del Fiore using cosmic rays.

The dome of Santa Maria del Fiore, Florence Cathedral, was built between 1420 and 1436 by architect Filippo Brunelleschi and it is now cracking under its own weight. Engineering efforts are under way to model the dome's structure and reinforce it against further deterioration. According to some scholars, Brunelleschi might have built reinforcement structures into the dome itself; however, the only known reinforcement is a wood chain 7.75 m above the springing of the Cupola. Multiple scattering muon radiography is a non-destructive imaging method that can be used to image the interior of the dome's wall and therefore ascertain the layout and status of any iron substructure in it. A demonstration measurement was performed at the Los Alamos National Laboratory on a mock-up wall to show the feasibility of the work proposed, and a lightweight and modular imaging system is currently under construction. We will discuss here the results of the demonstration measurement and the potential of the proposed technique, describe the imaging system under construction and outline the plans for the measurement.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

A study of CR-39 plastic charged-particle detector replacement by consumer imaging sensors.

Consumer imaging sensors (CIS) are examined for real-time charged-particle detection and CR-39 plastic detector replacement. Removing cover glass from CIS is hard if not impossible, in particular for the latest inexpensive webcam models. We show that $10-class CIS are sensitive to MeV and higher energy protons and α-particles by using a 90Sr ß-source with its cover glass in place. Indirect, real-time, high-resolution detection is also feasible when combining CIS with a ZnS:Ag phosphor screen and optics. Noise reduction in CIS is nevertheless important for the indirect approach.

Tackling the social and structural drivers of HIV in Canada.

There is new hope that we can significantly reduce HIV rates. The United Nations AIDS organization, UNAIDS, has challenged all countries to strive for aggressive targets that could significantly bend the curve on HIV infections and deaths: 90% of people living with HIV diagnosed; 90% of people diagnosed on treatment; and 90% of people on treatment virally suppressed. This new optimism is largely driven by strong research findings that early and ongoing HIV treatment improves individual health outcomes and reduces people's viral load, making them less infectious. However, the risk of HIV infection is far from evenly distributed among populations most at risk. Those most at risk will find it hardest to reach these targets as they are caught in a syndemic (synergistic epidemic) of intertwining health and social issues. Our research, and that of others, shows that those who are in a syndemic of co-occurring mental health, addiction and social issues (e.g. homelessness, food insecurity) are significantly more likely to fall out of care, less likely to adhere to treatment and less likely to achieve/maintain an undetectable viral load. Intervention studies have found that a combination approach to HIV prevention and treatment that goes beyond primary care and mental health tools to include social and structural interventions has a protective effect, and can reduce risk and improve adherence. People living with and at risk of HIV need better access to social and mental health services as well as clinical treatment services that will help them achieve and maintain optimal health and well-being. We strongly encourage those in the HIV sector across the country to identify a common vision, with clear goals and targets. With concerted and targeted efforts, a focus on program and implementation science, and a willingness to see and treat HIV as a social as well as a biomedical problem-the fourth decade of HIV in Canada could well be the last.

Hydroxytyrosyl ethyl ether exhibits stronger intestinal anticarcinogenic potency and effects on transcript profiles compared to hydroxytyrosol.

The anticarcinogenic activity of hydroxytyrosyl ethyl ether (HTy-Et) compared to its precursor hydroxytyrosol (HTy) has been studied in human Caco-2 colon adenocarcinoma cells. 451 and 977 genes were differentially expressed in Caco-2 cells exposed to HTy or HTy-Et for 24h, respectively, compared with untreated cells (P<0.005; FDR=0), using Affymetrix microarrays. Results showed that both HTy and HTy-Et inhibited cell proliferation and arrested the cell cycle by up-regulating p21 and CCNG2 and down-regulating CCNB1 protein expression. HTy and HTy-Et also altered the transcription of specific genes involved in apoptosis, as suggested by the up-regulation of BNIP3, BNIP3L, PDCD4 and ATF3 and the activation of caspase-3. Moreover, these polyphenols up-regulated xenobiotic metabolizing enzymes UGT1A10 and CYP1A1, enhancing carcinogen detoxification. In conclusion, these results highlight that HTy and its derivative HTy-Et modulate molecular mechanisms involved in colon cancer, with HTy-Et being more effective than HTy.

Testing the level of ant activity associated with quorum sensing: an empirical approach leading to the establishment and test of a null-model (response to the comment of Richardson et al.).

In a paper in this journal (Nouvellet et al., 2010), we presented results from experiments on the behaviour of the Pharaoh's ant, Monomorium pharaonis, along with a substantial statistical and theoretical analysis of the results. In a minor part of our paper, we compared our results with the related work of Richardson et al. (2010a). These authors have subsequently commented on our interpretation of their work (Richardson et al., 2011). In this Letter we respond to the comments of Richardson et al. (2011), and give detailed arguments why we stand by our original conclusions.

SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study.

BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.

Testing the level of ant activity associated with quorum sensing: An empirical approach leading to the establishment and test of a null-model.

On the basis of experimental observations, this paper develops two well-defined mathematical models for the level of activity of Pharaoh's ants within their nesting area, with the aim of providing a more general understanding of animal activity. Under specific conditions, we observe that the activity of ants within their nesting area appears to show no dependence on their density. Making the assumption that all ants move independently of one another, this behaviour can be mathematically modelled as a random process based on the binomial distribution. Developing the model on this basis allows an exponential distribution to be exposed that underlies the time-intervals between ants leaving the nesting area. Such a distribution is present, irrespective of whether the ant population in the nesting area remains constant or steadily depletes, and suggests that ant-ant interactions do not play any significant role in determining ant activity under the experimental conditions adopted. The mathematical framework presented plays the role of a null model that will have a wide range of applications for detecting other determinants of activity-level (not addressed in this study) including environmental and social factors such as food availability, temperature, humidity, presence of pheromone trails, along with intraspecific and interspecific interactions outside the nest and, indeed, more generally. The null model should have applications to a range of organisms. Lastly, we discuss our data in relation to a recent study of ants leaving their nest (Richardson et al., 2010) in which the null model was rejected in favour of record dynamics, where ant-ant interactions were conjectured to play a role.

Rapid disease course in African Americans with multiple sclerosis.

OBJECTIVE: To investigate utility of a Multiple Sclerosis Severity Scale (MSSS)-based classification system for comparing African American (AA) and white American (WA) multiple sclerosis (MS) subpopulations in the New York State Multiple Sclerosis Consortium (NYSMSC) database. MSSS is a frequency-rank algorithm relating MS disability to disease duration in a large, untreated reference population. Design/ METHODS: Distributions of patients in 6 MSSS-based severity grades were calculated for AA and WA registrants. RESULTS: There were 419 AA and 5,809 WA patients in the NYSMSC, who had EDSS recorded during years 1-30 since symptom onset. Median EDSS was not different in AA and WA (3.5 vs 3.0, p = 0.60), whereas median MSSS in AA was higher than in WA (6.0 vs 4.8, p = 0.001). AA patients were overrepresented in the 2 most severe grades (41.5% vs 29.3% for WA) and underrepresented in the 2 lowest grades (23.4% vs 35.4%; p < 0.001). In multivariable analysis (ordered logistic and median regression), MSSS for AA remained significantly higher than in WA after adjusting for age, gender, disease duration, disease type distribution, and treatment with disease-modifying therapies. CONCLUSIONS: The 6-tiered MSSS grading system is a powerful tool for comparing rate of disease progression in subpopulations of interest. MSSS-based analysis demonstrates that African ancestry is a risk factor for a more rapidly disabling disease course.

Migraine is comorbid with multiple sclerosis and associated with a more symptomatic MS course.

The objectives of this study were: (1) to assess relative frequency of migraine in multiple sclerosis (MS) patients using the validated self-administered diagnostic questionnaire, and to compare the migraine rates in MS outpatients to age- and gender-matched historical population controls; (2) to compare clinical and radiographic characteristics in MS patients with migraine and headache-free MS patients. We conducted a cross-sectional study to assess the demographic profiles, headache features and clinical characteristics of MS patients attending a MS clinic using a questionnaire based on the American Migraine Prevalence and Prevention (AMPP) study. We compared the relative frequency of migraine in MS clinic patients and AMPP cohort. We also compared clinical and radiographic features in MS patients with migraine to an MS control group without headache. Among 204 MS patients, the relative frequency of migraine was threefold higher than in population controls both for women [55.7 vs. 17.1%; prevalence ratio (PR) =3.26, p<0.001] and men (18.4 vs. 5.6%; PR=3.29, p<0.001). In a series of logistic regression models that controlled for age, gender, disease duration, ß-interferon use, and depression, migraine in MS patients was significantly associated (p<0.01) with trigeminal and occipital neuralgia, facial pain, Lhermitte's sign, temporomandibular joint pain, non-headache pain and a past history of depression. Migraine status was not significantly associated with disability on patient-derived disability steps scale or T2 lesion burden on brain MRI. Migraine is three-times more common in MS clinic patients than in general population. MS-migraine group was more symptomatic than the MS-no headache group.

Antioxidant activity of oak (Quercus) leaves infusions against free radicals and their cardioprotective potential.

The aim of present study was to evaluate antioxidant capacity and cardioprotective potential of leaves infusions and partially purified fractions of Quercus sideroxyla and Q. eduardii (red oaks) and Q. resinosa (white oak). Consumption of polyphenol-rich beverages derived from plants, such as oak may represent a beneficial diet in terms of cardiovascular protection. Infusions from Oak leaves were obtained and probed for total phenolics by Folin-Ciocalteu, DPPH and hydroxyl radicals scavenging by DPPH test and Deoxy-D-ribose method, the antioxidant capacity was evaluated by FRAP and ORAC tests, inhibitions of Low Density Lipoproteins (LDL) oxidation and Angiotensin Converting Enzyme (ACE) activity were measured. A HPLC analysis was performed by HPLC-MS. Bioactive polyphenols such as gallic and ellagic acids, catechin, quercetin and derivatives: naringenin and naringin were detected in Quercus infusions. A distinctive HPLC profile was observed among the red and white oak samples. Q. resinosa infusions have exhibited the highest antioxidant activity in comparison with the other species, although in the inhibition of LDL oxidation no differences were observed. In the inhibition of the ACE, Q. resinosa was more effective (IC50, 18 ppm) than Q. sideroxyla, showing same effect as the control Captopril. From the results it is possible to postulate that not only chelating activity is important in these infusions, especially in Q. resinosa.

Issue brief: addressing housing challenges faced by people with HIV in Ontario

About 26,630 Ontarians are living with HIV and about 1,000 more are newly diagnosed each year.(1) Of those who are newly diagnosed, over 50% are gay men, about a quarter are members of the African and Caribbean community, and about 8% are injection drug users.

Fundamental insights into the random movement of animals from a single distance-related statistic.

Statistical theories of animal movement have often been based on models of random walks, where movements take place in discrete steps and occur at discrete times. The multiplicity of distributions required in these approaches to describe animal movement (i.e., the distributions of angles, discrete steps, and times) have effects that cannot be simply disentangled, and hence they cannot be unambiguously determined. Here we present a mathematical formulation of continuous animal movements. In this new framework, it is shown that a single time-dependent distance statistic, the mean square displacement, which may be directly measured or mathematically modeled, is a central determinant of such random walks and encapsulates key information about the statistical properties of animal movements. The model and methodology presented here not only allow the determination of what were previously viewed as independent aspects of animal movements, such as the distribution of angular changes in direction, but also, because of the new emphasis on the mean square displacement, they may open up a new set of questions concerning animal movement and related phenomena. The results established in this work are directly applied to the foraging behavior of Pharaoh's ants, and very close agreement is found between observation and theory.

Five-year results of incompetent perforator vein closure using TRans-Luminal Occlusion of Perforator.

UNLABELLED: In 2000, we developed a percutaneous method of treating incompetent perforator veins (IPV) using ultrasound-guided radiofrequency ablation (RFA), which we termed TRansluminal Occlusion of Perforator (TRLOP). OBJECTIVE: To audit the five-year outcome of the TRLOP technique as indicated by the rate of IPV closure on duplex ultrasound (DUS). METHODS: Patients underwent DUS five years post-TRLOP. Experienced vascular technologists documented the presence of IPVs using a two co-ordinate system, blinded to previous results. Results were then compared with preoperative scans. IPVs were classified as: closed; not closed/reopened; or de novo. Closed IPVs were defined as the absence of any IPV at or within 5 cm of a previous IPV in the vertical and horizontal plane. Any IPVs found outside the delineated area were defined as de novo IPVs. RESULTS: Of 67 patients invited, 37 attended DUS (55% participation rate; men to women ratio of 14:23, age 40-84; mean 64). Preoperative clinical, aetiological, anatomical and pathological classification: C2, 36.2%; C3, 27.6%; C4, 34.5%; C6, 1.7%. From 125 IPVs analysed, 101 were closed (81%), 24 were not closed/reopened (19%) and 14 de novo IPVs were found. DISCUSSION: Despite these results representing our learning curve for the procedure, we found TRLOP to be an effective treatment for IPVs. The closure rates described are comparable with the published clinical series data for subfascial endoscopic perforator surgery.

Religiosity, spirituality and antenatal anxiety in Southern U.S. women.

INTRODUCTION: We investigated the association between religiosity, spirituality, and anxiety in pregnant women, taking into account potential confounders. MATERIALS AND METHODS: From September 2005 through March 2006, pregnant women in three obstetrics practices in the American South were included in a cross-sectional study. The anxiety subscale of the Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety. RESULTS: Of the 344 participating women, 23 screened positive for moderate to severe anxiety (HADS [anxiety] score greater than 10). Overall religiosity or spirituality (odds ratio [OR], 0.53; p=0.006) and social support (OR, 0.42; p<0.0001) were significantly associated with significantly lower odds of a positive anxiety screen. Among the specific measures of religiosity or spirituality, self-rated religiosity, self-rated spirituality, and participation in nonorganizational religious activities were significantly associated with lower odds of moderate to severe anxiety symptoms. DISCUSSION AND CONCLUSIONS: Religiosity and spirituality are associated with reduced anxiety in pregnant women. Additional study is needed to evaluate whether the association is causal.

Parameter-free testing of the shape of a probability distribution.

The Kolmogorov-Smirnov test determines the consistency of empirical data with a particular probability distribution. Often, parameters in the distribution are unknown, and have to be estimated from the data. In this case, the Kolmogorov-Smirnov test depends on the form of the particular probability distribution under consideration, even when the estimated parameter-values are used within the distribution. In the present work, we address a less specific problem: to determine the consistency of data with a given functional form of a probability distribution (for example the normal distribution), without enquiring into values of unknown parameters in the distribution. For a wide class of distributions, we present a direct method for determining whether empirical data are consistent with a given functional form of the probability distribution. This utilizes a transformation of the data. If the data are from the class of distributions considered here, the transformation leads to an empirical distribution with no unknown parameters, and hence is susceptible to a standard Kolmogorov-Smirnov test. We give some general analytical results for some of the distributions from the class of distributions considered here. The significance level and power of the tests introduced in this work are estimated from simulations. Some biological applications of the method are given.