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Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (K d = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood-brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. SIGNIFICANCE: Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275.

Cysteine-rich receptor-like kinases (CRKs) are a large family of plasma membrane-bound receptors ubiquitous in higher plants. They are transcriptionally regulated by a wide variety of environmental cues and stresses, however their precise biological roles remain largely unknown. Here we report a novel mutant isolated for the CYSTEINE-RICH RECEPTOR-LIKE KINASE 10 (CRK10) of Arabidopsis thaliana which harbours the substitution of alanine 397 by a threonine in the αC-helix of its kinase domain and which we registered as crk10-A397T in the community database. In situ phosphorylation assays with the His-tagged wild type (WT) and crk10-A397T versions of the CRK10 kinase domain revealed that both alleles are active kinases capable of auto-phosphorylation with the newly introduced threonine acting as an additional phosphorylation site in crk10-A397T. Phenotypically the mutant is a dwarf and the analysis of thin cross sections with light and transmission electron microscopy revealed that collapsed xylem vessels in roots and hypocotyls are very likely the cause for this reduction in stature. Transcriptomic analysis of WT and mutant hypocotyls revealed that predominantly biotic and abiotic stress-responsive genes are constitutively up-regulated in the mutant. Root-infection assays with the vascular pathogen Fusarium oxysporum demonstrated that the crk10-A397T mutant has enhanced resistance to this pathogen compared to WT plants. Taken together our results suggest that crk10-A397T is a gain-of-function allele of CRK10 and open up new avenues for the investigation of this elusive receptor-like kinase family.

Background: This study assessed whether a theoretically conceptualised tailored intervention centred on multidisciplinary teams (MDTs) increased clinician referral behaviours in line with clinical practice guideline recommendations. Methods: Nine hospital Sites in New South Wales (NSW), Australia with a urological MDT and involvement in a state-wide urological clinical network participated in this pragmatic stepped wedge, cluster randomised implementation trial. Intervention strategies included flagging of high-risk patients by pathologists, clinical leadership, education, and audit and feedback of individuals’ and study Sites’ practices. The primary outcome was the proportion of patients referred to radiation oncology within 4 months after prostatectomy. Secondary outcomes were proportion of patients discussed at a MDT meeting within 4 months after surgery; proportion of patients who consulted a radiation oncologist within 6 months; and the proportion who commenced radiotherapy within 6 months. Urologists’ attitudes towards adjuvant radiotherapy were surveyed pre- and post-intervention. A process evaluation measured intervention fidelity, response to intervention components and contextual factors that impacted on implementation and sustainability. Results: Records for 1071 high-risk post-RP patients operated on by 37 urologists were reviewed: 505 control-phase; and 407 intervention-phase. The proportion of patients discussed at a MDT meeting increased from 17% in the controlphase to 59% in the intervention-phase (adjusted RR = 4.32; 95% CI [2.40 to 7.75]; p < 0·001). After adjustment, there was no significant difference in referral to radiation oncology (intervention 32% vs control 30%; adjusted RR = 1.06; 95% CI [0.74 to 1.51]; p = 0.879). Sites with the largest relative increases in the percentage of patients discussed also tended to have greater increases in referral (p = 0·001). In the intervention phase, urologists failed to provide referrals to more than half of patients whom the MDT had recommended for referral (78 of 140; 56%). Conclusions: The intervention resulted in significantly more patients being discussed by a MDT. However, the recommendations from MDTs were not uniformly recorded or followed. Although practice varied markedly between MDTs, the intervention did not result in a significant overall change in referral rates, probably reflecting a lack of change in urologists’ attitudes. Our results suggest that interventions focused on structures and processes that enable health system-level change, rather than those focused on individual-level change, are likely to have the greatest effect.

Background The simultaneous adoption of laparoscopy and partial nephrectomy (PN) has been reported to result in unintended consequences. We aim to examine the contemporary (2001–2009) trends in use of PN and laparoscopy within a population‐wide database. Methods All renal cell carcinomas diagnosed between 2001 and 2009 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment were electronically linked. All patients with localized renal cell carcinoma who underwent surgical treatment were selected for this study (3771 patients). Follow‐up was to the end of 2010. Multivariable logistic regression analysis was used to determine predictors of PN and laparoscopy. Results In the entire cohort, 150 (4%), 495 (13%), 1516 (40%) and 1610 (43%) received laparoscopic PN, open PN, laparoscopic radical nephrectomy (RN) and open RN, respectively. Between the years 2001 and 2009, there was a gradual increase in the use of PN except between 2005 and 2007. Between 2001 and 2009, a rapid uptake of laparoscopy was observed. Multivariable analysis demonstrated that age (OR: 0.99 (0.98–0.99)), year of surgery (OR: 1.15 (1.11–1.19)), comorbidity (OR: 1.40 (1.12–1.76)) and hospital case load >8/year (OR: 2.39 (1.49–3.81)) predicted use of PN. Year of surgery (OR: 1.19 (1.15–1.21)), comorbidity (OR: 0.70 (0.58–0.85)), non‐teaching hospital (OR: 0.70 (0.53–0.93)), private hospital (OR: 1.86 (1.45–2.38)) and hospital case load > 8/year (OR: 3.36 (2.22–5.09)) predicted use of laparoscopy. Conclusion The unintended decrease in PN associated with increased use of laparoscopic RN had reversed by 2009. Hospital case load predicts the use of PN and laparoscopy.

Prostate cancer (PC) is the most common non-cutaneous cancer in men worldwide. The relationships between PC and possible risk factors for PC cases (n = 1,181) and male controls (n = 875) from the New South Wales (NSW) Cancer, Lifestyle and Evaluation of Risk Study (CLEAR) were examined in this study. The associations between PC risk and paternal history of PC, body mass index (BMI), medical conditions, sexual behaviour, balding pattern and puberty, after adjusting for age, income, region of birth, place of residence, and PSA testing, were examined. Adjusted risk of PC was higher for men with a paternal history of PC (OR = 2.31; 95%CI: 1.70-3.14), personal history of prostatitis (OR = 2.30; 95%CI: 1.44-3.70), benign prostatic hyperplasia (OR = 2.29; 95%CI: 1.79-2.93), being overweight (vs. normal; OR = 1.24; 95%CI: 0.99-1.55) or obese (vs. normal; OR = 1.44; 95%CI: 1.09-1.89), having reported more than seven sexual partners in a lifetime (vs.

OBJECTIVE: To estimate costs on the Medicare Benefits Schedule (MBS) and the Pharmaceutical Benefits Scheme (PBS) attributable to the diagnosis and treatment of prostate cancer. METHODS: We used data from a cohort study of 1064 men with localized prostate cancer recruited between 2005 and 2007 by 24 urologists across 10 sites in Queensland, Australia (ProsCan). We estimated the MBS and PBS costs attributable to prostate cancer from the date of initial appointment to 12 months after diagnosis in 2013 Australian dollars using a comparison group without prostate cancer. We used generalized linear modeling to identify key determinants of higher treatment-related costs. RESULTS: From the date of initial appointment to 12 months postdiagnosis, the average MBS costs attributable to prostate cancer were $9,357 (SD $191) per patient. These MBS costs were most sensitive to having private health insurance and the type of primary treatment received. The PBS costs were higher in the control group than in the ProsCan group ($5,641 vs $1,924). CONCLUSIONS: The costs of treating and managing prostate cancer are high and these result in a substantial financial burden for the Australian MBS. Costs attributable to prostate cancer appear to vary widely based on initial treatment and these are likely to increase with the introduction of more expensive services and pharmaceuticals. There is a pressing need for better prognostic tools to distinguish between indolent and aggressive prostate tumors to reduce potential over treatment and help ease the burden of prostate cancer.

The use of cytoreductive nephrectomy (CRN) in the targeted therapy era is still debated. We aimed to determine factors associated with reduced use of CRN and determine the effect of CRN on overall survival in patients with metastatic renal cell carcinoma (RCC). All advanced RCC diagnosed between 2001 and 2009 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment and death were electronically linked. Follow-up was to the end of 2011. Multivariable logistic regression analysis was used to determine factors associated with the receipt of CRN. Cox proportional hazards model was used to determine factors associated with survival. A total of 1062 patients were identified with metastatic RCC of whom 289 (27%) received CRN. There was no difference in the use of CRN over the time period of the study. Females (OR 0.68 (95% CI: 0.48-0.96)), unmarried individuals (OR 0.68 (95% CI: 0.48-0.96)), treatment in a nonteaching hospital (OR 0.26 (95% CI: 0.18-0.36)) and individuals without private insurance (OR 0.29 (95% CI: 0.20-0.41)) all had reduced likelihood of receiving CRN. On multivariable analysis, not receiving CRN resulted in a 90% increase in death (HR 1.90 (95% CI: 1.61-2.25)). In addition, increasing age (P < 0.001), increasing Charlson comorbidity status (P = 0.002) and female gender also had a significant independent association with death. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or have no private insurance have a reduced likelihood of receiving CRN.

Background The multiple imputation approach to missing data has been validated by a number of simulation studies by artificially inducing missingness on fully observed stage data under a pre-specified missing data mechanism. However, the validity of multiple imputation has not yet been assessed using real data. The objective of this study was to assess the validity of using multiple imputation for “unknown” prostate cancer stage recorded in the New South Wales Cancer Registry (NSWCR) in real-world conditions. Methods Data from the population-based cohort study NSW Prostate Cancer Care and Outcomes Study (PCOS) were linked to 2000–2002 NSWCR data. For cases with “unknown” NSWCR stage, PCOS-stage was extracted from clinical notes. Logistic regression was used to evaluate the missing at random assumption adjusted for variables from two imputation models: a basic model including NSWCR variables only and an enhanced model including the same NSWCR variables together with PCOS primary treatment. Cox regression was used to evaluate the performance of MI. Results Of the 1864 prostate cancer cases 32.7% were recorded as having “unknown” NSWCR stage. The missing at random assumption was satisfied when the logistic regression included the variables included in the enhanced model, but not those in the basic model only. The Cox models using data with imputed stage from either imputation model provided generally similar estimated hazard ratios but with wider confidence intervals compared with those derived from analysis of the data with PCOS-stage. However, the complete-case analysis of the data provided a considerably higher estimated hazard ratio for the low socio-economic status group and rural areas in comparison with those obtained from all other datasets. Conclusions Using MI to deal with “unknown” stage data recorded in a population-based cancer registry appears to provide valid estimates. We would recommend a cautious approach to the use of this method elsewhere.

© 2016 John Wiley & Sons Australia, Ltd Aim: Prostate cancer (PCa) is the most commonly diagnosed cancer in Australian males. There are limited data on the long-term health system costs associated with PCa. The aim of this study is to estimate long-term health care costs of PCa. Methods: We estimated the health system costs for a cohort of 1873 males diagnosed with PCa between 2000 and 2002, using linked medical, pharmaceutical and hospital data. Treatment was defined by an initial phase, measuring health care costs up to 6 months following diagnosis and a continuing phase (including metastatic treatment), measuring treatments to 9.5 years. Nonparametric models were used to calculate average health care costs by PCa risk groups at diagnosis (low to metastatic) and treatment pathways. Results: Health system costs increased with increasing PCa risk category, from $16 923 (low risk) to $39 101 (metastatic risk group). For men with initial localized risk, costs were $8 454 for the active surveillance treatment pathway, $9621 for external beam radiation therapy/brachytherapy, $19 210 for androgen deprivation therapy, $20 636 for radical prostatectomy, $21 161 for radical prostatectomy + external beam radiation therapy/brachytherapy, $21 388 for any of the treatments previously listed + androgen deprivation therapy, with an additional cost of $55 370 if metastatic treatment was undertaken. Conclusions: Treatment costs are highest during two phases over the natural cycle of the disease, the initial diagnosis phase and the metastatic treatment phase. Both the initial phase costs and low-risk category costs are driven largely by the rates of radical prostatectomy. Our study provides comprehensive long-term estimates of PCa costs.

OBJECTIVE: To compare prostate cancer mortality for Aboriginal and non-Aboriginal men and to describe prostate cancer treatments received by Aboriginal men. PATIENTS AND METHODS: We analysed cancer registry records for all men diagnosed with prostate cancer in New South Wales (NSW) in 2001-2007 linked to hospital inpatient episodes and deaths. More detailed information on androgen-deprivation therapy and radiotherapy was obtained from medical records for 87 NSW Aboriginal men diagnosed in 2000-2011. The main outcomes were primary treatment for, and death from, prostate cancer. Analysis included Cox proportional hazards regression and logistic regression. RESULTS: There were 259 Aboriginal men among 35,214 prostate cancer cases diagnosed in 2001-2007. Age and spread of disease at diagnosis were similar for Aboriginal and non-Aboriginal men. Prostate cancer mortality 5 years after diagnosis was higher for Aboriginal men (17.5%, 95% confidence interval (CI) 12.4-23.3) than non-Aboriginal men (11.4%, 95% CI 11.0-11.8). Aboriginal men were 49% more likely to die from prostate cancer (hazard ratio 1.49, 95% CI 1.07-1.99) after adjusting for differences in demographic factors, stage at diagnosis, health access and comorbidities. Aboriginal men were less likely to have a prostatectomy for localised or regional cancer than non-Aboriginal men (adjusted odds ratio 0.60, 95% CI 0.40-0.91). Of 87 Aboriginal men with full staging and treatment information, 60% were diagnosed with localised disease. Of these, 38% had a prostatectomy (± radiotherapy), 29% had radiotherapy only and 33% had neither. CONCLUSION: More research is required to explain differences in treatment and mortality for Aboriginal men with prostate cancer compared with non-Aboriginal men. In the meantime, ongoing monitoring and efforts are needed to ensure Aboriginal men have equitable access to best care. This work was produced as part of the APOCC, which was funded by a National Health and MRC Health Services grant (Application Ref: 440202). Linkage of the ‘Patterns of Primary Treatment’ data set to the APDC was funded by a Cancer Institute NSW Epidemiology Linkage Grant (10/EPI/2-05).

As previously found in various members of the Mucorales, 3-hydroxy oxylipins in Mucor genevensis are associated with the sporangia, i.e. mainly the columella structure and between aggregating sporangiospores. To determine if this phenomenon is also true in distantly related members, the mucoralean fungus Pilobolus was examined. This fungus is characterized by relatively large sub sporangial-columella structures which actively eject sporangia in a sticky liquid for attachment onto herbage surrounding its growth medium--in this case horse dung. Strikingly, this fungus produced a novel oxylipin i.e. a 3-hydroxy monounsaturated fatty acid, possibly a nonenoic acid, which is mainly associated with the sub sporangial-columella structure and aggregating sporangiospores. The specificity of the antibody against 3-hydroxy oxylipins used in immunofluorescence mapping of the mucoralean fungi, was further confirmed in the yeast, Saccharomycopsis malanga which produces 3-hydroxy palmitate in crystal form. These crystals occur between aggregating yeast cells. On the basis of the available data, we hypothesize that 3-hydroxy oxylipins probably function as adhesives, attaching fungal cells to each other or to other surfaces through entropic based hydrophobic forces and/or hydrogen bonds.

BACKGROUND: While several studies have examined factors that influence the use of breast screening mammography, faecal occult blood tests (FOBT) for bowel cancer screening and prostate specific antigen (PSA) tests for prostate disease in Australia, research directly comparing the use of these tests is sparse. We examined sociodemographic and health-related factors associated with the use of these tests in the previous two years either alone or in combination. METHODS: Cross-sectional analysis of self-reported questionnaire data from 96,711 women and 82,648 men aged 50 or over in The 45 and Up Study in NSW (2006--2010). RESULTS: 5.9% of men had a FOBT alone, 44.9% had a PSA test alone, 18.7% had both tests, and 30.6% had neither test. 3.2% of women had a FOBT alone, 56.0% had a mammogram alone, 16.2% had both and 24.7% had neither test. Among men, age and socioeconomic factors were largely associated with having both FOBT and PSA tests. PSA testing alone was largely associated with age, family history of prostate cancer, health insurance status and visiting a doctor. Among women, age, use of hormone replacement therapy (HRT), health insurance status, family history of breast cancer, being retired and not having a disability were associated with both FOBT and mammograms. Mammography use alone was largely associated with age, use of HRT and family history of breast cancer. FOBT use alone among men was associated with high income, living in regional areas and being fully-retired and among women, being fully-retired or sick/disabled. CONCLUSIONS: These results add to the literature on sociodemographic discrepancies related to cancer screening uptake and highlight the fact that many people are being screened for one cancer when they could be screened for two

A complementary DNA (cDNA) encoding the receptor for porcine parathyroid hormone /parathyroid hormone-related peptide (PTH/PTHrP) was isolated from a porcine kidney cDNA library. The porcine PTH/PTHrP receptor is a 585 amino acid protein containing seven putative membrane-spanning domains. The porcine PTH/PTHrP receptor has amino acid identity of 95.6%, 80.4%, and 88.7% with human, opossum, and rat PTH/PTHrP receptors, respectively and 53.4% identity to the recently cloned human PTH2 receptor. The receptor cDNA was subsequently cloned into a mammalian cell expression vector (pRC/CMV) which contains a human cytomegalovirus promoter. A human kidney cell line (293), stably transfected with this vector, expressed the receptor at a high level and, when challenged with human PTH(1–34), increased cytoplasmic CAMP and inositol triphosphate production. Radioligand binding studies revealed that the receptor bound both human PTH(1–34), and PTHM(1–36). Scatchard analyses of three clones showed that the cells harbor a single class of high affinity receptor (K d = 1−4 nM for human PTH(1–34)) but had varying receptor numbers (10) 5 – 10 6 receptors/cell). In contrast to PTH(1–34), the [Arg 2 ]PTH(1–34) analog bound to the porcine PTH/PTHrP receptor with low affinity and was a weak agonist for cAMP stimulation with the cloned receptor. These response characteristics differentiate the porcine receptor from the previously cloned rat and opossum PTH/PTHrP receptors.

Nitrogen transformations and their effect on aerobic suspended growth treatment of an industrial wastewater were studied in three parallel bench-scale reactors operated at 5 degrees C at mean cell residence times (MCRT) of 15, 30, and 60 days. In normal process wastewater, the bulk of influent nitrogen was in organic form, and the fraction transformed was almost totally incorporated into synthesized biomass. Assimilative control by heterotrophs maintained ammonia-nitrogen levels below permitted effluent levels, and nitrification was not significant. Although volatile suspended solids had a nitrogen content of only 5% to 8%, effective organics removal was maintained, and total organic carbon and filtered daily average five-day biochemical oxygen demand (BOD5) were below permitted effluent levels. A marked improvement in settleability and lower effluent total suspended solids was achieved by adding ammonia-nitrogen to the wastewater in excess of stoichiometric growth requirements. During a batch production cycle of a cationic chemical, the ratio of nitrogen to chemical oxygen demand and the fraction of the total influent nitrogen in soluble form increased in the wastewater. Reactor effluent ammonia levels increased to above permit levels at all three MCRTs during treatment of wastewater containing cationic production effluents. The magnitude of ammonia increase was greater for longer MCRTs, suggesting that synthesis of cell mass was not capable of assimilating the increased ammonia supply under these non-steady conditions. The experimental results suggest several potential strategies for operating the aerobic process at the treatment facility, including adding nitrogen to improve settleability and discontinuing these additions when wastewater contains a high ratio of nitrogen to chemical oxygen demand and an elevated soluble nitrogen fraction.

OBJECTIVE: To describe values of serum prostate-specific antigen (PSA) in older men without diagnosed prostate cancer, categorised by age and country of birth, and to describe self-reported prostate cancer screening. DESIGN, PARTICIPANTS AND SETTING: A cohort study (the Concord Health and Ageing in Men Project) involving a representative sample of 1434 eligible community-dwelling men with no diagnosis of prostate cancer who were aged 70 years and over and living in a defined geographic area in Sydney, with baseline data collected between 28 January 2005 and 4 June 2007. MAIN OUTCOME MEASURES: Serum PSA levels and self-reported prostate cancer screening. RESULTS: 11% of men (155) had a PSA level of >/= 6.5 ng/mL, increasing from 7.5% of men aged 70-74 years to 31.4% of men aged >/= 90 years. PSA levels varied with ethnicity, with Australian-born men (695) having the highest levels (median, 2.3 ng/mL; 5th-95th percentile, 0.4-10.1 ng/mL), followed by men born in China (n = 42; 2.1 ng/mL; 0.4-12.4 ng/mL), United Kingdom and Ireland (n = 70; 1.9 ng/mL; 0.3-8.9 ng/mL), Greece (n = 59; 1.5 ng/mL; 0.2-6.1 ng/mL), and Italy (n = 293; 1.4 ng/mL; 0.3-7.2 ng/mL). A PSA test in the previous 2 years was reported by 48% of participants, and a digital rectal examination (DRE) in the previous 2 years by 37%. CONCLUSIONS: A significant number of men aged over 70 years reported recent prostate cancer tests. The PSA level ranges reported in this cohort will help with interpreting serum PSA level findings in men aged over 70 years

Introduction Current strategies for the management of prostate cancer are inadequate in Australia. We will, in this study, estimate current service needs and project the future needs for prostate cancer patients in Australia. Methods and analysis First, we will project the future prevalence of prostate cancer for 2010-2018 using data for 1972-2008 from the New South Wales (NSW) Central Cancer Registry. These projections, based on modelled incidence and survival estimates, will be estimated using PIAMOD (Prevalence, Incidence, Analysis MODel) software. Then the total prevalence will be decomposed into five stages of care: initial care, continued monitoring, recurrence, last year of life and long-term survivor. Finally, data from the NSW Prostate Cancer Care and Outcomes Study, including data on patterns of treatment and associated quality of life, will be used to estimate the type and amount of services that will be needed by prostate cancer patients in each stage of care. In addition, Central Cancer Registry episode data will be used to estimate transition rates from localised or locally advanced prostate cancer to metastatic disease. Medicare and Pharmaceutical Benefits data, linked with Prostate Cancer Care and Outcomes Study data, will be used to complement the Cancer Registry episode data. The methods developed will be applied Australia-wide to obtain national estimates of the future prevalence of prostate cancer for different stages of clinical care. Ethics and dissemination This study was approved by the NSW Population and Health Services Research Ethics Committee. Results of the study will be disseminated widely to different interest groups and organisations through a report, conference presentations and peer-reviewed articles

BACKGROUND: Population-based patterns of care studies are important for monitoring cancer care but conducting them is expensive and resource-intensive. Linkage of routinely collected administrative health data may provide an efficient alternative. Our aim was to determine the accuracy of linked routinely collected administrative data for monitoring prostate cancer care in New South Wales (NSW), Australia. METHODS: The NSW Prostate Cancer Care and Outcomes Study (PCOS), a population-based survey of patterns of care for men aged less than 70 years diagnosed with prostate cancer in NSW, was linked to the NSW Cancer Registry, electronic hospital discharge records and Medicare and Pharmaceutical claims data from Medicare Australia. The main outcome measures were treatment with radical prostatectomy, any radiotherapy, external beam radiotherapy, brachytherapy or androgen deprivation therapy, and cancer staging. PCOS data were considered to represent the true treatment status. The sensitivity and specificity of the administrative data were estimated and relevant patient characteristics were compared using chi-squared tests. RESULTS: The validation data set comprised 1857 PCOS patients with treatment information linked to Cancer Registry records. Hospital and Medicare claims data combined described treatment more accurately than either one alone. The combined data accurately recorded radical prostatectomy (96% sensitivity) and brachytherapy (93% sensitivity), but not androgen deprivation therapy (76% sensitivity). External beam radiotherapy was rarely captured (5% sensitivity), but this was improved by including Medicare claims for radiation field setting or dosimetry (86% sensitivity). False positive rates were near 0%. Disease stage comparisons were limited by one-third of cases having unknown stage in the Cancer Registry. Administrative data recorded treatment more accurately for cases in urban areas. CONCLUSIONS: Cancer Registry and hospital inpatient data accurately captured radical prostatectomy and brachytherapy treatment, but not external beam radiotherapy or disease stage. Medicare claims data substantially improved the accuracy with which all major treatments were recorded. These administrative data combined are valid for population-based studies of some aspects of prostate cancer care

Large-scale randomised controlled trials in Europe and the United States are informing evidence-based clinical advice

PURPOSE: It is important to meet the supportive care needs of cancer patients to ensure their satisfaction with their care. A population-wide sample of men younger than 70 years and newly diagnosed with prostate cancer was surveyed to determine their unmet needs in five domains and the factors predicting them. PATIENTS AND METHODS: Eligible men were younger than 70 years and residents in New South Wales, Australia, with newly diagnosed histopathologically confirmed prostate cancer. Sixty-seven percent of eligible men diagnosed between October 2000 and October 2001 participated. Demographic, treatment, and self-reported health data were collected. Information on cancer stage, grade, and prostate-specific antigen was obtained from medical records. Logistic regression analyses determined patient and treatment variables that predicted higher unmet needs. RESULTS: More than half (54%) of men with prostate cancer expressed some level of unmet psychological need, and 47% expressed unmet sexuality needs. Nearly one fourth expressed a moderate or high level of unmet need with respect to changes in sexuality. Sexuality needs were independently predicted by being younger, having had a secondary school education only, having had surgery, and being married, living as married, or divorced. Uncertainty about the future was also an important area of unmet need. CONCLUSION: Attention should be given to sexual and psychological needs in the early months after diagnosis or treatment of prostate cancer, particularly in younger men, those with less education, and those having surgery. Research into better ways of meeting these needs will enable us to meet them with as much rigor as we meet clinical treatment needs

OBJECTIVES: Prostate cancer is the most commonly registered cancer in Australian men, yet there is a lack of information about its management. We described the patterns and trends in the surgical treatment of men with prostate cancer in New South Wales (NSW). METHOD: We used probabilistic record linkage to link cancer registry data with hospital admissions. All NSW men diagnosed with prostate cancer between 1993 and 2002 were eligible for the study. Rates of radical prostatectomy, bilateral orchidectomy and transurethral resection of the prostate were calculated. Factors affecting the probability of undergoing these procedures were examined using log-binomial regression. RESULTS: Between January 1993 and December 2002, 38,712 men were diagnosed with prostate cancer in NSW. Of these, 33,200 (85.8%) cancer registry records were linked to at least one hospital admission record. Men resident in rural areas at diagnosis (RR = 0.69, 95% Cl 0.65-0.73) and men resident in more socio-economically disadvantaged areas (RR =0.83, 95% Cl 0.78-0.89 for most disadvantaged) were significantly less likely to undergo a radical prostatectomy after adjusting for age and disease stage. While orchidectomy rates fell significantly during the period, rates were significantly higher in rural and lower socio-economic areas after adjusting for age and stage. CONCLUSION AND IMPLICATIONS: Further investigation is needed to understand the reasons for the variation in the surgical patterns of care for prostate cancer so that interventions can be implemented to ensure appropriate access for all men

Growth hormone-releasing hormone (GHRH) belongs to the family of gutneuropeptide hormones which also includes glucagon, secretin and vasoactive intestinal peptide (VIP). All receptors for this peptide hormone family seem to involve similar signal transduction pathways. Upon hormone binding, these receptors interact with guanine nucleotide binding protein ‘Gs’ and cause the stimulation of adenylate cyclase. The secretin and VIP receptor cDNAs have recently been cloned and found to be homologous to those of calcitonin and parathyroid hormone receptors. Based on cDNA sequences of these receptors, we designed several oligonucleotide primers which were used to amplify two novel porcine pituitary cDNA fragments by the polymerase chain reaction. One novel receptor cDNA fragment was used to screen a porcine pituitary cDNA library and a full-length cDNA encoding a putative porcine GHRH receptor of 451 amino acids was isolated. This putative receptor mRNA is present specifically in porcine anterior pituitary cells and not in eight other porcine tissues as shown by Northern hybridization analysis. The receptor cDNA was subsequently cloned into a mammalian cell expression vector containing the cytomegalo-virus promoter. A human kidney tumor cell line (293) stably transfected with this vector was found to express the receptor efficiently and to bind [ 125 I]-GHRH specifically. Furthermore, challenge of the 293 cells expressing the receptor by GHRH leads to efficient stimulation of cytoplasmic cAMP production.

We report results of a study of electron tunneling into bulk samples of the new high-${T}_{c}$ superconductor Y-Ba-Cu-O using point-contact tunneling. Based on a superconductive tunneling interpretation, the results show exceptionally large energy gaps in these materials (roughly 2\ensuremath{\Delta}=100 meV), implying 2\ensuremath{\Delta}/${k}_{C}$${T}_{c}$\ensuremath{\sim}13. Similar values were found previously by us for La-Sr-Cu-O. We also see Structure in the I-V curves similar to that seen in La-Sr-Cu-O. On the basis of the asymmetries observed in the I-V characteristics, we believe that the natural tunneling barrier on this material is of the Schottky type.

In the aftermath of World War II the United States found itself in a position of unexpected economic strength and confronting a resurgence in births quite beyond what demographers had come to consider reasonable for a developed country. It has taken nearly 30 years for fertility to become ‘reasonable’ again, and its interim course had seemed to call for exceptional efforts at interpretation. The best known and most respected of these efforts is Richard Easterlin's, which sees cohort fertility as directly related to cohort incomes in early adult life, indexed on parental incomes, and cohort incomes as inversely related to cohort sizes. Under some circumstances the mechanism is said to generate long swings in annual numbers of births. This paper takes issue with the Easterlin model, both as regards the actual course of fertility and the ability of Easterlin's concept of ‘relative incomes’ to explain the observed patterns. We find that cohort fertility behaviour has tended not to be stable throughou...

© 2017 John Wiley & Sons Ltd The purpose of this study was to provide in-depth insight into men's experiences of prostate cancer, specifically: perceived stigma and self-blame, social isolation, unmet need and help-seeking. A qualitative descriptive approach was used. Semi-structured interviews were undertaken with 20 men diagnosed with prostate cancer, and thematic analysis was undertaken. Some participants perceived a stigma associated with prostate cancer and cancer in general, which sometimes acted as a barrier to disclosure. Self-blame and internalisation of cause was not a prominent issue. Participants’ descriptions of emotional distress, social isolation and anxiety demonstrated the impact of prostate cancer. Social isolation was most commonly reported as a physical consequence of treatment and/or side effects. Participants felt both support and ongoing care were limited at post-treatment. Most did not seek or receive help for emotional or psychosocial problems from a formal source due to anticipated awkwardness, autonomous coping, not burdening others, unwanted sympathy and retaining privacy. Prostate cancer can cause considerable emotional and social burden for some men, and many are unlikely to seek or receive help. Men, and their support networks, require active encouragement throughout diagnosis, treatment and follow-up to overcome barriers and access additional support, particularly for sexual, emotional and psychosocial issues.

Carbapenem antibiotics have become therapeutics of last resort for the treatment of difficult infections. The emergence of class-A β-lactamases that have the ability to inactivate carbapenems in the past few years is a disconcerting clinical development in light of the diminished options for treatment of infections. A member of the GES-type β-lactamase family, GES-1, turns over imipenem poorly, but the GES-5 β-lactamase is an avid catalyst for turnover of this antibiotic. We report herein high-resolution X-ray structures of the apo GES-5 β- lactamase and the GES-1 and GES-5 β-lactamases in complex with imipenem. The latter are the first structures of native class-A carbapenemases with a clinically used carbapenem antibiotic in the active site. The structural information is supplemented by information from molecular dynamics simulations, which collectively for the first time discloses how the second step of catalysis by these enzymes, namely, hydrolytic deacylation of the acylenzyme species, takes place effectively in the case of the GES-5 β-lactamase and significantly less so in GES-1. This information illuminates one evolutionary path that nature has taken in the direction of the inexorable emergence of resistance to carbapenem antibiotics. Refereed/Peer-reviewed

Background: Recent evidence suggests that a lower extent of the retronasal aroma release correspond to a higher amount of ad libitum food intake. This has been regarded as one of the bases of behavioral choices towards food consumption in obese people. In this pilot study we investigated the hypothesis that saliva from obese individuals could be responsible for an alteration of the retro-nasal aroma release. We tested this hypothesis in vitro, by comparing the release of volatiles from a liquid food matrix (wine) after its interaction with saliva from 28 obese (O) and 28 normal-weight (N) individuals. Methods and Findings: Amplicon sequencing of the 16S rRNA V4 region indicated that Firmicutes and Actinobacteria were more abundant in O, while Proteobacteria and Fusobacteria dominated in N. Streptococcaceae were significantly more abundant in the O subjects and constituted 34% and 19% on average of the saliva microbiota of O and N subjects, respectively. The Total Antioxidant Capacity was higher in O vs N saliva samples. A model mouth system was used to test whether the in-mouth wine aroma release differs after the interaction with O or N saliva. In O samples, a 18% to 60% significant decrease in the mean concentration of wine volatiles was detected as a result of interaction with saliva, compared with N. This suppression was linked to biochemical differences in O and N saliva composition, which include protein content. Conclusion: Microbiological and biochemical differences were found in O vs N saliva samples. An impaired retronasal aroma release from white wine was detected in vitro and linked to compositional differences between saliva from obese and normal-weight subjects. Additional in vivo investigations on diverse food matrices could contribute to understanding whether a lower olfactory stimulation due to saliva composition can be a co-factor in the development/maintenance of obesity. © 2014 Piombino et al.