Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

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.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Highly transparent and conductive Al-doped ZnO nanoparticulate thin films using direct write processing.

Solution processable Al-doped ZnO (AZO) thin films are attractive candidates for low cost transparent electrodes. We demonstrate here an optimized nanoparticulate ink for the fabrication of AZO thin films using scalable, low-cost direct write processing (ultrasonic spray deposition) in air at atmospheric pressure. The thin films were made via thermal processing of as-deposited films. AZO films deposited using the proposed nanoparticulate ink with further reducing in vacuum and rf plasma of forming gas exhibited optical transparency greater than 95% across the visible spectrum, and electrical resistivity of 0.5 Ω cm and it drops down to 7.0 × 10(-2) Ω cm after illuminating with UV light, which is comparable to commercially available tin doped indium oxide colloidal coatings. Various structural analyses were performed to investigate the influence of ink chemistry, deposition parameters, and annealing temperatures on the structural, optical, and electrical characteristics of the spray deposited AZO thin films. Optical micrographs confirmed the presence of surface defects and cracks using the AZO NPs ink without any additives. After adding N-(2-Aminoethyl)-3-aminopropylmethyldimethoxy silane to the ink, AZO films exhibited an optical transparency which was virtually identical to that of the plain glass substrate.

The STAMPEDE2 Trial: a Site Survey of Current Patterns of Care, Access to Imaging and Treatment of Metastatic Prostate Cancer.

AIMS: The forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2. MATERIALS AND METHODS: The survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 (177Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging. RESULTS: From 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment. CONCLUSION: There is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial.

Food web controls on mercury fluxes and fate in the Colorado River, Grand Canyon.

Mercury (Hg) biomagnification in aquatic food webs is a global concern; yet, the ways species traits and interactions mediate these fluxes remain poorly understood. Few pathways dominated Hg flux in the Colorado River despite large spatial differences in food web complexity, and fluxes were mediated by one functional trait, predation resistance. New Zealand mudsnails are predator resistant and a trophic dead end for Hg in food webs we studied. Fishes preferred blackflies, which accounted for 56 to 80% of Hg flux to fishes, even where blackflies were rare. Food web properties, i.e., match/mismatch between insect production and fish consumption, governed amounts of Hg retained in the river versus exported to land. An experimental flood redistributed Hg fluxes in the simplified tailwater food web, but not in complex downstream food webs. Recognizing that species traits, species interactions, and disturbance mediate contaminant exposure can improve risk management of linked aquatic-terrestrial ecosystems.

A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter.

Nurses and midwives of Australia now is the time for change! As powerfully placed, Indigenous and non-Indigenous nursing and midwifery professionals, together we can ensure an effective and robust Indigenous curriculum in our nursing and midwifery schools of education. Today, Australia finds itself in a shifting tide of social change, where the voices for better and safer health care ring out loud. Voices for justice, equity and equality reverberate across our cities, our streets, homes, and institutions of learning. It is a call for new songlines of reform. The need to embed meaningful Indigenous health curricula is stronger now than it ever was for Australian nursing and midwifery. It is essential that nursing and midwifery leadership continue to build an authentic collaborative environment for Indigenous curriculum development. Bipartisan alliance is imperative for all academic staff to be confident in their teaching and learning experiences with Indigenous health syllabus. This paper is a call out. Now is the time for Indigenous and non-Indigenous nurses and midwives to make a stand together, for justice and equity in our teaching, learning, and practice. Together we will dismantle systems, policy, and practices in health that oppress. The Black Lives Matter movement provides us with a 'now window' of accepted dialogue to build a better, culturally safe Australian nursing and midwifery workforce, ensuring that Black Lives Matter in all aspects of health care.

Trends in non-metastatic prostate cancer management in the Northern and Yorkshire region of England, 2000-2006.

BACKGROUND: Our objective was to analyse variation in non-metastatic prostate cancer management in the Northern and Yorkshire region of England. METHODS: We included 21,334 men aged > or = 55, diagnosed between 2000 and 2006. Principal treatment received was categorised into radical prostatectomy (11%), brachytherapy (2%), external beam radiotherapy (16%), hormone therapy (42%) and no treatment (29%). RESULTS: The odds ratio (OR) for receiving a radical prostatectomy was 1.53 in 2006 compared with 2000 (95% CI 1.26-1.86), whereas the OR for receiving hormone therapy was 0.57 (0.51-0.64). Age was strongly associated with treatment received; radical treatments were significantly less likely in men aged > or = 75 compared with men aged 55-64 years, whereas the odds of receiving hormone therapy or no treatment were significantly higher in the older age group. The OR for receiving radical prostatectomy, brachytherapy or external beam radiotherapy were all significantly lower in the most deprived areas when compared with the most affluent (0.64 (0.55-0.75), 0.32 (0.22-0.47) and 0.83 (0.74-0.94), respectively) whereas the OR for receiving hormone therapy was 1.56 (1.42-1.71). CONCLUSIONS: This study highlights the variation and inequalities that exist in the management of non-metastatic prostate cancer in the Northern and Yorkshire region of England.

Precipitation and temperature drive continental-scale patterns in stream invertebrate production.

Secondary production, the growth of new heterotrophic biomass, is a key process in aquatic and terrestrial ecosystems that has been carefully measured in many flowing water ecosystems. We combine structural equation modeling with the first worldwide dataset on annual secondary production of stream invertebrate communities to reveal core pathways linking air temperature and precipitation to secondary production. In the United States, where the most extensive set of secondary production estimates and covariate data were available, we show that precipitation-mediated, low-stream flow events have a strong negative effect on secondary production. At larger scales (United States, Europe, Central America, and Pacific), we demonstrate the significance of a positive two-step pathway from air to water temperature to increasing secondary production. Our results provide insights into the potential effects of climate change on secondary production and demonstrate a modeling framework that can be applied across ecosystems.

Case control analysis of repeat expansion size in ataxia.

Spinocerebellar ataxias (SCAs) are a group of clinically and genetically heterogeneous neurological diseases. The expansion of unstable microsatellite repeats has been identified as the underlying pathogenic cause of 10 subtypes of autosomal dominant SCAs. The aetiology of sporadic SCA is unknown. The aim of this study was to investigate the effect of large normal repeats in patients presenting with sporadic or familial ataxia compared to a control population. The size of the expansion was determined using a fluorescent PCR approach in 10 common SCA genes: SCA-1 (ATXN1), SCA-2 (ATXN2), SCA-3 (ATXN3), SCA-6 (CACNA1A), SCA-7 (ATXN7), SCA-8 (ATXN8OS), SCA-10 (ATXN10), SCA-12 (PPP2R2B), SCA-17 (TBP) and DRPLA (ATN1), in 165 ataxia patients and 307 controls of Welsh origin. There was no difference between cases and controls in the distribution of the large normal alleles, or in the distribution of the combined CAG repeats. The normal allele distribution in the Welsh population was largely similar to that of other Caucasian populations. Our study failed to demonstrate an effect of large normal repeats on the susceptibility to develop ataxia.

Whole-system nutrient enrichment increases secondary production in a detritus-based ecosystem.

Although the effects of nutrient enrichment on consumer-resource dynamics are relatively well studied in ecosystems based on living plants, little is known about the manner in which enrichment influences the dynamics and productivity of consumers and resources in detritus-based ecosystems. Because nutrients can stimulate loss of carbon at the base of detrital food webs, effects on higher consumers may be fundamentally different than what is expected for living-plant-based food webs in which nutrients typically increase basal carbon. We experimentally enriched a detritus-based headwater stream for two years to examine the effects of nutrient-induced changes at the base of the food web on higher metazoan (predominantly invertebrate) consumers. Our paired-catchment design was aimed at quantifying organic matter and invertebrate dynamics in the enriched stream and an adjacent reference stream for two years prior to enrichment and two years during enrichment. Enrichment had a strong negative effect on standing crop of leaf litter, but no apparent effect on that of fine benthic organic matter. Despite large nutrient-induced reductions in the quantity of leaf litter, invertebrate secondary production during the enrichment was the highest ever reported for headwater streams at this Long Term Ecological Research site and was 1.2-3.3 times higher than predicted based on 15 years of data from these streams. Abundance, biomass, and secondary production of invertebrate consumers increased significantly in response to enrichment, and the response was greater among taxa with larval life spans < or = 1 yr than among those with larval life spans >1 yr. Production of invertebrate predators closely tracked the increased production of their prey. The response of invertebrates was largely habitat-specific with little effect of enrichment on food webs inhabiting bedrock outcrops. Our results demonstrate that positive nutrient-induced changes to food quality likely override negative changes to food quantity for consumers during the initial years of enrichment of detritus-based stream ecosystems. Longer-term enrichment may impact consumers through eventual reductions in the quantity of detritus.

Rapid rejoining of DNA strand breaks in resting human lymphocytes after irradiation by low doses of 60Co gamma rays or 14.6-MeV neutrons.

The production and repair of DNA strand breaks was studied in human lymphocytes by means of a sensitive fluorometric technique. Lymphocytes were isolated by conventional methods and air-equilibrated suspensions were irradiated by low doses (less than or equal to 2 Gy) of either 60Co gamma rays or 14.6-MeV neutrons at 0 degree C. The apparent yield of initial strand breaks induced by neutrons was only 36% of that induced by gamma rays, in agreement with the observations of other workers. Resting lymphocytes were found to be proficient in their ability to rejoin gamma-induced strand breaks at 37 degrees C; rejoining followed biphasic kinetics, with 70% of the breaks disappearing with a half-life of about 3 min. Although the initial number of breaks induced by neutron irradiation was low, after 20 min of incubation the residual number of breaks was very similar for the two forms of radiation.

Laminaria as an adjunct in induction of labor.

The safety and efficacy of laminaria tents as an adjunct to labor induction near term were examined in a prospective, controlled, and randomized study involving insertion of laminaria into the cervical canal the evening prior to planned induction. Six of 35 subjects in whom laminaria were used entered labor spontaneously and delivered overnight, compared with 1 of 39 controls. Of the remainder, the Bishop score increased an average of 3.7 points, a highly significant change, in the laminaria-treated group compared with no change in the controls. Labor, induced primarily by amniotomy with intravenous oxytocin then given to patients in whom regular contractions did not begin within 8 hours, was shorter with laminaria use than in controls, though the amniotomy-to-delivery interval did not differ significantly. However, comparison of the subgroup with cervices relatively unfavorable for induction, indicated by an initial Bishop score of 5 or less, showed both length of labor and amniotomy-to-delivery interval to be significantly shorter (each by an average of 3 hours) in the laminaria-treated group compared with controls. Complications, including febrile morbidity, did not differ. We conclude that laminaria tents are both effective and safe as an adjunct to labor induction, acting by accelerating the preparatory changes in the cervix which normally occur in late pregnancy.

Crystal engineering of microporous 'Chinese-lantern' compounds to improve their ability to reversibly adsorb sulfur dioxide.

Three new 'Chinese lantern' complexes [XMn(mu-dppO2)4MnX](2+)2X-.4MeOH.Me2CO [X = Cl, Br, I; dppO2 = 1,3-bis(diphenylphosphinoyl)propane], have been structurally characterised using single-crystal X-ray diffraction and shown to have increasing affinity for SO2 across the series Cl < Br < I via thermogravimetric measurements.

Calculation of beta-ray dose distributions from ophthalmic applicators and comparison with measurements in a model eye.

Dose distributions throughout the eye, from three types of beta-ray ophthalmic applicators, were calculated using the EGS4, ACCEPT 3.0, and other Monte Carlo codes. The applicators were those for which doses were measured in a recent international intercomparison [Med. Phys. 28, 1373 (2001)], planar applicators of 106Ru-106Rh and 90Sr-90Y and a concave 106Ru-106Rh applicator. The main purpose was to compare the results of the various codes with average experimental values. For the planar applicators, calculated and measured doses on the source axis agreed within the experimental errors (<10%) to a depth of 7 mm for 106Ru-106Rh and 5 mm for 90Sr-90Y. At greater distances the measured values are larger than those calculated. For the concave 106Ru-106Rh applicator, there was poor agreement among available calculations and only those calculated by ACCEPT 3.0 agreed with measured values. In the past, attempts have been made to derive such dose distributions simply, by integrating the appropriate point-source dose function over the source. Here, we investigated the accuracy of this procedure for encapsulated sources, by comparing such results with values calculated by Monte Carlo. An attempt was made to allow for the effects of the silver source window but no corrections were made for scattering from the source backing. In these circumstances, at 6 mm depth, the difference in the results of the two calculations was 14%-18% for a planar 106Ru-l06Rh applicator and up to 30% for the concave applicator. It becomes worse at greater depths. These errors are probably caused mainly by differences between the spectrum of beta particles transmitted by the silver window and those transmitted by a thickness of water having the same attenuation properties.

Dosimetry of beta-ray ophthalmic applicators: comparison of different measurement methods.

An international intercomparison of the dosimetry of three beta particle emitting ophthalmic applicators was performed, which involved measurements with radiochromic film, thermoluminescence dosimeters (TLDs), alanine pellets, plastic scintillators, extrapolation ionization chambers, a small fixed-volume ionization chambers, a diode detector and a diamond detector. The sources studied were planar applicators of 90Sr-90Y and 106Ru-106Rh, and a concave applicator of 106Ru-106Rh. Comparisons were made of absolute dosimetry determined at 1 mm from the source surface in water or water-equivalent plastic, and relative dosimetry along and perpendicular to the source axes. The results of the intercomparison indicate that the various methods yield consistent absolute dosimetry results at the level of 10%-14% (one standard deviation) depending on the source. For relative dosimetry along the source axis at depths of 5 mm or less, the agreement was 3%-9% (one standard deviation) depending on the source and the depth. Crucial to the proper interpretation of the measurement results is an accurate knowledge of the detector geometry, i.e., sensitive volume and amount of insensitive covering material. From the results of these measurements, functions which describe the relative dose rate along and perpendicular to the source axes are suggested.

Spectra and dosimetry related to neutron irradiations of the human body.

Neutron spectra at various locations in a phantom, irradiated by collimated beams of 14 MeV neutrons and neutrons from 252 Cf and Po-Be sources, were calculated using the Monte Carlo technique. These spectra give an indication of the distortion in source spectra associated with neutron irradiations of the body for therapeutic and diagnostic purposes. The effect of the spectral distortions on the dose response of several activation and damage track detectors was investigated. Of the dosemeters studied, Np has a dose response most nearly independent (+/-10%) of the spectral changes.

Theory behind surgical correction of presbyopia.

This relatively new procedure is interesting, promising, and appears to be safe. These issues are currently being evaluated by the US FDA and in several other countries, most notably Canada. The procedure is based on Ronald A. Schachar's new theory of how accommodation occurs. The clinical course of the patients and the new wavefront analysis appear to support the theory. Regardless of the exact mechanism, clinically, the patients read and behave as though they have had their accommodation restored. The author certainly has been very impressed and excited with the results in his patients whose surgeons he has proctored.