Descriptive analysis of prostate cancer pathology data from diagnosis and surgery in men from the 45 and Up Study.

Information available from the New South Wales Cancer Registry (NSWCR) about the aggressiveness of prostate cancer is limited to the summary stage variable 'degree of spread', which contains a high proportion of cases defined as 'unknown'. In this study we demonstrate the feasibility of obtaining and analysing prostate cancer pathology data from stored pathology records. Pathology data were extracted from stored pathology records of incident prostate cancer cases in men participating in the 45 and Up Study, a large Australian prospective cohort study, who were diagnosed between January 2006 and December 2013. Baseline questionnaires from the 45 and Up Study were linked to the NSWCR. Demographic and pathology items were tabulated and associations described. We evaluated the completeness of pathological characteristics by degree of spread of cancer at diagnosis. Among the 123,921 men enrolled in the 45 and Up Study, 5,091 had incident prostate cancer and 5,085 were linked to a pathology record. The most complete variables included grade group of diagnostic (85.8%) and surgical (99.8%) specimens, margin status (98.1%), extraprostatic extension (95.1%) and seminal vesicle invasion (96.8%). Most diagnostic specimens were grade group 1 (26.6%) or 2 (23.5%). Of the 5,085 cases, 30.8% were classified by the NSWCR with unknown degree of spread; a pathology record could be extracted for 99.4% of these. The unknown degree of spread cases had similar levels of completeness and distribution of diagnostic and surgical pathology features to those with a localised degree of spread. This study demonstrated the feasibility of obtaining and analysing data derived from pathology reports from centralised state-based cancer registry notifications. Supplementing degree of spread information with pathology data from diagnosis and surgery will improve both the quality of research and policy aimed at improving the lives of men with prostate cancer.

Exploring COVID-19 Vaccine Confidence with People from Black and Asian Backgrounds in England.

AIMS: Little research has examined factors underlying COVID-19 vaccine hesitancy or refusal in Black and Asian individuals in England, among whom hesitancy tends to be higher than in the general population. This qualitative study aimed to gain an understanding of factors affecting hesitancy in Black and Asian individuals in England, to help address concerns about having the vaccine. METHOD: Ninety-five participants (51 women, 42 men, 2 other; 58% were aged between 30 and 49) recruited via a market recruitment agency, local Healthwatch networks, and using a snowballing method, participated in four activities on an online engagement platform, sharing their attitudes towards the COVID-19 vaccine roll-out, and factors shaping their beliefs and concerns, over 5 weeks from April to March 2021. RESULTS: Inductive thematic analysis revealed five themes: (1) a variety of views on the COVID-19 vaccine, (2) targeted messaging for Black and Asian people as counterproductive, (3) confusion over the purpose of the vaccine roll-out, (4) hesitancy to take the vaccine, and (5) local networks as a trusted source of information. CONCLUSIONS: Our findings suggest that respecting individuals' agency, transparency of information provided, and the independence of the bodies providing this information are important. Instead of targeted messaging, local networks should be used in campaigns to increase COVID-19 vaccine uptake among Black and Asian individuals.

Implementing Toxicity Testing in the 21st Century (TT21C): Making safety decisions using toxicity pathways, and progress in a prototype risk assessment.

Risk assessment methodologies in toxicology have remained largely unchanged for decades. The default approach uses high dose animal studies, together with human exposure estimates, and conservative assessment (uncertainty) factors or linear extrapolations to determine whether a specific chemical exposure is 'safe' or 'unsafe'. Although some incremental changes have appeared over the years, results from all new approaches are still judged against this process of extrapolating high-dose effects in animals to low-dose exposures in humans. The US National Research Council blueprint for change, entitled Toxicity Testing in the 21st Century: A Vision and Strategy called for a transformation of toxicity testing from a system based on high-dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. More recently, this concept of pathways-based approaches to risk assessment has been expanded by the description of 'Adverse Outcome Pathways' (AOPs). The question, however, has been how to translate this AOP/TT21C vision into the practical tools that will be useful to those expected to make safety decisions. We have sought to provide a practical example of how the TT21C vision can be implemented to facilitate a safety assessment for a commercial chemical without the use of animal testing. To this end, the key elements of the TT21C vision have been broken down to a set of actions that can be brought together to achieve such a safety assessment. Such components of a pathways-based risk assessment have been widely discussed, however to-date, no worked examples of the entire risk assessment process exist. In order to begin to test the process, we have taken the approach of examining a prototype toxicity pathway (DNA damage responses mediated by the p53 network) and constructing a strategy for the development of a pathway based risk assessment for a specific chemical in a case study mode. This contribution represents a 'work-in-progress' and is meant to both highlight concepts that are well-developed and identify aspects of the overall process which require additional development. To guide our understanding of what a pathways-based risk assessment could look like in practice, we chose to work on a case study chemical (quercetin) with a defined human exposure and to bring a multidisciplinary team of chemists, biologists, modellers and risk assessors to work together towards a safety assessment. Our goal was to see if the in vitro dose response for quercetin could be sufficiently understood to construct a TT21C risk assessment without recourse to rodent carcinogenicity study data. The data presented include high throughput pathway biomarkers (p-H2AX, p-ATM, p-ATR, p-Chk2, p53, p-p53, MDM2 and Wip1) and markers of cell-cycle, apoptosis and micronuclei formation, plus gene transcription in HT1080 cells. Eighteen point dose response curves were generated using flow cytometry and imaging to determine the concentrations that resulted in significant perturbation. NOELs and BMDs were compared to the output from biokinetic modelling and the potential for in vitro to in vivo extrapolation explored. A first tier risk assessment was performed comparing the total quercetin concentration in the in vitro systems with the predicted total quercetin concentration in plasma and tissues. The shortcomings of this approach and recommendations for improvement are described. This paper therefore describes the current progress in an ongoing research effort aimed at providing a pathways-based, proof-of-concept in vitro-only safety assessment for a consumer use product.

Viewpoint - An open and honest approach to diagnosis.

THE CONCEPT of pre- and post-diagnostic counselling is not new. If it is delivered effectively, it can be empowering for patients and give them a sense of control. While every service may not have a clear system to support all the principles, every member of the nursing team can improve the communication skills they bring to the counselling process.

Forum focus - taking part counts.

INCREASED PARTICIPATION of members is vital to the success of the Royal College of Nursing, which is why congress is such a pivotal event in the organisation's calendar. Two major changes at this month's congress aim to highlight the importance of member participation: the annual general meeting will be held and the forum steering committee elections launched.

Osteoporosis - pharmacological prevention and management in older people.

BACKGROUND: Osteoporosis remains undertreated in Australian primary care, with as few as 30% of postmenopausal women with a fracture and 10% of men with osteoporosis receiving pharmacological treatment. OBJECTIVE: This article presents an overview of the pharmacological management of osteoporosis in older people in the general practice setting. DISCUSSION: Lifestyle factors and ensuring adequate calcium and vitamin D intake are important in preventing and treating osteoporosis. Pharmacological treatments are recommended for patients with a minimal trauma fracture, for those aged 70 years or over with a T-score of -3.0 or lower, or for those who are currently taking prolonged high dose corticosteroids and who have a T-score of -1.5 or lower. Bisphosphonates are recommended as first line therapy for established postmenopausal osteoporosis. Medicine selection is guided by patient gender, menopausal status, medical and fracture history, patient preference and eligibility for government subsidy.

Surgical treatment of active native aortic valve endocarditis with allografts and mechanical prostheses.

BACKGROUND: Surgical intervention for persistent active native aortic valve endocarditis (NVE) remains challenging. We analyzed our combined experience with allografts and mechanical prostheses (MP) in NVE operations. METHODS: Between 1980 and 2002, 138 patients (81% males) underwent aortic valve replacement for NVE in 2 centers (106 allografts; 32 MPs). Perioperative characteristics and early and late morbidity and mortality were analyzed. RESULTS: Mean age was 47 years (range, 14 to 76 years), and 34% required emergency surgery. Abscess rate was 38% for allografts vs 18% for MPs. Concomitant mitral valve replacement was required in 38% MP patients and in 5% allograft patients. Hospital mortality was 8% (n = 11; p = 0.25): 10 allograft patients (9%) and 1 MP patient (3%). During a mean 8-year follow-up (range, 0 to 25 years) 33 patients died: 22 allograft (24%) and 11 MP patients (21%; p = 0.14). Survival at 15 years was 59% +/- 6% for allograft patients and 66% +/- 9% for MP patients (p = 0.68). Late recurrent endocarditis developed in 6 allograft patients and 1 MP patient (p = 0.29). Overall 15-year freedom from reoperation was 76% +/- 9% for allografts and 93% +/- 6% for MPs (p = 0.02). CONCLUSIONS: Mechanical prostheses have comparable rates of midterm survival and freedom from recurrent infection. However, this is in combination with extensive excision of destructive tissue in a specific patient subset. Allograft reoperation rates increase with time. The importance of the mechanical prosthesis in NVE might be established in the coming years.

An evaluation of the Ross operation in adults.

BACKGROUND AND AIM OF THE STUDY: Pulmonary autograft replacement of the aortic valve (the Ross operation) is the operation of choice in infants and children. Although this procedure can offer theoretical advantages at any age, its use in adults remains controversial. METHODS: A total of 264 consecutive patients (203 males, 61 females; mean age 35.0 +/- 11.5 years; range: 18-66 years) was studied. These patients underwent the Ross operation at two institutions and were followed up for a total of 1,634 patient-years. The etiology was mainly congenital (52%), degenerative (22%), and rheumatic (8%). Among patients, 21% underwent prior aortic valve replacement. RESULTS: Thirty-day mortality was 2.3% (n = 6), and four more patients died during follow up (mean follow up 6.2 years; range 0-15.4 years). Cumulative survival at five years was 96.8%, and at 10 years was 95.4%. Eleven patients underwent reoperation on the aortic valve; this was due to progressive dilatation and aortic regurgitation in 10 cases, and to dissection of the arterial wall of the autograft in one case. Overall freedom from pulmonary homograft reoperation was 94.9% at 10 years, and for autograft reoperation was 92.9%. Estimated freedom from autograft reoperation at Harefield was 98.6% at five and 10 years, and at Rotterdam 96.0% at five years and 88.2% at 10 years (p = 0.10, Tyrone-Ware). No risk factors for early and late mortality and reoperation were detected. CONCLUSION: In this combined series, the Ross operation in adult patients resulted in excellent survival and acceptable reoperation rates. A prospective randomized trial is proposed to study whether this observation truly reflects the potential advantages of the Ross procedure, or whether it is caused by patient selection.

Components of the diurnal cortisol cycle in relation to upper respiratory symptoms and perceived stress.

OBJECTIVE: The purpose of this study was to investigate the relationship between the diurnal pattern of salivary free cortisol to perceived stress and susceptibility to symptoms of upper respiratory illness (URI). METHODS: Salivary free cortisol concentration was determined in 34 healthy participants (students) at eight time points, synchronized to awakening, on 2 consecutive days. Participants completed a standard questionnaire to assess perceived stress and subsequently kept a daily record of social proximity and symptoms of upper respiratory illness for 2 weeks. RESULTS: Participants characterized by consistently larger awakening responses went on to report significantly more URI symptoms. Participants with less pronounced diurnal decline (flatter profiles) reported fewer URI symptoms. The two cortisol components were themselves related and interacted such that participants high on an interactive vector reported approximately three times more URI symptoms than other participants. The URI-associated cortisol components (dynamic changes) were not related to perceived stress, but underlying cortisol secretory activity (overall levels) in the first 45 minutes after awakening was. Dynamic components were, however, related to a social proximity measure, which in turn was related to URI symptoms. Proximity and the interactive cortisol vector together explained a substantial (28%) percentage of the variance in URI symptom reports. The cortisol vector independently and significantly explained 12% of the variation; the proximity measure independently and nonsignificantly contributed 6% of the variation. CONCLUSIONS: URI symptoms were associated with two related dynamic components of the cortisol cycle as determined by synchronization to awakening, whereas stress was related to a measure of overall secretory activity.

Effects of nighttime low frequency noise on the cortisol response to awakening and subjective sleep quality.

The effects of night-time exposure to traffic noise (TN) or low frequency noise (LFN) on the cortisol awakening response and subjective sleep quality were determined. Twelve male subjects slept for five consecutive nights in a noise-sleep laboratory. After one night of acclimatisation and one reference night, subjects were exposed to either TN (35dB L(Aeq), 50dB L(Amax)) or LFN (40dB L(Aeq)) on alternating nights (with an additional reference night in between). Salivary free cortisol concentration was determined in saliva samples taken immediately at awakening and at three 15-minute intervals after awakening. The subjects completed questionnaires on mood and sleep quality. The awakening cortisol response on the reference nights showed a normal cortisol pattern. A significant interaction between night time exposure and time was found for the cortisol response upon awakening. The awakening cortisol response following exposure to LFN was attenuated at 30 minutes after awakening. Subjects took longer to fall asleep during exposure to LFN. Exposure to TN induced greater irritation. Cortisol levels at 30 minutes after awakening were related to "activity" and "pleasantness" in the morning after exposure to LFN. Cortisol levels 30 minutes after awakening were related to sleep quality after exposure to TN. This study thus showed that night time exposure to LFN may affect the cortisol response upon wake up and that lower cortisol levels after awakening were associated with subjective reports of lower sleep quality and mood.