Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer.

BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS AND METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. RESULTS: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSIONS: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

Resigning oneself to a life of wound-related odour - A thematic analysis of patient experiences.

AIMS: To determine how patients with chronic wounds describe wound odour, identify what strategies they use to manage it and how effective these are. MATERIALS AND METHODS: Using a qualitative descriptive approach, semi-structured interviews were conducted between July and August 2021 with seven patients living with an odorous chronic wound at home. Data were analysed using Braun and Clarke's thematic analysis framework. RESULTS: The results were organised into two main themes: 1) becoming resigned to living with wound-related odour 2) strategies used to manage wound-related odour. Participants were sad, embarrassed and felt isolated but became resigned to living with this odour and accepting of it as a consequence of having a wound. Frequent dressing changes, household cleaning along with the use of sprays were the most frequently used tactics to manage odour none of which were deemed to be very effective. CONCLUSION: This study highlights the problem of odour management in clinical practice and how individuals develop strategies to overcome odour. Sadly, patients were resigned to living with wound odour and were accepting of it as part of daily life. This highlights the importance for healthcare professionals to recognise, assess for and ensure a better understanding of how people experience wound odour, the impact it can have on them personally. Frequent dressing changes can help manage wound odour from the patient's perspective.

Systematic review of topical interventions for the management of odour in patients with chronic or malignant fungating wounds.

Chronic wounds adversely affect the quality of life of individuals and odour is a well-recognised associated factor. Odour can affect sleep, well-being, social interactions, diet and potentially wound healing. This systematic review aims to examine the effectiveness of topical interventions in the management of odour associated with chronic and malignant fungating wounds. A systematic review guided by PRISMA recommendations of randomised controlled trials where odour intensity/odour is the primary outcome was undertaken. Inclusion criteria were adults (18 years and over) with chronic venous, arterial, diabetic or pressure ulcers or with malignant fungating wounds where odour has been managed through topical application of pharmacological/non-pharmacological agents. Searches were conducted in CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, and Web of Science. Eligibility screening, risk of bias assessment and data extraction was completed by authors working independently. Searches retrieved 171 titles and abstracts (157 post de-duplication). Thirteen studies were retained for full text review of which five (n = 137 individuals) examining the following treatments remained: metronidazole (n = 4), silver (n = 1). Meta-analysis was not possible but individual studies suggest improved outcomes (i.e., reduced odour) using metronidazole. Treatment options to manage wound odour are limited and hampered by lack of clinical trials, small sample sizes, and absence of standardised outcomes and consistent measurement. Whereas metronidazole and silver may have a role in controlling wound odour, robust and well-designed interventions with rigorous procedures and standardised odour outcomes are necessary to evaluate their contribution.

Pneumopericardium after peritoneopericardial diaphragmatic hernia repair in a dog.

A one-year-old neutered, Goldendoodle presented for evaluation. One week prior to presentation, the surgical closure of a peritoneopericardial diaphragmatic hernia was performed via ventral midline celiotomy. Since the procedure, the dog had been lethargic and anorexic at home. Thoracic radiographs revealed a pneumopericardium. Pericardiocentesis was performed which evacuated approximately 100 mL of air from the pericardial sac. The dog recovered well and began eating in the hospital and resumed normal activity. This is the first reported case of a pneumopericardium post-peritoneopericardial diaphragmatic hernia repair requiring pericardiocentesis. Clinicians should be aware of this rare complication in patients with post-operative peritoneopericardial diaphragmatic hernia.

Difficulties associated with Reporting Radiographer working practices - A narrative evidence synthesis.

OBJECTIVES: This narrative synthesis of evidence identifies and explores issues that impact upon the expansion or effectiveness of Reporting Radiographers working in all diagnostic modalities within the United Kingdom (UK). The publication focuses on working practices affecting trainees and qualified Reporting Radiographers. KEY FINDINGS: Fourteen studies informed the themes of this article, they were published between 2014 and 2021. Delays to commencement of reporting roles and variance in performance monitoring was common. Lack of formalisation, overly restrictive and out of date scopes of practice were also found. Whilst, staffing shortages contributed to underutilisation. Failure to utilise skills was most prevalent in cross sectional imaging modalities. Considerable variance in practice was also found between centres. Meanwhile, Reporting Radiographer involvement in professional development, education and research is far from universal and often dependant on individuals sacrificing their own time. CONCLUSION: Governance in many centres would benefit from renewal and standardisation, particularly relating to scopes of practice and performance monitoring audits. Measures are also required to encourage compliance with guidance, address staffing issues and reduce variation between centres. Failure to address these issues has the potential to impair collaboration, delay patient care and increase economic inefficiencies whilst negatively impacting satisfaction for service users and staff. Lack of involvement in professional development, education and research suggests Reporting Radiographers are not accomplishing their full potential, educating the next generation of the reporting workforce and driving evidence-based change for further development of the specialism. IMPLICATIONS FOR PRACTICE: Better use of the existing workforce is essential to increase productivity, value, and security of Reporting Radiographer services, which are essential to improve patient outcomes and efficiency.

Difficulties associated with access to training and clinical support for Reporting Radiographers - A narrative evidence synthesis.

OBJECTIVES: This narrative synthesis of evidence identifies and explores issues that impact upon the expansion or effectiveness of Reporting Radiographers working in all diagnostic modalities within the United Kingdom (UK). The publication focuses on accessibility to training for prospective Reporting Radiographers as well as clinical support within and beyond training. KEY FINDINGS: Fifteen studies informed the themes of this article, they were published between 2014 and 2021. Reporting Radiographers often found it difficult find support during training and once qualified, this was usually due to the availability and workload of supervising staff. Although resistance and obstruction were experienced by many. Concerns relating to pay, promotion and interest were expressed by some respondents whilst access to courses and finance were highlighted as areas of variance across the UK. CONCLUSION: Inadequate support of Reporting Radiographers is impairing expansion of the specialism, whilst impacting capability and morale. This increases risk of patient harm, delays to care and inefficiency, it also threatens the sustainability of services. Negative interactions between Reporting Radiographers and Radiologists or managers is disappointing considering development of the specialism; evidence of Reporting Radiographer effectiveness and current collaboration between Royal College of Radiologists and Society of Radiographers. Issues raised in relation to pay/promotion and litigation could be clarified with ease, this should be considered when guidance is updated. Access to finance and courses is a major barrier in some regions of the UK. Scope exists for further exploration of training. England has used grants to facilitate uptake, these may prove to be an important tool in other countries. IMPLICATIONS FOR PRACTICE: Drivers to increase recruitment should be implemented alongside measures to facilitate accessibility to training and improvements to support infrastructure.

A multicenter prospective evaluation of owner medication adherence for feline cardiovascular disease in the referral setting.

OBJECTIVE: The aim of this paper is to evaluate owners' chronic medication adherence for management of feline cardiovascular disease in the small animal referral setting. ANIMALS, MATERIALS AND METHODS: A questionnaire-based study of owners at five multispecialty, small animal referral centers was conducted. Owners completed a written survey evaluating demographics, degree of medication adherence, and difficulties encountered for medication adherence. Owners were free to decline participation in the study. RESULTS: Fifty-four questionnaires were available for review. The most common diagnosis was hypertrophic cardiomyopathy (n = 31, 57.4%). Clopidogrel was the most cited medication that was difficult to administer consistently (n = 13, 24.0%) although twenty owners (37.0%) reported no difficulty consistently administering medications. "Taste of medication" (n = 14, 25.9%) was the most reported reason for difficulty medicating their cat, and most owners (n = 36, 66.7%) stated twice daily was the highest frequency of heart medications they feel they can consistently administer. Fifty owners (92.6%) met the criteria for medication adherence. CONCLUSIONS: Chronic medication adherence in this study population was high. Clopidogrel was the most difficult medication to consistently administer, and twice a day dosing was the highest frequency of medication administration most owners could achieve. Cardiologists should be aware of these factors when determining optimal treatment protocols for the management of cardiovascular disease in cats.

Gene expression analysis of MAOA and the clock gene ARNTL in individuals with bipolar disorder compared to healthy controls.

INTRODUCTION: Circadian rhythms are associated with bipolar disorder (BD). This cross-sectional study aimed at investigating ARNTL and MAOA gene expression differences (1) between individuals with BD and controls, (2) between affective episodes, and (3) the relationship between ARNTL and MAOA expression. METHODS: ARNTL and MAOA gene expression in peripheral mononuclear blood cells were analysed from fasting blood samples (BD n = 81, controls n = 54) with quantitative real-time PCR operating on TaqMan® assays (normalised to 18S RNA expression). ANCOVAs corrected for age, sex, body mass index, and medication was used to evaluate expression differences and correlation analyses for the relation between ARNTL and MAOA expression. RESULTS: ARNTL gene expression differed between affective episodes (F(2,78) = 3.198, p = 0.047, Partial Eta2= 0.083), but not between BD and controls (n.s.). ARNTL and MAOA expression correlated positively in BD (r = 0.704, p < 0.001) and in controls (r = 0.932, p < 0.001). MAOA expression differed neither between BD and controls nor between affective episodes (n.s.). DISCUSSION: Clock gene expression changes were observed in different affective states of BD. More precisely, ARNTL gene expression was significantly higher in euthymia than in depression. ARNTL and MAOA gene expression correlated significantly in BD and in controls, which emphasises the strong concatenation between circadian rhythms and neurotransmitter breakdown.

Evaluation of owner medication adherence for canine cardiovascular disease in the referral setting.

OBJECTIVE: To evaluate owners' medication adherence for management of cardiovascular disease in the small animal specialty setting. ANIMALS, MATERIALS, AND METHODS: A questionnaire-based study of owners at a single, multispecialty, small animal referral center was conducted. Owners completed a written survey evaluating demographics, degree of medication adherence, and difficulties encountered for medication adherence. Owners were free to decline participation in the study. RESULTS: Ninety-six questionnaires were completed during the study period. Fifty-four respondents (56.3%) reported treating their pet for over one year for cardiovascular disease, and myxomatous mitral valve disease was the most common diagnosis (76.0%). Twenty-nine (30.2%) respondents felt they could consistently administer a maximum of three medications daily, and 46 (47.9%) respondents reported twice-daily dosing was the highest frequency of administration that could be consistently achieved. Twenty-two respondents (22.9%) reported that their pet required daily medications for at least one other chronic condition besides cardiac disease. Seventeen respondents (17.7%) reported at least occasionally missing medications, although only one (1.0%) reported it was more than 20% of medications per week. CONCLUSIONS: Medication adherence was high in this study population. Almost one-half of owners surveyed reported being unable to consistently administer more than three medications daily, and approximately one-quarter of patients were treated for at least one additional chronic condition requiring daily medications, in addition to cardiac disease. Clinicians should be aware of these factors when determining optimal treatment protocols for the management of cardiovascular disease in dogs.

Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy.

AIMS: Anal squamous cell carcinomas (ASCC) are strongly associated with human papillomaviruses. Standard of care is chemoradiotherapy at uniform doses with no treatment stratification. Immunohistochemical staining for p16INK4A (p16), a surrogate for human papillomaviruses, is prognostic for outcomes. We investigated this alongside clinical-pathological factors, including tumour infiltrating lymphocyte (TIL) scores. MATERIALS AND METHODS: Using an independent, multicentre cohort of 257 ASCC treated with chemoradiotherapy, pretreatment biopsies were stained and scored for p16 and TIL. Kaplan-Meier curves were derived for outcomes (disease-free survival [DFS], overall survival and cancer-specific survival), by stage, p16 and TIL scores and Log-rank tests were carried out to investigate prognostic effect. A multivariate analysis was carried out using Cox regression. RESULTS: Stage, sex, p16 and TILs were independently prognostic. Hazard ratios for death (overall survival) were 2.51 (95% confidence interval 1.36-4.63) for p16 negative versus p16 positive, 2.17 (1.34-3.5) for T3/4 versus T1/2, 2.42 (1.52-3.8) for males versus females and 3.30 (1.52-7.14) for TIL1 versus TIL3 (all P < 0.05). CONCLUSIONS: We have refined prognostic factors in ASCC. p16 adds to stratification by stage with respect to DFS in early disease and overall survival/DFS in locally advanced cancers. Our data support the role of the host immune response in mediating outcomes. These factors will be prospectively evaluated in PLATO (ISRCTN88455282).

Evaluation of owners' attitudes towards veterinary insurance in a specialty hospital.

OBJECTIVES: The purpose of this study was to investigate the frequency and perception of veterinary insurance among owners' at a small animal specialty hospital around a large urban city. MATERIALS AND METHODS: A questionnaire evaluated the prevalence and perception of insurance among owners at a small animal specialty hospital over a 2 month period. Respondents provided demographic information including age, sex, educational level and household income. Respondents without insurance were asked reasons for not having insurance, approximate cost of insurance per month desired and percentage of coverage of medical expenses they would want insurance to provide. Respondents with insurance were asked how they chose their current plan, how it affects their medical decisions for their pet and their overall satisfaction. RESULTS: Sixty-seven (28.5%) owners reporting having insurance for at least one pet. Owners most commonly selected their current insurance plan based on online research (27, 40.3%). Fifty-two respondents (77.6%) reported being satisfied with their insurance plan and 49 (73.2%) stated that would recommend their current insurance plan to a friend. CLINICAL SIGNIFICANCE: Insurance had a relatively high prevalence in this study group with most owners being satisfied with their current plan and would be likely to recommend it to a friend. The role of insurance in how it affects owner's medical decisions, care for their pet and interactions with veterinarians in companion animal medicine requires further evaluation.

Dietary polyphenol impact on gut health and microbiota.

Polyphenols are naturally occurring compounds in plants and they are the most abundant antioxidants in the human diet. Due to their considerable structural diversity, this largely influences their bioavailability. Since a large proportion of polyphenols remains unabsorbed along the gastrointestinal tract, they may accumulate in the large intestine, where most of them are extensively metabolized by the intestinal microbiota. The formation of bioactive polyphenol-derived metabolites may also benefit the health status of the subjects, although the mechanisms have not been delineated. This review aims to highlight the impact of polyphenols on gut health and the modes of action could be through modulation of intestinal barrier function, innate and adaptive immune response, signaling pathways, as well as the ability to modify gut microbiota composition. The review will conclude by presenting future perspective and challenges of polyphenols application in food products to be used for preventing or treating diseases.

The profile of patients with venous leg ulcers: A systematic review and global perspective.

BACKGROUND: A holistic profile that includes demographic, medical history and wound characteristics of individuals with venous leg ulceration is lacking. Lack of such a profile negatively impacts the ability to develop interventions to improve patient outcomes. OBJECTIVES: To describe the profile of the patient population with venous leg ulceration from published observational (non-interventional) studies and to identify gaps in the knowledge base for future research in this area. METHODS: A systematic review of observational studies that included more than 50 patients, from any world region, of any age and in any care setting. RESULTS: twenty studies, involving 3395 patients, from all world regions met our criteria. Demographic characteristics were well reported and showed a female to male ratio of 1.2:1, average age of 47-65 years, high levels of co-morbidities including hypertension (53-71%) and diabetes (16-20%), and only one study reporting ethnicity. When reported, approximately 4-30% had high levels of depression. The average wound size was 18.6-43.39 cm2; mean wound duration was 13.8-65.5 months, mean number of recurrences was four. No study reported on demographic factors plus medical history plus wound characteristics together. CONCLUSION: a comprehensive, holistic profile of the population with VLU is lacking. There is a critical need for more comprehensive profiling to enable the development of targeted interventions to improve outcomes.

Exposure to bisphenol A differentially impacts neurodevelopment and behavior in Drosophila melanogaster from distinct genetic backgrounds.

Bisphenol A (BPA) is a ubiquitous environmental chemical that has been linked to behavioral differences in children and shown to impact critical neurodevelopmental processes in animal models. Though data is emerging, we still have an incomplete picture of how BPA disrupts neurodevelopment; in particular, how its impacts may vary across different genetic backgrounds. Given the genetic tractability of Drosophila melanogaster, they present a valuable model to address this question. Fruit flies are increasingly being used for assessment of neurotoxicants because of their relatively simple brain structure and variety of measurable behaviors. Here we investigated the neurodevelopmental impacts of BPA across two genetic strains of Drosophila-w1118 (control) and the Fragile X Syndrome (FXS) model-by examining both behavioral and neuronal phenotypes. We show that BPA induces hyperactivity in larvae, increases repetitive grooming behavior in adults, reduces courtship behavior, impairs axon guidance in the mushroom body, and disrupts neural stem cell development in the w1118 genetic strain. Remarkably, for every behavioral and neuronal phenotype examined, the impact of BPA in FXS flies was either insignificant or contrasted with the phenotypes observed in the w1118 strain. This data indicates that the neurodevelopmental impacts of BPA can vary widely depending on genetic background and suggests BPA may elicit a gene-environment interaction with Drosophila fragile X mental retardation 1 (dFmr1)-the ortholog of human FMR1, which causes Fragile X Syndrome and is associated with autism spectrum disorder.

Implementation Evaluation of a Complex Intervention to Improve Timeliness of Care for Veterans with Transient Ischemic Attack.

BACKGROUND: The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurologic Symptoms (PREVENT) program was designed to address systemic barriers to providing timely guideline-concordant care for patients with transient ischemic attack (TIA). OBJECTIVE: We evaluated an implementation bundle used to promote local adaptation and adoption of a multi-component, complex quality improvement (QI) intervention to improve the quality of TIA care Bravata et al. (BMC Neurology 19:294, 2019). DESIGN: A stepped-wedge implementation trial with six geographically diverse sites. PARTICIPANTS: The six facility QI teams were multi-disciplinary, clinical staff. INTERVENTIONS: PREVENT employed a bundle of key implementation strategies: team activation; external facilitation; and a community of practice. This strategy bundle had direct ties to four constructs from the Consolidated Framework for Implementation Research (CFIR): Champions, Reflecting & Evaluating, Planning, and Goals & Feedback. MAIN MEASURES: Using a mixed-methods approach guided by the CFIR and data matrix analyses, we evaluated the degree to which implementation success and clinical improvement were associated with implementation strategies. The primary outcomes were the number of completed implementation activities, the level of team organization and > 15 points improvement in the Without Fail Rate (WFR) over 1 year. KEY RESULTS: Facility QI teams actively engaged in the implementation strategies with high utilization. Facilities with the greatest implementation success were those with central champions whose teams engaged in planning and goal setting, and regularly reflected upon their quality data and evaluated their progress against their QI plan. The strong presence of effective champions acted as a pre-condition for the strong presence of Reflecting & Evaluating, Goals & Feedback, and Planning (rather than the other way around), helping to explain how champions at the +2 level influenced ongoing implementation. CONCLUSIONS: The CFIR-guided bundle of implementation strategies facilitated the local implementation of the PREVENT QI program and was associated with clinical improvement in the national VA healthcare system. TRIAL REGISTRATION: clinicaltrials.gov: NCT02769338.