COVID-19 Vaccination: Guidance for Ethical, Informed Consent in a National Context.

This Guidance addresses the essential elements of informed consent to novel, provisionally registered COVID-19 vaccines which conform to the current definition of an investigational vaccine namely, lacking requirements for approval for full registration. 1 First, it addresses the ethical obtaining of informed consent in a setting of short and long term knowns and unknowns, by structuring the personal nature of informed consent into its twelve component parts. Second, as a guidance for family physicians, it explores reasonable medical concerns arising for individuals from both knowns and unknowns about COVID-19 disease and vaccines.Where there are waves of pandemic pressure impelling political, economic, social and public health forces to promote vaccination to health care providers and their patients, the necessary constituents of valid informed consent can be sublimated and possibly forfeited. This context of informed consent for COVID-19 vaccines is not unique to Australia. The analysis and presentation of international data by Australian Government agencies is a process occurring in all countries. Therefore, the Australian experience of consenting for vaccination is relevant to informed consent across the globe.The purpose of this Guidance is to assist personalised risk-benefit assessment for the informed consent of the vaccinee. Its aim is not to give a therapeutic guide nor to draw conclusions which can only rightly be drawn pertaining to each individual recipient in discussion with a health care provider. This is especially true in the setting of incomplete research where the many unknowns may be more significant for some than others. Since data is changing over time, national tables have not been used for specifics which the vaccine provider should access at the time of consultation.While we recommend the Guidance be read in conjunction with Government issued information, this Guidance will address specific fields relevant to informed consent which may not be addressed in those communications, but which a consenting individual as a person with their own values and experiences may wish to know. Aim: To address the requirements of ethical informed consent of the individual adult in the context of reasonable concerns pertaining to the unknowns and incomplete research attending novel, provisionally registered COVID-19 vaccines. Methodology: To elucidate what might be reasonable concerns for individuals considering vaccination, Public Assessment Reports of regulatory authorities (Food and Drug Administration and Therapeutic Goods Administration) and published trials of currently available vaccines were reviewed. International Covid-19 vaccine safety discussions were observed for peer-reviewed and, if necessary, pre-print references base. These references were studied for potential relevance to vaccine recipients. Vaccine Development Guidelines were also reviewed for pre-clinical requirements and compared with pre-clinical data presented at licensing. Missing information was requested from the Therapeutic Goods Administration (TGA).Pertinent unknowns were thereby identified as issues potentially relevant to fully informed consent, and compared with the content of standard Government-issued vaccine consent advice forms. Disparities were selected as relevant unknowns or reflecting incomplete research.Pertinent issues were incorporated into a twelve point structure for reasonable consideration to guide ethical inform consent. Paediatric COVID disease and vaccination are mentioned briefly due to paediatric vaccination being unapproved in Australia at the time of writing in under 12-year-olds, and exclusion of minors from phase III safety and efficacy trials. Conclusion: The provision of ethically obtained, fully informed consent is very pertinent to an investigational vaccine notwithstanding the pandemic context. To ascertain informed consent to the best of our ability, the gap between officially delivered information and reasonable concerns generated by knowns and relevant unknowns, can be addressed in a structured manner by physicians. Consent should not be coerced but be free of inducements and reprisals, respecting declarations of human rights, particularly given the investigational nature of COVID-19 vaccines. Each recipient requires adequate information to make their own judgment. The process of validly informed consent will therefore include discussion of concerns and of relevant information we do and do not yet have. Ethical informed consent should address those concerns as best is possible.

Warm Ischemia Time at Vascular Anastomosis is an Independent Predictor for Delayed Graft Function in Kidney Transplant Recipients.

OBJECTIVES: Delayed graft function after kidney transplant can affect patient and graft survival, resulting in prolonged hospital stay and need for dialysis. Ischemia times during organ procurement and reanastomosis at transplant are key factors in delayed graft function. MATERIALS AND METHODS: We analyzed all living- and deceased-donor renal transplants in Ireland over a 33-month period, with effect of warm ischemia time during anastomosis on delayed graft function being the primary outcome. We performed statistical regression analyses to account for confounding variables. Patients had identical surgical technique and immunosuppression protocols. RESULTS: Of 481 transplants during the study period, 20 patients were excluded because of paired-kidney exchange, nephron dosing transplant, or simul-taneous pancreas-kidney transplant. In the donor pool, 70% were donors after brainstem death, 3.6% were donors after cardiac death, and 26% were living donors. All living donors were direct altruistic donors and underwent stringent assessment via the ethics committee and multidisciplinary team meeting. Of living donors, 8% were not related. These were true altruistic donors who were acquaintances of the recipients and volunteered themselves for assessment. They were assessed in accordance with the declaration of Istanbul and received no compensation of any kind for donation. Of total patients, 18% had delayed graft function, defined as need for dialysis within 7 days of transplant. Warm ischemia time during anastomosis significantly affected risk of delayed graft function but not graft survival or function at 3 months. This factor did not correlate with hospital stay duration. Time on dialysis and recipient weight significantly correlated with risk of delayed graft function. CONCLUSIONS: Our findings support a role for minimizing warm ischemia time during anastomosis to reduce delayed graft function and need for dialysis in the perioperative period. However, a longer time does not appear to affect creatinine levels and therefore graft function at 3 months.

epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer.

PURPOSE: Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa. We investigated the accuracy of a six-gene DNA methylation panel (Epigenetic Cancer of the Prostate Test in Urine [epiCaPture]) at detecting PCa, high-grade (Gleason score greater than or equal to 8) and high-risk (D'Amico and Cancer of the Prostate Risk Assessment] PCa from urine. PATIENTS AND METHODS: Prognostic utility of epiCaPture genes was first validated in two independent prostate tissue cohorts. epiCaPture was assessed in a multicenter prospective study of 463 men undergoing prostate biopsy. epiCaPture was performed by quantitative methylation-specific polymerase chain reaction in DNA isolated from prebiopsy urine sediments and evaluated by receiver operating characteristic and decision curves (clinical benefit). The epiCaPture score was developed and validated on a two thirds training set to one third test set. RESULTS: Higher methylation of epiCaPture genes was significantly associated with increasing aggressiveness in PCa tissues. In urine, area under the receiver operating characteristic curve was 0.64, 0.86, and 0.83 for detecting PCa, high-grade PCa, and high-risk PCa, respectively. Decision curves revealed a net benefit across relevant threshold probabilities. Independent analysis of two epiCaPture genes in the same clinical cohort provided analytical validation. Parallel epiCaPture analysis in urine and matched biopsy cores showed added value of a liquid biopsy. CONCLUSION: epiCaPture is a urine DNA methylation test for high-risk PCa. Its tumor specificity out-performs that of prostate-specific antigen (greater than 3 ng/mL). Used as an adjunct to prostate-specific antigen, epiCaPture could aid patient stratification to determine need for biopsy.

Integrating biomarkers across omic platforms: an approach to improve stratification of patients with indolent and aggressive prostate cancer.

Classifying indolent prostate cancer represents a significant clinical challenge. We investigated whether integrating data from different omic platforms could identify a biomarker panel with improved performance compared to individual platforms alone. DNA methylation, transcripts, protein and glycosylation biomarkers were assessed in a single cohort of patients treated by radical prostatectomy. Novel multiblock statistical data integration approaches were used to deal with missing data and modelled via stepwise multinomial logistic regression, or LASSO. After applying leave-one-out cross-validation to each model, the probabilistic predictions of disease type for each individual panel were aggregated to improve prediction accuracy using all available information for a given patient. Through assessment of three performance parameters of area under the curve (AUC) values, calibration and decision curve analysis, the study identified an integrated biomarker panel which predicts disease type with a high level of accuracy, with Multi AUC value of 0.91 (0.89, 0.94) and Ordinal C-Index (ORC) value of 0.94 (0.91, 0.96), which was significantly improved compared to the values for the clinical panel alone of 0.67 (0.62, 0.72) Multi AUC and 0.72 (0.67, 0.78) ORC. Biomarker integration across different omic platforms significantly improves prediction accuracy. We provide a novel multiplatform approach for the analysis, determination and performance assessment of novel panels which can be applied to other diseases. With further refinement and validation, this panel could form a tool to help inform appropriate treatment strategies impacting on patient outcome in early stage prostate cancer.

Ascending cholangitis: rare presentation of a ruptured right-sided renal angiomyolipoma.

We report the case of a 46-year-old female who presented to the Emergency Department with acute, painful obstructive jaundice, with evidence of secondary ascending cholangitis. Surprisingly, imaging revealed the clinical picture to be caused not by hepatobiliary pathology, but by external compression of the biliary tree from a ruptured renal angiomyolipoma (AML) of the right kidney. The patient remained haemodynamically stable and conservative management saw resolution of biliary obstruction. We believe this to be the first report of a renal AML presenting in this way. This report highlights the diverse spectrum of presentations of renal angiomyolipomas.

Long noncoding RNAs and prostate carcinogenesis: the missing 'linc'?

Long noncoding RNAs (lncRNAs) are rapidly becoming essential pieces in the cancer puzzle. Our understanding of their functional capabilities is in its infancy. One certain fact, however, is that their molecular interactions extend beyond chromatin complexes into diverse biological processes. In prostate cancer, aberrant expression of lncRNAs is associated with disease progression. Overexpression of oncogenic lncRNAs promotes tumor-cell proliferation and metastasis through chromatin looping and distal engagement with the androgen receptor, antisense gene regulation, alternative splicing, and impeding DNA repair. Several lncRNAs, such as prostate cancer antigen 3 (PCA3), prostate cancer gene expression marker 1 (PCGEM1), and prostate cancer associated ncRNA transcript 1 (PCAT1), are highly prostate-specific, posing as attractive biomarkers. Herein we review the mechanisms of action of lncRNAs in prostate carcinogenesis and their potential clinical utility for disease.

Noncoding RNAs in prostate cancer: the long and the short of it.

As the leading culprit in cancer incidence for American men, prostate cancer continues to pose significant diagnostic, prognostic, and therapeutic tribulations for clinicians. The vast spectrum of disease behavior warrants better molecular classification to facilitate the development of more robust biomarkers that can identify the more aggressive and clinically significant tumor subtypes that require treatment. The untranslated portion of the human transcriptome, namely noncoding RNAs (ncRNA), is emerging as a key player in cancer initiation and progression and boasts many attractive features for both biomarker and therapeutic research. Genetic linkage studies show that many ncRNAs are located in cancer-associated genomic regions that are frequently deleted or amplified in prostate cancer, whereas aberrant ncRNA expression patterns have well-established links with prostate tumor cell proliferation and survival. The dysregulation of pathways controlled by ncRNAs results in a cascade of multicellular events leading to carcinogenesis and tumor progression. The characterization of RNA species, their functions, and their clinical applicability is a major area of biologic and clinical importance. This review summarizes the growing body of evidence, supporting a pivotal role for ncRNAs in the pathogenesis of prostate cancer. We highlight the most promising ncRNA biomarkers for detection and risk stratification and present the state-of-play for RNA-based personalized medicine in treating the "untreatable" prostate tumors.