International Policy Frameworks for Consent in Minimal-risk Pragmatic Trials.

There is intense debate around the use of altered and waived consent for pragmatic trials. Those in favor argue that traditional consent compromises the internal and external validity of these trials. Those against, warn that the resultant loss of autonomy compromises respect for persons and could undermine trust in the research enterprise.This article examines whether international ethical guidelines and the policy frameworks in three countries-the United States, England, and Australia-permit altered and waived consent for minimal-risk pragmatic trials conducted outside the emergency setting. Provisions for both are clearly articulated in U.S. regulations, but many countries do not have equivalent frameworks. Investigators should not assume that all consent models permitted in the United States are legal in their jurisdictions, even if they are deemed ethically defensible.The authors summarize ethical and regulatory considerations and present a framework for investigators contemplating trials with altered or waived consent.

A platform in the use of medicines to treat chronic hepatitis C (PLATINUM C): protocol for a prospective treatment registry of real-world outcomes for hepatitis C.

BACKGROUND: Safe, highly curative, short course, direct acting antiviral (DAA) therapies are now available to treat chronic hepatitis C. DAA therapy is freely available to all adults chronically infected with the hepatitis C virus (HCV) in Australia. If left untreated, hepatitis C may lead to progressive hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Australia is committed to eliminating hepatitis as a public health threat by 2030 set by the World Health Organization. However, since the introduction of funded DAA treatment, uptake has been suboptimal. Australia needs improved strategies for testing, treatment uptake and treatment completion to address the persisting hepatitis C public health problem. PLATINUM C is a HCV treatment registry and research platform for assessing the comparative effectiveness of alternative interventions for achieving virological cure. METHODS: PLATINUM C will prospectively enrol people with active HCV infection confirmed by recent detection of HCV ribonucleic acid (RNA) in blood. Those enrolled will agree to allow standardised collection of demographic, lifestyle, treatment, virological outcome and other relevant clinical data to better inform the future management of HCV infection. The primary outcome is virological cure evidenced by sustained virological response (SVR), which is defined as a negative HCV PCR result 6 to 18 months after initial prescription of DAA therapy and no less than 12 weeks after the completion of treatment. Study participants will be invited to opt-in to medication adherence monitoring and quality of life assessments using validated self-reported instruments (EQ-5D-5L). DISCUSSION: PLATINUM C is a treatment registry and platform for nesting pragmatic trials. Data collected will inform the design, development and implementation of pragmatic trials. The digital infrastructure, study procedures and governing systems established by the registry will allow PLATINUM C to support a wider research platform in the management of hepatitis C in primary care. TRIAL REGISTRATION: The trial is registered with the Australia and New Zealand Clinical Trials Register ( ACTRN12619000023156 ). Date of registration: 10/01/2019.

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model.

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease.

Serious adverse event reporting in investigator-initiated clinical trials.

Reporting adverse events (AEs) and serious AEs (SAEs) are practical steps to ensure safety for volunteers and patients in medical research involving medications, treatments and devices. However, the burden and cost of reporting should be proportionate with the public health benefit of this information. Unfortunately, in Australia there is clear evidence of ever-increasing requirements from sponsors and ethics committees to report AEs and SAEs unnecessarily, leading to a decrease in the uptake of research, particularly less well funded investigator-initiated trials. We believe that individual AE reports to ethics committees serve no useful purpose, because in most cases the study group identity (drug exposure) is not known in studies with blinded treatment arms and their value is limited. Pragmatic, investigator-initiated Phase IV clinical trials of post-marketed drugs or devices are needed to understand their role in everyday clinical practice. In this setting, the workload and costs of systematic, complete reporting of all AEs and SAEs (independent of whether these are treatment-related) is wasteful, and mostly unnecessary. A trial data safety and monitoring committee is in the unique position of being able to review safety information according to the blinded treatment arms of the study. This enables safety data to be analysed appropriately and a summary report provided to the trial steering committee, principal investigators and the relevant ethics committees in a meaningful way. Defined trial endpoints do not need to be reported as safety events (because they are being properly monitored and analysed).

International network of cancer genome projects.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil­based chemotherapy.

BACKGROUND & AIMS: Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil­based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T(17) intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T(17) could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. METHODS: We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T(17) affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II­III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17). RESULTS: HSP110 and HSP110DE9 interacted in a1:1 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T(17) were mostly biallelic in primary tumor samples with MSI. Patients with stage II­III cancer who received chemotherapy and had large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012­0.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). CONCLUSIONS: About 25% of patients with stages II­III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of HSP110 in tumor DNA.

CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer.

The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1α, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.

Villin expression is frequently lost in poorly differentiated colon cancer.

Colorectal cancers (CRCs) are classified as having microsatellite instability (MSI) or chromosomal instability (CIN); herein termed microsatellite stable (MSS). MSI colon cancers frequently display a poorly differentiated histology for which the molecular basis is not well understood. Gene expression and immunohistochemical profiling of MSS and MSI CRC cell lines and tumors revealed significant down-regulation of the intestinal-specific cytoskeletal protein villin in MSI colon cancer, with complete absence in 62% and 17% of MSI cell lines and tumors, respectively. Investigation of 577 CRCs linked loss of villin expression to poorly differentiated histology in MSI and MSS tumors. Furthermore, mislocalization of villin from the membrane was prognostic for poorer outcome in MSS patients. Loss of villin expression was not due to coding sequence mutations, epigenetic inactivation, or promoter mutation. Conversely, in transient transfection assays villin promoter activity reflected endogenous villin expression, suggesting transcriptional control. A screen of gut-specific transcription factors revealed a significant correlation between expression of villin and the homeobox transcription factor Cdx-1. Cdx-1 overexpression induced villin promoter activity, Cdx-1 knockdown down-regulated endogenous villin expression, and deletion of a key Cdx-binding site within the villin promoter attenuated promoter activity. Loss of Cdx-1 expression in CRC lines was associated with Cdx-1 promoter methylation. These findings demonstrate that loss of villin expression due to Cdx-1 loss is a feature of poorly differentiated CRCs.

Receptor activator of NF-κB ligand promotes proliferation of a putative mammary stem cell unique to the lactating epithelium.

In mice, CD49f(hi) mammary stem cells (MaSCs) asymmetrically divide to generate CD49f(+) committed progenitor cells that differentiate into CD49f(-) phenotypes of the milk-secreting tissue at the onset of pregnancy. We show CD49f(+) primary mammary epithelial cells (PMECs) isolated from lactating tissue uniquely respond to pregnancy-associated hormones (PAH) compared with CD49f(+) cells from nonlactating tissue. Differentiation of CD49f(+) PMEC in extracellular matrix produces CD49f(-) luminal cells to form differentiated alveoli. The PAH prolactin and placental lactogen specifically stimulate division of CD49f(-) luminal cells, while receptor activator of nuclear factor (NF)-κB ligand (RANKL) specifically stimulates division of basal CD49f(+) cells. In nondifferentiating conditions, we observed a greater proportion of multipotent self-renewing cells, and RANKL treatment activated the RANK pathway in these cultures. Furthermore, we observed the deposition of calcium nodules in a proportion of these cells. These data imply that a MaSC unique to the lactating breast exists in humans, which generates progeny with discrete lineages and distinct response to PAH.

Hospital length of stay prediction for general surgery and total knee arthroplasty admissions: Systematic review and meta-analysis of published prediction models.

Objective: Systematic review of length of stay (LOS) prediction models to assess the study methods (including prediction variables), study quality, and performance of predictive models (using area under receiver operating curve (AUROC)) for general surgery populations and total knee arthroplasty (TKA). Method: LOS prediction models published since 2010 were identified in five major research databases. The main outcomes were model performance metrics including AUROC, prediction variables, and level of validation. Risk of bias was assessed using the PROBAST checklist. Results: Five general surgery studies (15 models) and 10 TKA studies (24 models) were identified. All general surgery and 20 TKA models used statistical approaches; 4 TKA models used machine learning approaches. Risk scores, diagnosis, and procedure types were predominant predictors used. Risk of bias was ranked as moderate in 3/15 and high in 12/15 studies. Discrimination measures were reported in 14/15 and calibration measures in 3/15 studies, with only 4/39 externally validated models (3 general surgery and 1 TKA). Meta-analysis of externally validated models (3 general surgery) suggested the AUROC 95% prediction interval is excellent and ranges between 0.803 and 0.970. Conclusion: This is the first systematic review assessing quality of risk prediction models for prolonged LOS in general surgery and TKA groups. We showed that these risk prediction models were infrequently externally validated with poor study quality, typically related to poor reporting. Both machine learning and statistical modelling methods, plus the meta-analysis, showed acceptable to good predictive performance, which are encouraging. Moving forward, a focus on quality methods and external validation is needed before clinical application.

Does the registry speak your language? A case study of the Global Angelman Syndrome Registry.

Global disease registries are critical to capturing common patient related information on rare illnesses, allowing patients and their families to provide information about their condition in a safe, accessible, and engaging manner that enables researchers to undertake critical research aimed at improving outcomes. Typically, English is the default language of choice for these global digital health platforms. Unfortunately, language barriers can significantly inhibit participation from non-English speaking participants. In addition, there is potential for compromises in data quality and completeness. In contrast, multinational commercial entities provide access to their websites in the local language of the country they are operating in, and often provide multiple options reflecting ethnic diversity. This paper presents a case study of how the Global Angelman Syndrome Registry (GASR) has used a novel approach to enable multiple language translations for its website. Using a "semi-automated language translation" approach, the GASR, which was originally launched in English in September 2016, is now available in several other languages. In 2020, the GASR adopted a novel approach using crowd-sourcing and machine translation tools leading to the availability of the GASR in Spanish, Traditional Chinese, Italian, and Hindi. As a result, enrolments increased by 124% percent for Spain, 67% percent for Latin America, 46% percent for Asia, 24% for Italy, and 43% for India. We describe our approach here, which we believe presents an opportunity for cost-effective and timely translations responsive to changes to the registry and helps build and maintain engagement with global disease communities.

Hospital length of stay prediction tools for all hospital admissions and general medicine populations: systematic review and meta-analysis.

Background: Unwarranted extended length of stay (LOS) increases the risk of hospital-acquired complications, morbidity, and all-cause mortality and needs to be recognized and addressed proactively. Objective: This systematic review aimed to identify validated prediction variables and methods used in tools that predict the risk of prolonged LOS in all hospital admissions and specifically General Medicine (GenMed) admissions. Method: LOS prediction tools published since 2010 were identified in five major research databases. The main outcomes were model performance metrics, prediction variables, and level of validation. Meta-analysis was completed for validated models. The risk of bias was assessed using the PROBAST checklist. Results: Overall, 25 all admission studies and 14 GenMed studies were identified. Statistical and machine learning methods were used almost equally in both groups. Calibration metrics were reported infrequently, with only 2 of 39 studies performing external validation. Meta-analysis of all admissions validation studies revealed a 95% prediction interval for theta of 0.596 to 0.798 for the area under the curve. Important predictor categories were co-morbidity diagnoses and illness severity risk scores, demographics, and admission characteristics. Overall study quality was deemed low due to poor data processing and analysis reporting. Conclusion: To the best of our knowledge, this is the first systematic review assessing the quality of risk prediction models for hospital LOS in GenMed and all admissions groups. Notably, both machine learning and statistical modeling demonstrated good predictive performance, but models were infrequently externally validated and had poor overall study quality. Moving forward, a focus on quality methods by the adoption of existing guidelines and external validation is needed before clinical application. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021272198.

Secreted frizzled-related protein 4 expression is positively associated with responsiveness to cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers.

BACKGROUND: Ovarian cancer is one of the most lethal malignancies in women, as it is frequently detected at an advanced stage, and cancers often become refractory to chemotherapy. Evidence suggests that dysregulation of pro-apoptotic genes plays a key role in the onset of chemoresistance. The secreted Frizzled-Related Protein (sFRP) family is pro-apoptotic and also a negative modulator of the Wnt signalling cascade. Studies have demonstrated that the re-expression of sFRPs, in particular sFRP4, is associated with a better prognosis, and that experimentally induced expression results in cell death. RESULTS: In vitro experimental models determined that sFRP4 was differentially expressed in chemosensitive (A2780) and chemoresistant (A2780 ADR and A2780 Cis) ovarian cell lines, with chemosensitive cells expressing significantly higher levels of sFRP4. Transfection of the chemoresistant cell lines with sFRP4 significantly increased their sensitivity to chemotherapy. Conversely, silencing of sFRP4 expression in the chemosensitive cell line resulted in a corresponding increase in chemoresistance. Comparison of sFRP4 expression in tumour biopsies revealed a positive trend between sFRP4 expression and tumour grade, with mucinous cyst adenocarcinomas exhibiting significantly decreased sFRP4 levels compared to mucinous borderline tumours. CONCLUSIONS: This study indicates a role for sFRP4 as a predictive marker of chemosensitivity in ovarian cancer and suggests that this pathway may be worth exploiting for novel therapies.

Practical implementation issues and challenges for biobanks in the return of individual research results.

Whether or not to give research results back to individuals whose specimens are used for biomedical research is a subject of considerable controversy. Much of the debate has been focused around the ethical and legal concerns with some consideration of broader social issues such as whether or not people will be affected by such information for employment or health care. Much less attention has been paid to biobanks that collect the specimens used to generate the research findings and the issues and operational requirements for implementing return of individual research results. In this article, we give the biobanks' perspective and highlight that given the diversity among the types of biobanks, it may be difficult to design and implement a blanket policy in this complex area. We discuss the variability in the types of biobanks and some important issues that should be considered in determining whether or not research results should be provided to individuals whose specimens are used in biomedical research. We also discuss challenges that should be considered in implementing any approaches to the return of research results.

Chasing the immortal strand: evidence for nature's way of protecting the breast genome.

Mutations arise during cell division at a predictable rate. Besides DNA repair mechanisms, the existence of cellular hierarchies that originate with a stem cell serve to reduce the number of divisions necessary for normal physiology. In a previous issue, Bussard and colleagues demonstrate that mammary stem cells have an additional remarkable trait; namely the ability to selectively retain a template DNA strand during self renewal. In doing so, they avoid the accumulation of mutations in that so called 'immortal strand'. The implications of this are discussed with reference to the development and treatment of cancer.

Trade in human tissue products.

Trade in human tissue in Australia is prohibited by state law, and in ethical guidelines by the National Health and Medical Research Council: National statement on ethical conduct in human research; Organ and tissue donation by living donors: guidelines for ethical practice for health professionals. However, trade in human tissue products is a common practice especially for: reconstructive orthopaedic or plastic surgery; novel human tissue products such as a replacement trachea created by using human mesenchymal stem cells; biomedical research using cell lines, DNA and protein provided through biobanks. Cost pressures on these have forced consideration of commercial models to sustain their operations. Both the existing and novel activities require a robust framework to enable commercial uses of human tissue products while maintaining community acceptability of such practices, but to date no such framework exists. In this article, we propose a model ethical framework for ethical governance which identifies specific ethical issues such as: privacy; unique value of a person's tissue; commodification of the body; equity and benefit to the community; perverse incentives; and "attenuation" as a potentially useful concept to help deal with the broad range of subjective views relevant to whether it is acceptable to commercialise certain human tissue products.

Ethics and regulatory considerations for the clinical translation of somatic cell human epigenetic editing.

Altering the human epigenome with gene-editing technology in attempt to treat a variety of diseases and conditions seems scientifically feasible. We explore some of the ethical and regulatory issues related to the clinical translation of human epigenetic editing arguing that such approaches should be considered akin to somatic therapies.

Moving with the Times: The Health Science Alliance (HSA) Biobank, Pathway to Sustainability.

Human biobanks are recognised as vital components of translational research infrastructure. With the growth in personalised and precision medicine, and the associated expansion of biomarkers and novel therapeutics under development, it is critical that researchers can access a strong collection of patient biospecimens, annotated with clinical data. Biobanks globally are undertaking transformation of their operating models in response to changing research needs; transition from a 'classic' model representing a largely retrospective collection of pre-defined specimens to a more targeted, prospective collection model, although there remains a research need for both models to co-exist. Here we introduce the Health Science Alliance (HSA) Biobank, established in 2012 as a classic biobank, now transitioning to a hybrid operational model. Some of the past and current challenges encountered are discussed including clinical annotation, specimen utilisation and biobank sustainability, along with the measures the HSA Biobank is taking to address these challenges. We describe new directions being explored, going beyond traditional specimen collection into areas involving bioimages, microbiota and live cell culture. The HSA Biobank is working in collaboration with clinicians, pathologists and researchers, piloting a sustainable, robust platform with the potential to integrate future needs.

Normalising comparative effectiveness trials as clinical practice.

There is a lack of high-quality evidence underpinning many contemporary clinical practice guidelines embedded in the healthcare systems, leading to treatment uncertainty and practice variation in most medical disciplines. Comparative effectiveness trials (CETs) represent a diverse range of research that focuses on optimising health outcomes by comparing currently approved interventions to generate high-quality evidence to inform decision makers. Yet, despite their ability to produce real-world evidence that addresses the key priorities of patients and health systems, many implementation challenges exist within the healthcare environment.This manuscript aims to highlight common barriers to conducting CETs and describes potential solutions to normalise their conduct as part of a learning healthcare system.