Patient and Surrogate Views of Community Consultation for Emergency Research

ObjectivePretrial community consultation (CC) is required for emergency research conducted under an exception from informed consent (EFIC) in the United States. CC remains controversial and challenging, and minimal data exist regarding the views of individuals enrolled in EFIC trials on this process. It is important to know whether participants perceive CC to be meaningful and, if so, whom they believe should be consulted.MethodsWe conducted a secondary analysis of data from two studies interviewing patients and surrogates of two recent EFIC trials (PEER‐RAMPART and PEER‐ProTECT). These interviews included similar open‐ and closed‐ended questions regarding participants’ views of the importance of CC, the rationale for their responses, and their views regarding which populations should be included in consultation efforts. A template analytic strategy was used for qualitative analysis of textual data, and descriptive statistics were tabulated to characterize demographic data and instances of major themes.ResultsNinety percent of participants perceived CC to be valuable. Participants’ reasons for finding CC valuable clustered in two categories: 1) as a method of informing the public about the trial to be conducted and 2) as a way of obtaining input and feedback from the community. Participants cited the medical community (43%) and individuals with a connection to the study condition (41%) as the most important groups to involve in consultation efforts; only 5% suggested consulting the general public in the area where the research will be conducted.ConclusionParticipants in EFIC trials and their decision makers generally valued CC as a method of informing and seeking input from the community. Participants felt that the most appropriate groups to consult were the medical community and individuals with connections to the condition under study. Consultation efforts focused on these two groups, rather than the general public, may be more efficient and more meaningful to individuals involved in EFIC trials. These findings also reinforce the importance of the distinction between public disclosure and CC.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139974/1/acem13265-sup-0001-DataSupplementS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139974/2/acem13265_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139974/3/acem13265.pd

Balancing Ethical Goals in Challenging Individual Participant Scenarios Occurring in a Trial Conducted with Exception from Informed Consent

In 1996, federal regulations were put into effect that allowed enrollment of critically ill or injured patients into Food and Drug Administration (FDA)‐regulated clinical trials using an exception from informed consent (EFIC) under narrowly prescribed research circumstances. Despite the low likelihood that a legally authorized representative (LAR) would be present within the interventional time frame, the EFIC regulations require the availability of an informed consent process, to be applied if an LAR is present and able to provide prospective consent for patient enrollment into the trial. The purpose of this article is to describe a series of unanticipated consent‐related questions arising when a potential surrogate decision‐maker appeared to be available at the time of patient enrollment into a trial proceeding under EFIC.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110828/1/acem12602.pd

Prion infection impairs cholesterol metabolism in neuronal cells

Conversion of prion protein (PrPC) into a pathological isoform (PrPSc) during prion infection occurs in lipid rafts and is dependent on cholesterol. Here, we show that prion infection increases the abundance of cholesterol transporter, ATP-binding cassette transporter type A1 (ATP-binding cassette transporter type A1), but reduces cholesterol efflux from neuronal cells leading to the accumulation of cellular cholesterol. Increased abundance of ABCA1 in prion disease was confirmed in prion-infected mice. Mechanistically, conversion of PrPC to the pathological isoform led to PrPSc accumulation in rafts, displacement of ABCA1 from rafts and the cell surface, and enhanced internalization of ABCA1. These effects were abolished with reversal of prion infection or by loading cells with cholesterol. Stimulation of ABCA1 expression with liver X receptor agonist or overexpression of heterologous ABCA1 reduced the conversion of prion protein into the pathological form upon infection. These findings demonstrate a reciprocal connection between prion infection and cellular cholesterol metabolism, which plays an important role in the pathogenesis of prion infection in neuronal cells

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth

Validation of a host response assay, SeptiCyte LAB, for discriminating sepsis from systemic inflammatory response syndrome in the ICU

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the largeMARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands (www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. Measurements and Main Results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation