Showing papers by "Rush University Medical Center published in 2014"

Comprehensive molecular profiling of lung adenocarcinoma: The cancer genome atlas research network

Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This s ...

Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement

Abstract: Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related...

Primary age-related tauopathy (PART): a common pathology associated with human aging

Abstract: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium

Abstract: We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Incidence and Trends of Anterior Cruciate Ligament Reconstruction in the United States

Abstract: >> Background: Anterior cruciate ligament (ACL) injury is among the most commonly studied injuries in orthopaedics. The previously reported incidence of ACL injury in the United States has varied considerably and is often based on expert opinion or single insurance databases. Purpose: To determine the incidence of ACL reconstruction (ACLR) in the United States; to identify changes in this incidence between 1994 and 2006; to identify changes in the demographics of ACLR over the same time period with respect to location (inpatient vs outpatient), sex, and age; and to determine the most frequent concomitant procedures performed at the time of ACLR. Study Design: Descriptive epidemiological study. Methods: International Classification of Diseases, 9th Revision (ICD-9) codes 844.2 and 717.83 were used to search the National Hospital Discharge Survey (NHDS) and the National Survey of Ambulatory Surgery (NSAS) for the diagnosis of ACL tear, and the procedure code 81.45 was used to search for ACLR. The incidence of ACLR in 1994 and 2006 was determined by use of US Census Data, and the results were then stratified based on patient age, sex, facility, concomitant diagnoses, and concomitant procedures. Results: The incidence of ACLR in the United States rose from 86,687 (95% CI, 51,844-121,530; 32.9 per 100,000 person-years) in 1994 to 129,836 (95% CI, 94,993-164,679; 43.5 per 100,000 person-years) in 2006 (P = .015). The number of ACLRs increased in patients younger than 20 years and those who were 40 years or older over this 12-year period. The incidence of ACLR in females significantly increased from 10.36 to 18.06 per 100,000 person-years between 1994 and 2006 (P = .0003), while that in males rose at a slower rate, with an incidence of 22.58 per 100,000 person-years in 1994 and 25.42 per 100,000 person-years in 2006. In 2006, 95% of ACLRs were performed in an outpatient setting, while in 1994 only 43% of ACLRs were performed in an outpatient setting. The most common concomitant procedures were partial meniscectomy and chondroplasty. Conclusion: The incidence of ACLR increased between 1994 and 2006, particularly in females as well as those younger than 20 years and those 40 years or older. Research efforts as well as cost-saving measures may be best served by targeting prevention and outcomes measures in these groups. Surgeons should be aware that concomitant injury is common.

Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.

Abstract: We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

REST and stress resistance in ageing and Alzheimer’s disease

Abstract: Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain. REST, a developmental regulator, is markedly induced in human neurons during ageing but is lost in Alzheimer’s disease; REST represses genes that promote neurodegeneration, is neuroprotective in animal models, and is associated with cognitive preservation and longevity in humans. Age is the biggest risk factor for neurodegenerative disease. But why do some age with cognitive function intact, yet others decline and develop Alzheimer's disease? Here Bruce Yankner and colleagues show that during ageing, a protein known as REST (repressor element 1-silencing transcription factor, also called NRSF) is increasingly expressed in human cortical and hippocampal neurons. REST levels are strongly correlated with cognitive preservation and longevity. REST represses genes that promote cell death and Alzheimer's disease pathology and induces those that mediate the stress response. Moreover, REST protects neurons from oxidative stress and amyloid β-protein toxicity. Deleting REST from the mouse brain results in age-related neuronal cell death. And, in humans with mild cognitive impairment or Alzheimer's disease, REST is excluded from the nucleus in neurons, and this exclusion is associated with autophagy and misfolded proteins. This work suggests that the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

Rates of post-traumatic stress disorder in trauma-exposed children and adolescents: meta-analysis

Abstract: Background It is unclear how many children and adolescents develop post-traumatic stress disorder (PTSD) after trauma. Aims To determine the incidence of PTSD in trauma-exposed children and adolescents as assessed with well-established diagnostic interviews and to examine potential moderators of the estimate. Method A systematic literature search identified 72 peer-reviewed articles on 43 independent samples ( n = 3563). Samples consisting only of participants seeking or receiving mental health treatment were excluded. Main analyses involved pooled incidence estimates and meta-analyses of variance. Results The overall rate of PTSD was 15.9% (95% CI 11.5-21.5), which varied according to the type of trauma and gender. Least at risk were boys exposed to non-interpersonal trauma (8.4%, 95% CI 4.7-14.5), whereas girls exposed to interpersonal trauma showed the highest rate (32.9%, 95% CI 19.8-49.3). No significant difference was found for the choice of assessment interview or the informant of the assessment. Conclusions Research conducted with the best available assessment instruments shows that a significant minority of children and adolescents develop PTSD after trauma exposure, with those exposed to interpersonal trauma and girls at particular risk. The estimates provide a benchmark for DSM-5 and ICD-11.

Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

Abstract: SummaryObjective To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. Methods Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. Results All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. Significance Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Soluble Markers of Inflammation and Coagulation but Not T-Cell Activation Predict Non–AIDS-Defining Morbid Events During Suppressive Antiretroviral Treatment

Abstract: Background. Defining the association of non–AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)–infected persons with antiretroviral therapy (ART)–associated virological suppression is critical to identifying interventions to decrease the occurrence of these events. Methods. We conducted acase-control studyof HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non–AIDS-defining events, defined as myocardial infarction, stroke, non–AIDS-defining cancer, non–AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4 + T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non–AIDSdefining event (hereafter, pre-event) were analyzed for activated CD4 + and CD8 + T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-totryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders. Results. Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non–AIDS-defining event. Significant associations were also seen between non– AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.

Ultrasonography versus computed tomography for suspected nephrolithiasis

Abstract: Background There is a lack of consensus about whether the initial imaging method for patients with suspected nephrolithiasis should be computed tomography (CT) or ultrasonography. Methods In this multicenter, pragmatic, comparative effectiveness trial, we randomly assigned patients 18 to 76 years of age who presented to the emergency department with suspected nephrolithiasis to undergo initial diagnostic ultrasonography performed by an emergency physician (point-of-care ultrasonography), ultrasonography performed by a radiologist (radiology ultrasonography), or abdominal CT. Subsequent management, including additional imaging, was at the discretion of the physician. We compared the three groups with respect to the 30-day incidence of high-risk diagnoses with complications that could be related to missed or delayed diagnosis and the 6-month cumulative radiation exposure. Secondary outcomes were serious adverse events, related serious adverse events (deemed attributable to study participation), pain (assess...

Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from four independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease.

The concordance between RNA-seq and microarray data depends on chemical treatment and transcript abundance

Abstract: The concordance of RNA-sequencing (RNA-seq) with microarrays for genome-wide analysis of differential gene expression has not been rigorously assessed using a range of chemical treatment conditions. Here we use a comprehensive study design to generate Illumina RNA-seq and Affymetrix microarray data from the same liver samples of rats exposed in triplicate to varying degrees of perturbation by 27 chemicals representing multiple modes of action (MOAs). The cross-platform concordance in terms of differentially expressed genes (DEGs) or enriched pathways is linearly correlated with treatment effect size (R(2)0.8). Furthermore, the concordance is also affected by transcript abundance and biological complexity of the MOA. RNA-seq outperforms microarray (93% versus 75%) in DEG verification as assessed by quantitative PCR, with the gain mainly due to its improved accuracy for low-abundance transcripts. Nonetheless, classifiers to predict MOAs perform similarly when developed using data from either platform. Therefore, the endpoint studied and its biological complexity, transcript abundance and the genomic application are important factors in transcriptomic research and for clinical and regulatory decision making.

The Appropriate Use of Neurostimulation of the Spinal Cord and Peripheral Nervous System for the Treatment of Chronic Pain and Ischemic Diseases: The Neuromodulation Appropriateness Consensus Committee

Abstract: Introduction: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. Methods: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. Results: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. Conclusions: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease

Abstract: With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.

A Compositional Look at the Human Gastrointestinal Microbiome and Immune Activation Parameters in HIV Infected Subjects

Abstract: HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.

Is HIV a Model of Accelerated or Accentuated Aging

Abstract: Background Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging? Methods Extensive literature review. Results The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants. Conclusions There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases.

Exploring the scope of post-intensive care syndrome therapy and care: engagement of non-critical care providers and survivors in a second stakeholders meeting.

Abstract: Background Increasing numbers of survivors of critical illness are at risk for physical, cognitive, and/or mental health impairments that may persist for months or years after hospital discharge. The post-intensive care syndrome framework encompassing these multidimensional morbidities was developed at the 2010 Society of Critical Care Medicine conference on improving long-term outcomes after critical illness for survivors and their families. Objectives To report on engagement with non-critical care providers and survivors during the 2012 Society of Critical Care Medicine post-intensive care syndrome stakeholder conference. Task groups developed strategies and resources required for raising awareness and education, understanding and addressing barriers to clinical practice, and identifying research gaps and resources, aimed at improving patient and family outcomes. Participants Representatives from 21 professional associations or health systems involved in the provision of both critical care and rehabilitation of ICU survivors in the United States and ICU survivors and family members. Design Stakeholder consensus meeting. Researchers presented summaries on morbidities for survivors and their families, whereas survivors presented their own experiences. Meeting outcomes Future steps were planned regarding 1) recognizing, preventing, and treating post-intensive care syndrome, 2) building strategies for institutional capacity to support and partner with survivors and families, and 3) understanding and addressing barriers to practice. There was recognition of the need for systematic and frequent assessment for post-intensive care syndrome across the continuum of care, including explicit "functional reconciliation" (assessing gaps between a patient's pre-ICU and current functional ability at all intra- and interinstitutional transitions of care). Future post-intensive care syndrome research topic areas were identified across the continuum of recovery: characterization of at-risk patients (including recognizing risk factors, mechanisms of injury, and optimal screening instruments), prevention and treatment interventions, and outcomes research for patients and families. Conclusions Raising awareness of post-intensive care syndrome for the public and both critical care and non-critical care clinicians will inform a more coordinated approach to treatment and support during recovery after critical illness. Continued conceptual development and engagement with additional stakeholders is required.