Mihaela Stefan

Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis*

Objective:Isotonic saline is the most commonly used crystalloid in the ICU, but recent evidence suggests that balanced fluids like Lactated Ringer’s solution may be preferable. We examined the association between choice of crystalloids and in-hospital mortality during the resuscitation of critically ill adults with sepsis. Design:A retrospective cohort study of patients admitted with sepsis, not undergoing any surgical procedures, and treated in an ICU by hospital day 2. We used propensity score matching to control for confounding and compared the following outcomes after resuscitation with balanced versus with no-balanced fluids: in-hospital mortality, acute renal failure with and without dialysis, and hospital and ICU lengths of stay. We also estimated the dose-response relationship between receipt of increasing proportions of balanced fluids and in-hospital mortality. Setting:Three hundred sixty U.S. hospitals that were members of the Premier Healthcare alliance between November 2005 and December 2010. Patients:A total of 53,448 patients with sepsis, treated with vasopressors and crystalloids in an ICU by hospital day 2 including 3,396 (6.4%) that received balanced fluids. Interventions:None. Measurements and Main Results:Patients treated with balanced fluids were younger and less likely to have heart or chronic renal failure, but they were more likely to receive mechanical ventilation, invasive monitoring, colloids, steroids, and larger crystalloid volumes (median 7 vs 5 L). Among 6,730 patients in a propensity-matched cohort, receipt of balanced fluids was associated with lower in-hospital mortality (19.6% vs 22.8%; relative risk, 0.86; 95% CI, 0.78, 0.94). Mortality was progressively lower among patients receiving larger proportions of balanced fluids. There were no significant differences in the prevalence of acute renal failure (with and without dialysis) or in-hospital and ICU lengths of stay. Conclusions:Among critically ill adults with sepsis, resuscitation with balanced fluids was associated with a lower risk of in-hospital mortality. If confirmed in randomized trials, this finding could have significant public health implications, as crystalloid resuscitation is nearly universal in sepsis.

DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology.

Type 1 diabetes (T1D) shows ∼40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional annotation of the genes with distinct CpG methylation profiles in T1D samples showed differential DNAm of immune response and defense response pathways between affected and unaffected twins. Integration of DNAm data with GWAS data mapped several known T1D associated genes, HLA, INS, IL-2RB, CD226, which showed significant differences in DNAm between affected and unaffected of twins. Our findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D.

Association between β-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension

Background β-Blocker therapy has been shown to improve survival among patients with ischaemic heart disease (IHD) and congestive heart failure (CHF) and is underused among patients with chronic obstructive pulmonary disease (COPD). Evidence regarding the optimal use of β-blocker therapy during an acute exacerbation of COPD is particularly weak. Methods We conducted a retrospective cohort study of patients aged ≥40 years with IHD, CHF or hypertension who were hospitalised for an acute exacerbation of COPD from 1 January 2006 to 1 December 2007 at 404 acute care hospitals throughout the USA. We examined the association between β-blocker therapy and in-hospital mortality, initiation of mechanical ventilation after day 2 of hospitalisation, 30-day all-cause readmission and length of stay. Results Of 35 082 patients who met the inclusion criteria, 29% were treated with β blockers in the first two hospital days, including 22% with β1-selective and 7% with non-selective β blockers. In a propensity-matched analysis, there was no association between β-blocker therapy and in-hospital mortality (OR 0.88, 95% CI 0.71 to 1.09), 30-day readmission (OR 0.96, 95% CI 0.89 to 1.03) or late mechanical ventilation (OR 0.98, 95% CI 0.77 to 1.24). However, when compared with β1 selective β blockers, receipt of non-selective β blockers was associated with an increased risk of 30-day readmission (OR 1.25, 95% CI 1.08 to 1.44). Conclusions Among patients with IHD, CHF or hypertension, continuing β1-selective β blockers during hospitalisation for COPD appears to be safe. Until additional evidence becomes available, β1-selective β blockers may be superior to treatment with a non-selective β blocker.

Outcomes associated with invasive and noninvasive ventilation among patients hospitalized with exacerbations of chronic obstructive pulmonary disease

IMPORTANCE Small clinical trials have shown that noninvasive ventilation (NIV) is efficacious in reducing the need for intubation and improving short-term survival among patients with severe exacerbations of chronic obstructive pulmonary disease (COPD). Little is known, however, about the effectiveness of NIV in routine clinical practice. OBJECTIVE To compare the outcomes of patients with COPD treated with NIV to those treated with invasive mechanical ventilation (IMV). DESIGN, SETTING, AND PARTICIPANTS This was a retrospective cohort study of 25 628 patients hospitalized for exacerbation of COPD who received mechanical ventilation on the first or second hospital day at 420 US hospitals participating in the Premier Inpatient Database. EXPOSURES Initial ventilation strategy. MAIN OUTCOMES AND MEASURES In-hospital mortality, hospital-acquired pneumonia, hospital length of stay and cost, and 30-day readmission. RESULTS In the study population, a total of 17 978 (70%) were initially treated with NIV on hospital day 1 or 2. When compared with those initially treated with IMV, NIV-treated patients were older, had less comorbidity, and were less likely to have concomitant pneumonia present on admission. In a propensity-adjusted analysis, NIV was associated with lower risk of mortality than IMV (odds ratio [OR] 0.54; [95% CI, 0.48-0.61]). Treatment with NIV was associated with lower risk of hospital-acquired pneumonia (OR, 0.53 [95% CI, 0.44-0.64]), lower costs (ratio, 0.68 [95% CI, 0.67-0.69]), and a shorter length of stay (ratio, 0.81 [95% CI, 0.79-0.82]), but no difference in 30-day all-cause readmission (OR, 1.04 [95% CI, 0.94-1.15]) or COPD-specific readmission (OR, 1.05 [95% CI, 0.91-1.22]). Propensity matching attenuated these associations. The benefits of NIV were similar in a sample restricted to patients younger than 85 years and were attenuated among patients with higher levels of comorbidity and concomitant pneumonia. Using the hospital as an instrumental variable, the strength of association between NIV and mortality was modestly attenuated (OR, 0.66 [95% CI, 0.47-0.91]). In sensitivity analyses, the benefit of NIV was robust in the face of a strong hypothetical unmeasured confounder. CONCLUSIONS AND RELEVANCE In a large retrospective cohort study, patients with COPD treated with NIV at the time of hospitalization had lower inpatient mortality, shorter length of stay, and lower costs compared with those treated with IMV.

The Impact of COPD on Management and Outcomes of Patients Hospitalized With Acute Myocardial Infarction: A 10-Year Retrospective Observational Study

BACKGROUND There are limited data describing contemporary trends in the management and outcomes of patients with COPD who develop acute myocardial infarction (AMI). METHODS The study population consisted of patients hospitalized with AMI at all greater Worcester, Massachusetts, medical centers between 1997 and 2007. RESULTS Of the 6,290 patients hospitalized with AMI, 17% had a history of COPD. Patients with COPD were less likely to be treated with β-blockers or lipid-lowering therapy or to have undergone interventional procedures during their index hospitalization than patients without COPD. Patients with COPD were at higher risk for dying during hospitalization (13.5% vs 10.1%) and at 30 days after discharge (18.7% vs 13.2%), and their outcomes did not improve during the decade-long period under study. After multivariable adjustment, the adverse effects of COPD remained on both in-hospital (OR, 1.25; 95% CI, 0.99-1.50) and 30-day all-cause mortality (OR, 1.31; 95% CI, 1.10-1.58). The use of evidence-based therapies for all patients with AMI increased between 1997 and 2007, with a particularly marked increase for patients with COPD. CONCLUSIONS Our results suggest that the gap in medical care between patients with and without COPD hospitalized with AMI narrowed substantially between 1997 and 2007. Patients with COPD, however, remain less aggressively treated and are at increased risk for hospital adverse outcomes than patients without COPD in the setting of AMI. Careful consideration is necessary to ensure that these high-risk complex patients are not denied the benefits of effective cardiac therapies.

Novel Variant of Thyroglobulin Promoter Triggers Thyroid Autoimmunity through an Epigenetic Interferon α-modulated Mechanism

Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified an SNP (−1623A→G) that was associated with AITD in the Caucasian population (p = 0.006). We show that the nucleotide substitution introduced by SNP (−1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5′ TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon α, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFNα) and genetic (TG) factors to trigger AITD.

IFN-α Mediates the Development of Autoimmunity both by Direct Tissue Toxicity and through Immune Cell Recruitment Mechanisms

IFN-α is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-α is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-α treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-α under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-α involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.

Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Significance Graves disease (GD) is an autoimmune disease caused by interactions between genetic, epigenetic, and environmental factors. The thyrotropin receptor (TSHR) is the major autoantigen in GD and is a key GD susceptibility gene. SNPs in intron 1 of the TSHR are associated with GD, but the causative variant and the mechanisms are unknown. By mapping epigenetic modifications induced by IFNα, a viral-induced cytokine triggering GD, we pinpointed the causative variant in intron 1 of the TSHR. We demonstrate that the disease-associated variant interacts epigenetically with a transcriptional repressor, promyelocytic leukemia zinc finger protein, and reduces thymic TSHR expression, leading to escape from tolerance and autoimmunity to the TSHR. These genetic–epigenetic interactions leading to decreased thymic self-antigen expression reveal a universal mechanism in autoimmunity. Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic–epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.

Epidemiology and outcomes of acute respiratory failure in the United States, 2001 to 2009: a national survey

BACKGROUND The objective of this study was to evaluate trends in hospitalization, cost, and short-term outcomes in acute respiratory failure (ARF) between 2001 and 2009 in the United States. METHODS Using the Nationwide Inpatient Sample we identified cases of ARF based on International Classification for Diseases, Ninth Revision, Clinical Modification codes. We calculated weighted frequencies of ARF hospitalizations by year and estimated population-adjusted incidence and mortality rates. We used logistic regression to examine hospital mortality rates over time while adjusting for changes in demographic characteristics and comorbidities of patients. RESULTS The number of hospitalizations with a diagnosis of ARF rose from 1,007,549 in 2001 to 1,917,910 in 2009, with an associated increase in total hospital costs from

Impact of COPD on the Mortality and Treatment of Patients Hospitalized With Acute Decompensated Heart Failure: The Worcester Heart Failure Study

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