Biology‐Driven Gene‐Gene Interaction Analysis of Age‐Related Cataract in the eMERGE Network

Bioinformatics approaches to examine gene‐gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge‐driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty‐three SNP‐SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell‐to‐cell adhesion signaling, cell‐cell junction organization, and cell‐cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP‐SNP models, which included signal transduction and PI3K‐Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology‐driven method, applicable for any genome‐wide association study dataset.     

Association of frailty with short-term outcomes,organ support and resource use in critically ill patients

Purpose

Frail patients are known to experience poor outcomes. Nevertheless, we know less about how frailty manifests itself in patients’ physiology during critical illness and how it affects resource use in intensive care units (ICU). We aimed to assess the association of frailty with short-term outcomes and organ support used by critically ill patients.

Methods

Retrospective analysis of prospective collected data from 93 ICUs in Brazil from 2014 to 2015. We assessed frailty using the modified frailty index (MFI). The primary outcome was in-hospital mortality. Secondary outcomes were discharge home without need for nursing care, ICU and hospital length of stay (LOS), and utilization of ICU organ support and transfusion. We used mixed logistic regression and competing risk models accounting for relevant confounders in outcome analyses.

Results

The analysis consisted of 129,680 eligible patients. There were 40,779 (31.4%) non-frail (MFI?=?0), 64,407 (49.7%) pre-frail (MFI?=?1–2) and 24,494 (18.9%) frail (MFI?≥?3) patients. After adjusted analysis, frailty was associated with higher in-hospital mortality (OR 2.42, 95% CI 1.89–3.08), particularly in patients admitted with lower SOFA scores. Frail patients were less likely to be discharged home (OR 0.36, 95% CI 0.54–0.79) and had higher hospital and ICU LOS than non-frail patients. Use of all forms of organ support (mechanical ventilation, non-invasive ventilation, vasopressors, dialysis and transfusions) were more common in frail patients and increased as MFI increased.

Conclusions

Frailty, as assessed by MFI, was associated with several patient-centered endpoints including not only survival, but also ICU LOS and organ support.

     

Remodeling of gap junctions in mouse hearts hypertrophied by forced retinoic acid signaling

BACKGROUND: Beta-MHC-hRARalpha transgenic mice express a constitutively active (truncated) form of the human retinoic acid receptor which triggers development of dilated cardiomyopathy. In those hearts, we studied expression of gap junction proteins in relation to electrical impulse propagation. METHODS AND RESULTS: As compared to wildtype mice, hearts of 4-6 month old mice with 7-12 inserted hRARalpha copies are marked by an increased heart weight/body weight- and heart weight/tibia length ratio. 3-extremity lead ECGs revealed prolongation of the Q-j interval suggesting delayed ventricular activation. Mapping of electrical activity of epi- and endocardial left ventricular free wall revealed activation delay, increased heterogeneity in conduction and regional conduction block. Ventricular tachycardias did not occur spontaneously nor could be induced by ventricular pacing. Immunohistochemical analysis showed profound and heterogeneous redistribution and down-regulation of the gap junction protein connexin43 (Cx43) in the left ventricular free wall. Here, hRARalpha expression induced re-expression of the hypertrophic markers alpha-skeletal actin and beta-MHC, and in 3 out of 10 severely affected mice, re-expression of Cx40. Concomitant with changes in expression/distribution of Cx43, changes in expression and distribution of beta-catenin and N-cadherin (two other intercalated disk associated proteins) were observed. CONCLUSIONS: Beta-MHC-hRARalpha transgenic hearts show heterogeneous re-expression of (early) sarcomeric genes while expression of connexin43, N-cadherin and beta-catenin is down-regulated. We postulate that the resulting aberrant ventricular activation does not trigger development of lethal arrhythmias due to the small size of remaining healthy ventricular tissue where the transgene is not expressed.     

Understanding and use of inhaler medication by asthmatics in specialty care in Trinidad: a study following development of Caribbean guidelines for asthma management and prevention

STUDY OBJECTIVES: Following the development of the Caribbean Guidelines for Asthma Care, we examined the utilization of inhaled medications in asthmatic patients in Trinidad, West Indies. SETTING: Chest Clinic, Ministry of Health, Trinidad. PARTICIPANTS: Physician-diagnosed asthmatic patients who attended the Chest Clinic between July 1998 and August 2000. MEASUREMENTS AND RESULTS: A consecutive sample of patients who were > 7 years of age (n = 402) was interviewed about compliance with, understanding of, and use of inhaler medication. The inhaler technique of these patients was directly observed. Inhaled steroid therapy was prescribed in 83% of patients but were prescribed the least in elderly patients (63%) and children (62%). Salbutamol was prescribed in 98% of patients, and ipratropium and sodium cromoglycate were selectively prescribed in elderly men and children, respectively. Only 33% of patients used the inhaler correctly, and children and the elderly were the least efficient in its use. The use of a spacer device was advised in 19% of patients, including only 6% of the elderly patients. Explanations for different inhaler therapies were given to 62% of patients, and 53% of patients could describe these reasons. The reported 40% noncompliance rate among patients in the sample was primarily a result of long waiting periods at the pharmacy (58%) and the personal cost incurred on purchasing the medication (52%). CONCLUSIONS: Educating patients, with a focus on children and the elderly, in inhaler techniques and reinforcing understanding of asthma medications can improve asthma management in Trinidad. Asthma caregivers in the Caribbean should ensure the appropriate dissemination of the guidelines and should outline strategies for their implementation.     

The Selvester 32-point QRS score for evaluation of myocardial infarct size after primary coronary angioplasty

In patients treated successfully with primary angioplasty for a first myocardial infarction, the Selvester 32-point score correlates well with infarct size measured with quantitative thallium-201 perfusion imaging. Therefore, it is a useful parameter for infarct sizing, particularly in patients with anterior infarction or reduced ejection fraction at discharge.     

Further characterization of the NB 1 antigen as a variably expressed 56–62 kD GPI-linked glycoprotein of plasma membranes and specific granules of neutrophils

The human neutrophil-specific alloantigen NB1 was identified as a glycosyl-phosphatidylinositol (GPI)-anchored N-glycosylated protein of M(r) 56-62 kD under reducing conditions. Under non-reducing conditions its M(r) was 49-55 kD. This glycoprotein antigen was found to be expressed by only a subpopulation of normal donor neutrophils, and could not be detected on other blood cells. The allotypic epitope recognized by human anti-NB1 IgG was also recognized by the mouse monoclonal antibody 1B5. The percentage of neutrophils stained by these antibodies varied greatly among healthy donors (range 0-100%). When 16 donors were repeatedly tested, the NB1-positive neutrophil fraction appeared to remain remarkably constant over time in most donors, but significant fluctuations were seen in some. NB1 antigen was found to be expressed not only on the plasma membrane, but also intracellularly on the membranes of small vesicles and specific granules. The neutrophils which expressed NB1 antigen on the plasma membrane were the same as those with intracellular expression of this antigen. Crosslinking of NB1 antigen on the plasma membrane with monoclonal antibody 1B5 and goat-anti-mouse Ig resulted in internalization of the complex, while in-vitro stimulation of neutrophils caused an increase of the intensity of plasma membrane staining with anti-NB1, but only of those cells that were positive already prior to stimulation. The NB1 glycoprotein thus appears to identify a distinct subset of neutrophils, the size of which greatly varies among healthy donors. The function of the NB1 glycoprotein remains unclear, but its behaviour upon crosslinking and chemotactic peptide stimulation suggests a possible role as receptor molecule.     

Effects of computerized guidelines for managing heart disease in primary care

BACKGROUND: Electronic information systems have been proposed as one means to reduce medical errors of commission (doing the wrong thing) and omission (not providing indicated care). OBJECTIVE: To assess the effects of computer-based cardiac care suggestions. DESIGN: A randomized, controlled trial targeting primary care physicians and pharmacists. SUBJECTS: A total of 706 outpatients with heart failure and/or ischemic heart disease. INTERVENTIONS: Evidence-based cardiac care suggestions, approved by a panel of local cardiologists and general internists, were displayed to physicians and pharmacists as they cared for enrolled patients. MEASUREMENTS: Adherence with the care suggestions, generic and condition-specific quality of life, acute exacerbations of their cardiac disease, medication compliance, health care costs, satisfaction with care, and physicians' attitudes toward guidelines. RESULTS: Subjects were followed for 1 year during which they made 3,419 primary care visits and were eligible for 2,609 separate cardiac care suggestions. The intervention had no effect on physicians' adherence to the care suggestions (23% for intervention patients vs 22% for controls). There were no intervention-control differences in quality of life, medication compliance, health care utilization, costs, or satisfaction with care. Physicians viewed guidelines as providing helpful information but constraining their practice and not helpful in making decisions for individual patients. CONCLUSIONS: Care suggestions generated by a sophisticated electronic medical record system failed to improve adherence to accepted practice guidelines or outcomes for patients with heart disease. Future studies must weigh the benefits and costs of different (and perhaps more Draconian) methods of affecting clinician behavior.     

Sonography in Crohn disease--the conclusions of an experts' group

Sonography is adding a new dimension to diagnosis of Crohn's disease: the analysis of the transmural and peri-intestinal manifestations of the chronic inflammation. Distortions in the structure of intestinal wall are recognizable, the impact on transport of intestinal content can be judged, penetration of inflammation into the bowel surrounding as fistula, abscess, mesenteriitis und peritonitis is safely seen. Differential diagnosis on a strictly sonographic basis is difficult. The paper represents the results of an expert meeting held at the University of Frankfurt/M.