Iowa City VA Medical Center

Artificial Intelligence (AI) has long promised to increase healthcare affordability, quality and accessibility but FDA, until recently, had never authorized an autonomous AI diagnostic system. This pivotal trial of an AI system to detect diabetic retinopathy (DR) in people with diabetes enrolled 900 subjects, with no history of DR at primary care clinics, by comparing to Wisconsin Fundus Photograph Reading Center (FPRC) widefield stereoscopic photography and macular Optical Coherence Tomography (OCT), by FPRC certified photographers, and FPRC grading of Early Treatment Diabetic Retinopathy Study Severity Scale (ETDRS) and Diabetic Macular Edema (DME). More than mild DR (mtmDR) was defined as ETDRS level 35 or higher, and/or DME, in at least one eye. AI system operators underwent a standardized training protocol before study start. Median age was 59 years (range, 22-84 years); among participants, 47.5% of participants were male; 16.1% were Hispanic, 83.3% not Hispanic; 28.6% African American and 63.4% were not; 198 (23.8%) had mtmDR. The AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% (95% CI, 81.8-91.2%) (>85%), specificity of 90.7% (95% CI, 88.3-92.7%) (>82.5%), and imageability rate of 96.1% (95% CI, 94.6-97.3%), demonstrating AI's ability to bring specialty-level diagnostics to primary care settings. Based on these results, FDA authorized the system for use by health care providers to detect more than mild DR and diabetic macular edema, making it, the first FDA authorized autonomous AI diagnostic system in any field of medicine, with the potential to help prevent vision loss in thousands of people with diabetes annually. ClinicalTrials.gov NCT02963441.

The distribution of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) was mapped in 39 cortical areas of 11 brains of patients with Alzheimer's disease (AD). Whole hemisphere blocks were embedded in polyethylene glycol (Carbowax), sectioned coronally, and stained with thioflavin S and thionin. The densities of NFTs and NPs were assessed using a numerical rating scale for each area. Scores were grouped by type of cortex and by lobe for statistical analysis. Highly significant differences were obtained. For example, limbic periallocortex and allocortex had more NFTs than any other type of cortex. In descending order, the density of NFTs was as follows: periallocortex (area 28) greater than allocortex (subiculum/CA1 zones of hippocampal formation, area 51) greater than corticoid areas (accessory basal nucleus of amygdala, nucleus basalis of Meynert) greater than proisocortex (areas 11, 12, 24, 23, anterior insula, 38, 35) greater than nonprimary association cortex (32, 46, superior temporal sulcus, 40, 39, posterior parahippocampal cortex, 37, 36) greater than primary sensory association cortex (7, 18, 19, 22, 21, 20) greater than agranular cortex (44-5, 8, 6, 4) greater than primary sensory cortex (41-2, 3-1-2, 17). The laminar distribution of NFTs tended to be selective, involving primarily layers III and V of association areas and layers II and IV of limbic periallocortex. There were far more NFTs in both limbic and temporal lobes than in frontal, parietal, and occipital lobes. In general, NPs were more evenly distributed throughout the cortex, with the exceptions of limbic periallocortex and allocortex, which had notably fewer NPs than other cortical areas. Temporal and occipital lobes had the highest NP densities, limbic and frontal lobes had the lowest, and parietal lobe was intermediate. No significant left-right hemispheric differences for NFT or NP densities were found across the population, and there was no relationship between duration of illness and densities of NFTs or NPs. The regional and laminar distribution of NFTs (and, to a lesser degree, that of NPs) suggests a consistent pattern of vulnerability within the cerebral cortices that seems correlated to the hierarchies of cortico-cortical connections. The higher-order association cortices, especially those in the anterior and ventromedial sectors of temporal lobe, are the most vulnerable, while other cortices appear less vulnerable to a degree commensurate with their connectional "distance" (i.e., synapses removed) from the limbic areas.

BACKGROUND: The role of clinical pharmacists in the care of hospitalized patients has evolved over time, with increased emphasis on collaborative care and patient interaction. The purpose of this review was to evaluate the published literature on the effects of interventions by clinical pharmacists on processes and outcomes of care in hospitalized adults. METHODS: Peer-reviewed, English-language articles were identified from January 1, 1985, through April 30, 2005. Three independent assessors evaluated 343 citations. Inpatient pharmacist interventions were selected if they included a control group and objective patient-specific health outcomes; type of intervention, study design, and outcomes such as adverse drug events, medication appropriateness, and resource use were abstracted. RESULTS: Thirty-six studies met inclusion criteria, including 10 evaluating pharmacists' participation on rounds, 11 medication reconciliation studies, and 15 on drug-specific pharmacist services. Adverse drug events, adverse drug reactions, or medication errors were reduced in 7 of 12 trials that included these outcomes. Medication adherence, knowledge, and appropriateness improved in 7 of 11 studies, while there was shortened hospital length of stay in 9 of 17 trials. No intervention led to worse clinical outcomes and only 1 reported higher health care use. Improvements in both inpatient and outpatient outcome measurements were observed. CONCLUSIONS: The addition of clinical pharmacist services in the care of inpatients generally resulted in improved care, with no evidence of harm. Interacting with the health care team on patient rounds, interviewing patients, reconciling medications, and providing patient discharge counseling and follow-up all resulted in improved outcomes. Future studies should include multiple sites, larger sample sizes, reproducible interventions, and identification of patient-specific factors that lead to improved outcomes.

Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes.

Inflammasomes continue to generate interest in an increasing number of disciplines owing to their unique ability to integrate a myriad of signals from pathogen- and damage-associated molecular patterns into a proinflammatory response. This potent caspase-1-dependent process is capable of activating the innate immune system, initiating pyroptosis (an inflammatory form of programmed cell death), and shaping adaptive immunity. The NLRP3 inflammasome is the most thoroughly studied of the inflammasome complexes that have been described thus far, perhaps owing to its disparate assortment of agonists. This review highlights our current understanding of the mechanisms of both priming and activation of the NLRP3 inflammasome.

The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

The vertebrate immune system recognizes bacterial DNA based on the presence of unmethylated CpG-dinucleotides in particular base contexts ("CpG motifs"). In contrast to mice, knowledge about CpG-mediated effects on human B cells is poor. In the present study we identify and determine an optimal human CpG motif. A phosphodiester oligonucleotide containing this motif strongly stimulated CD86, CD40, CD54, and MHC class II expression, IL-6 synthesis, and proliferation of primary human B cells. These effects required internalization of the oligonucleotide and endosomal maturation. The molecular mechanism of action of this CpG motif was associated with the sustained induction of the NF-kappaB p50/p65 heterodimer and of the transcription-factor complex AP-1. Transcription-factor activation by CpG DNA was preceded by increased phosphorylation of the stress kinases c-Jun N-terminal kinase and p38, and of activating transcription factor-2. In contrast to CpG, signaling through the B cell receptor led to activation of extracellular receptor kinase and to phosphorylation of a different isoform of c-Jun N-terminal kinase. These studies define the structure of a highly active human CpG motif and characterize its molecular mechanism of action in primary human B cells.

Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides within specific sequence contexts (CpG motifs) are detected, like bacterial or viral DNA, as a danger signal by the vertebrate immune system. CpG ODN synthesized with a nuclease-resistant phosphorothioate backbone have been shown to be potent Th1-directed adjuvants in mice, but these motifs have been relatively inactive on primate leukocytes in vitro. Moreover, in vitro assays that predict in vivo adjuvant activity for primates have not been reported. In the present study we tested a panel of CpG ODN for their in vitro and in vivo immune effects in mice and identified in vitro activation of B and NK cells as excellent predictors of in vivo adjuvant activity. Therefore, we tested >250 phosphorothioate ODN for their capacity to stimulate proliferation and CD86 expression of human B cells and to induce lytic activity and CD69 expression of human NK cells. These studies revealed that the sequence, number, and spacing of individual CpG motifs contribute to the immunostimulatory activity of a CpG phosphorothioate ODN. An ODN with a TpC dinucleotide at the 5' end followed by three 6 mer CpG motifs (5'-GTCGTT-3') separated by TpT dinucleotides consistently showed the highest activity for human, chimpanzee, and rhesus monkey leukocytes. Chimpanzees or monkeys vaccinated once against hepatitis B with this CpG ODN adjuvant developed 15 times higher anti-hepatitis B Ab titers than those receiving vaccine alone. In conclusion, we report an optimal human CpG motif for phosphorothioate ODN that is a candidate human vaccine adjuvant.

Reactive oxidant species (superoxide, hydrogen peroxide, hydroxyl radical, hypohalous acid, and nitric oxide) are involved in many of the complex interactions between the invading microorganism and its host. Regardless of the source of these compounds or whether they are produced under normal conditions or those of oxidative stress, these oxidants exhibit a broad range of toxic effects to biomolecules that are essential for cell survival. Production of these oxidants by microorganisms enables them to have a survival advantage in their environment. Host oxidant production, especially by phagocytes, is a counteractive mechanism aimed at microbial killing. However, this mechanism may be contribute to a deleterious consequence of oxidant exposure, i.e., inflammatory tissue injury. Both the host and the microorganism have evolved complex adaptive mechanisms to deflect oxidant-mediated damage, including enzymatic and nonenzymatic oxidant-scavenging systems. This review discusses the formation of reactive oxidant species in vivo and how they mediate many of the processes involved in the complex interplay between microbial invasion and host defense.

Although interactions of proteins with glycosaminoglycans (GAGs), such as heparin and heparan sulphate, are of great biological importance, structural requirements for protein-GAG binding have not been well-characterised. Ionic interactions are important in promoting protein-GAG binding. Polyelectrolyte theory suggests that much of the free energy of binding comes from entropically favourable release of cations from GAG chains. Despite their identical charges, arginine residues bind more tightly to GAGs than lysine residues. The spacing of these residues may determine protein-GAG affinity and specificity. Consensus sequences such as XBBBXXBX, XBBXBX and a critical 20 A spacing of basic residues are found in some protein sites that bind GAG. A new consensus sequence TXXBXXTBXXXTBB is described, where turns bring basic interacting amino acid residues into proximity. Clearly, protein-GAG interactions play a prominent role in cell-cell interaction and cell growth. Pathogens including virus particles might target GAG-binding sites in envelope proteins leading to infection.

The robust detection of red lesions in digital color fundus photographs is a critical step in the development of automated screening systems for diabetic retinopathy. In this paper, a novel red lesion detection method is presented based on a hybrid approach, combining prior works by Spencer et al. (1996) and Frame et al. (1998) with two important new contributions. The first contribution is a new red lesion candidate detection system based on pixel classification. Using this technique, vasculature and red lesions are separated from the background of the image. After removal of the connected vasculature the remaining objects are considered possible red lesions. Second, an extensive number of new features are added to those proposed by Spencer-Frame. The detected candidate objects are classified using all features and a k-nearest neighbor classifier. An extensive evaluation was performed on a test set composed of images representative of those normally found in a screening set. When determining whether an image contains red lesions the system achieves a sensitivity of 100% at a specificity of 87%. The method is compared with several different automatic systems and is shown to outperform them all. Performance is close to that of a human expert examining the images for the presence of red lesions.

Phagocytes mediate their innate immunological response by releasing products that damage invading microorganisms. These products include proteins such as lysozyme, peroxidases, and elastase as well as reactive oxygen species such as superoxide, hydrogen peroxide, hypohalous acid, and hydroxyl radical. Although it is clear that many phagocytic secretory products have direct cytotoxic potential, understanding is limited of how multiple products interact to generate and modulate the cytotoxic response. This review focuses on recent findings that elucidate the biochemical nature of secretory product interaction in the formation of free radicals, particularly the highly reactive hydroxyl radical. The possible role of these reactions in phagocyte microbicidal activity and inflammatory tissue injury is discussed.

Introduction of a normal human chromosome 6 into human melanoma cell lines results in suppression of tumorigenicity. This suggests that a gene(s) on chromosome 6 controls the malignant phenotype of human melanoma. Because antioxidants can suppress the tumor-promotion phase of carcinogenesis, and because the antioxidant enzyme manganese superoxide dismutase (MnSOD) has been localized to a region of chromosome 6 frequently lost in melanomas, we have examined the effect of transfecting sense and antisense human MnSOD cDNAs into melanoma cell lines. Cell lines expressing abundant (+)-sense MnSOD-5 cDNAs significantly altered their phenotype in culture and lost their ability to form colonies in soft agar and tumors in nude mice. In contrast, the introduction of antisense MnSOD or +psv2neo had no effect on melanoma tumorigenicity. These findings indicate that stable transfection of MnSOD cDNA into melanoma cell lines exerts a biological effect that mimics that observed after introduction of an entire human chromosome 6.

Chronic inflammatory diseases are associated with accelerated atherosclerosis and increased risk of cardiovascular diseases (CVD). As the pathogenesis of atherosclerosis is increasingly recognized as an inflammatory process, similarities between atherosclerosis and systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel diseases, lupus, psoriasis, spondyloarthritis and others have become a topic of interest. Endothelial dysfunction represents a key step in the initiation and maintenance of atherosclerosis and may serve as a marker for future risk of cardiovascular events. Patients with chronic inflammatory diseases manifest endothelial dysfunction, often early in the course of the disease. Therefore, mechanisms linking systemic inflammatory diseases and atherosclerosis may be best understood at the level of the endothelium. Multiple factors, including circulating inflammatory cytokines, TNF-α (tumor necrosis factor-α), reactive oxygen species, oxidized LDL (low density lipoprotein), autoantibodies and traditional risk factors directly and indirectly activate endothelial cells, leading to impaired vascular relaxation, increased leukocyte adhesion, increased endothelial permeability and generation of a pro-thrombotic state. Pharmacologic agents directed against TNF-α-mediated inflammation may decrease the risk of endothelial dysfunction and cardiovascular disease in these patients. Understanding the precise mechanisms driving endothelial dysfunction in patients with systemic inflammatory diseases may help elucidate the pathogenesis of atherosclerosis in the general population.

Chronic alcohol abuse exacts a major social and medical toll in the United States and other Western countries. One of the least appreciated medical complications of alcohol abuse is altered immune regulation leading to immunodeficiency and autoimmunity. The consequences of the immunodeficiency include increased susceptibility to bacterial pneumonia, tuberculosis, and other infectious diseases. In addition, the chronic alcoholic often has circulating autoantibodies, and recent investigations indicate that the most destructive complications of alcoholism, such as liver disease and liver failure, may have a component of autoimmunity. Current research on altered cytokine balance produced by alcohol is leading to new insights on the regulation of the immune system in the chronic alcoholic. There is also recent development of exciting new techniques designed to improve or restore immune function by manipulation of cytokine balance. Although much remains to be learned, both in the abnormalities produced by alcohol and in the techniques to reverse those abnormalities, current progress reflects a rapidly improving understanding of the basic immune disorders of the alcoholic.

Abstract Asthma has been increasing in industrialized countries. Evidence suggests that asthma is caused by a Th2 immune response to inhaled environmental Ags and that childhood infections protect against this. We have shown that bacterial DNA contains motifs, centered on unmethylated CpG dinucleotides, which induce Th1-type responses. We hypothesized that the Th1 effect of these CpG motifs may oppose the Th2 type allergic response and suggest that this may account for the protective effect of childhood infection against asthma. We examined the effects of CpG-motif oligodeoxynucleotides (CpG ODN) in a murine model of asthma. Airway eosinophilia, Th2 cytokine induction, IgE production, and bronchial hyperreactivity were prevented by coadministration of CpG ODN with the Ag. Significantly, in a previously sensitized mouse, CpG ODN can prevent allergen-induced airway inflammation. These studies suggest that exposure to CpG DNA may protect against asthma.

Translational medicine is concerned with the translation of research discoveries into clinical applications for the prevention, diagnosis, and treatment of human diseases. Here we briefly review the research concerning the role of the renal sympathetic nerves (efferent and afferent) in the control of renal function, with particular reference to hypertension. The accumulated evidence is compelling for a primary role of the renal innervation in the pathogenesis of hypertension. These research discoveries led to the development of a catheter-based procedure for renal denervation in human subjects. A proof-of-principle study in patients with hypertension resistant to conventional therapy has demonstrated that the procedure is safe and produces renal denervation with sustained lowering of arterial pressure.

BACKGROUND: Structural and functional abnormalities of the coronary microcirculation have been reported in experimental diabetes mellitus. The purpose of this study was to evaluate coronary microvascular function in human diabetes. METHODS AND RESULTS: Twenty-four diabetic and 31 nondiabetic patients were studied during cardiac catheterization. A Doppler catheter or guidewire was used to measure changes in coronary blood flow velocity in a nonstenotic artery. Maximal coronary blood flow reserve was determined by using intracoronary adenosine or papaverine. Coronary dilation in response to an increase in myocardial metabolic demand was assessed by using rapid atrial pacing. Maximal vasodilator responses to papaverine and adenosine were compared in 12 diabetic patients. Maximal pharmacologic coronary flow reserve was depressed in diabetic (2.8 +/- 0.2, n = 19) compared with nondiabetic (3.7 +/- 0.2, n = 21, P < .001) patients. During atrial pacing, the decrease in coronary vascular resistance was attenuated in the diabetic (-14 +/- 3%) compared with the nondiabetic (-24 +/- 2%, P < .05) patients. Differences in coronary microvascular function between diabetic and nondiabetic patients were not attributable to differences in drug therapy, resting hemodynamics, or incidence of hypertension. In 12 diabetic patients the maximal coronary vasodilator responses to papaverine and adenosine were similar. CONCLUSIONS: This study demonstrates both reduced maximal coronary vasodilation and impairment in the regulation of coronary flow in response to submaximal increases in myocardial demand in patients with diabetes mellitus. These microvascular abnormalities may lead to myocardial ischemia in the absence of epicardial coronary atherosclerosis in some circumstances, and thus contribute to adverse cardiovascular events in diabetic patients.

BACKGROUND: Previous studies of hospital readmission have focused on specific conditions or populations and generated complex prediction models. OBJECTIVE: To identify predictors of early hospital readmission in a diverse patient population and derive and validate a simple model for identifying patients at high readmission risk. DESIGN: Prospective observational cohort study. PATIENTS: Participants encompassed 10,946 patients discharged home from general medicine services at six academic medical centers and were randomly divided into derivation (n = 7,287) and validation (n = 3,659) cohorts. MEASUREMENTS: We identified readmissions from administrative data and 30-day post-discharge telephone follow-up. Patient-level factors were grouped into four categories: sociodemographic factors, social support, health condition, and healthcare utilization. We performed logistic regression analysis to identify significant predictors of unplanned readmission within 30 days of discharge and developed a scoring system for estimating readmission risk. RESULTS: Approximately 17.5% of patients were readmitted in each cohort. Among patients in the derivation cohort, seven factors emerged as significant predictors of early readmission: insurance status, marital status, having a regular physician, Charlson comorbidity index, SF12 physical component score, >or=1 admission(s) within the last year, and current length of stay >2 days. A cumulative risk score of >or=25 points identified 5% of patients with a readmission risk of approximately 30% in each cohort. Model discrimination was fair with a c-statistic of 0.65 and 0.61 for the derivation and validation cohorts, respectively. CONCLUSIONS: Select patient characteristics easily available shortly after admission can be used to identify a subset of patients at elevated risk of early readmission. This information may guide the efficient use of interventions to prevent readmission.