Scott & White Memorial Hospital

BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

BACKGROUND: The last decade has evidenced a dramatic increase in the development and utilization of pediatric health-related quality of life (HRQOL) measures in an effort to improve pediatric patient health and well-being and determine the value of healthcare services. The emerging paradigm shift toward patient-reported outcomes (PROs) in clinical trials has provided the opportunity to further emphasize the value and essential need for pediatric patient self-reported outcomes measurement. Data from the PedsQL DatabaseSM were utilized to test the hypothesis that children as young as 5 years of age can reliably and validly report their HRQOL. METHODS: The sample analyzed represented child self-report age data on 8,591 children ages 5 to 16 years from the PedsQL 4.0 Generic Core Scales DatabaseSM. Participants were recruited from general pediatric clinics, subspecialty clinics, and hospitals in which children were being seen for well-child checks, mild acute illness, or chronic illness care (n = 2,603, 30.3%), and from a State Children's Health Insurance Program (SCHIP) in California (n = 5,988, 69.7%). RESULTS: Items on the PedsQL 4.0 Generic Core Scales had minimal missing responses for children as young as 5 years old, supporting feasibility. The majority of the child self-report scales across the age subgroups, including for children as young as 5 years, exceeded the minimum internal consistency reliability standard of 0.70 required for group comparisons, while the Total Scale Scores across the age subgroups approached or exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores. Construct validity was demonstrated utilizing the known groups approach. For each PedsQL scale and summary score, across age subgroups, including children as young as 5 years, healthy children demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition, with most effect sizes in the medium to large effect size range. CONCLUSION: The results demonstrate that children as young as the 5 year old age subgroup can reliably and validly self-report their HRQOL when given the opportunity to do so with an age-appropriate instrument. These analyses are consistent with recent FDA guidelines which require instrument development and validation testing for children and adolescents within fairly narrow age groupings and which determine the lower age limit at which children can provide reliable and valid responses across age categories.

OBJECTIVES: This guideline provides evidence-based recommendations on managing benign paroxysmal positional vertigo (BPPV), which is the most common vestibular disorder in adults, with a lifetime prevalence of 2.4 percent. The guideline targets patients aged 18 years or older with a potential diagnosis of BPPV, evaluated in any setting in which an adult with BPPV would be identified, monitored, or managed. This guideline is intended for all clinicians who are likely to diagnose and manage adults with BPPV. PURPOSE: The primary purposes of this guideline are to improve quality of care and outcomes for BPPV by improving the accurate and efficient diagnosis of BPPV, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary tests such as radiographic imaging and vestibular testing, and to promote the use of effective repositioning maneuvers for treatment. In creating this guideline, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of audiology, chiropractic medicine, emergency medicine, family medicine, geriatric medicine, internal medicine, neurology, nursing, otolaryngology-head and neck surgery, physical therapy, and physical medicine and rehabilitation. RESULTS: The panel made strong recommendations that 1) clinicians should diagnose posterior semicircular canal BPPV when vertigo associated with nystagmus is provoked by the Dix-Hallpike maneuver. The panel made recommendations against 1) radiographic imaging, vestibular testing, or both in patients diagnosed with BPPV, unless the diagnosis is uncertain or there are additional symptoms or signs unrelated to BPPV that warrant testing; and 2) routinely treating BPPV with vestibular suppressant medications such as antihistamines or benzodiazepines. The panel made recommendations that 1) if the patient has a history compatible with BPPV and the Dix-Hallpike test is negative, clinicians should perform a supine roll test to assess for lateral semicircular canal BPPV; 2) clinicians should differentiate BPPV from other causes of imbalance, dizziness, and vertigo; 3) clinicians should question patients with BPPV for factors that modify management including impaired mobility or balance, CNS disorders, lack of home support, and increased risk for falling; 4) clinicians should treat patients with posterior canal BPPV with a particle repositioning maneuver (PRM); 5) clinicians should reassess patients within 1 month after an initial period of observation or treatment to confirm symptom resolution; 6) clinicians should evaluate patients with BPPV who are initial treatment failures for persistent BPPV or underlying peripheral vestibular or CNS disorders; and 7) clinicians should counsel patients regarding the impact of BPPV on their safety, the potential for disease recurrence, and the importance of follow-up. The panel offered as options that 1) clinicians may offer vestibular rehabilitation, either self-administered or with a clinician, for the initial treatment of BPPV and 2) clinicians may offer observation as initial management for patients with BPPV and with assurance of follow-up. The panel made no recommendation concerning audiometric testing in patients diagnosed with BPPV. DISCLAIMER: This clinical practice guideline is not intended as a sole source of guidance in managing benign paroxysmal positional vertigo. Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. The guideline is not intended to replace clinical judgement or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

IMPLICATIONS: We present evidence-based guidelines developed by an international panel of experts for the management of postoperative nausea and vomiting.

BACKGROUND: Advances in biomedical science and technology have resulted in dramatic improvements in the healthcare of pediatric chronic conditions. With enhanced survival, health-related quality of life (HRQOL) issues have become more salient. The objectives of this study were to compare generic HRQOL across ten chronic disease clusters and 33 disease categories/severities from the perspectives of patients and parents. Comparisons were also benchmarked with healthy children data. METHODS: The analyses were based on over 2,500 pediatric patients from 10 physician-diagnosed disease clusters and 33 disease categories/severities and over 9,500 healthy children utilizing the PedsQL 4.0 Generic Core Scales. Patients were recruited from general pediatric clinics, subspecialty clinics, and hospitals. RESULTS: Pediatric patients with diabetes, gastrointestinal conditions, cardiac conditions, asthma, obesity, end stage renal disease, psychiatric disorders, cancer, rheumatologic conditions, and cerebral palsy self-reported progressively more impaired overall HRQOL than healthy children, respectively, with medium to large effect sizes. Patients with cerebral palsy self-reported the most impaired HRQOL, while patients with diabetes self-reported the best HRQOL. Parent proxy-reports generally paralleled patient self-report, with several notable differences. CONCLUSION: The results demonstrate differential effects of pediatric chronic conditions on patient HRQOL across diseases clusters, categories, and severities utilizing the PedsQL 4.0 Generic Core Scales from the perspectives of pediatric patients and parents. The data contained within this study represents a larger and more diverse population of pediatric patients with chronic conditions than previously reported in the extant literature. The findings contribute important information on the differential effects of pediatric chronic conditions on generic HRQOL from the perspectives of children and parents utilizing the PedsQL 4.0 Generic Core Scales. These findings with the PedsQL have clinical implications for the healthcare services provided for children with chronic health conditions. Given the degree of reported impairment based on PedsQL scores across different pediatric chronic conditions, the need for more efficacious targeted treatments for those pediatric patients with more severely impaired HRQOL is clearly and urgently indicated.

Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E2 (PGE2). The PGE2 converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1. Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E2 (PGE2). The PGE2 converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1. We and other vertebrates are equipped to live in a sea of microorganisms. The reason we survive is because we have formidable inflammatory and immune response systems to protect us against both external confrontations with microorganisms and internal confrontations with the bacteria in our intestinal flora that outnumber the cells in our bodies.1Berg RD The indigenous gastrointestinal microflora.Trends Microbiol. 1996; 4: 430-435Abstract Full Text PDF PubMed Scopus (853) Google Scholar,2Savage DC Microbial ecology of the gastrointestinal tract.Annu Rev Microbiol. 1977; 31: 107-133Crossref PubMed Scopus (1667) Google Scholar However, the same systems need multiple checks to protect us against excessive inflammatory and immune responses. In fact, there is an increasing realization that excessive or nonresolving inflammation makes a major contribution to the damage wrought by diseases such as obesity, diabetes, myocardial infarction (MI), stroke, parkinsonism, and Alzheimer's disease.3Nathan C Ding A Nonresolving inflammation.Cell. 2010; 140: 871-882Abstract Full Text Full Text PDF PubMed Scopus (1416) Google Scholar,4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar Fortunately, we have multiple systems for resolving and modulating inflammation. The systems include small molecules such as prostaglandins, lipoxins, protectins, and resolvins.5Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361Crossref PubMed Scopus (2200) Google Scholar They also include cellular phenotypes such as alternatively activated M2 macrophages6Gordon S Martinez FO Alternative activation of macrophages: mechanism and functions.Immunity. 2010; 32: 593-604Abstract Full Text Full Text PDF PubMed Scopus (2799) Google Scholar and regulatory T cells.7Izcue A Coombes JL Powrie F Regulatory lymphocytes and intestinal inflammation.Annu Rev Immunol. 2009; 27: 313-338Crossref PubMed Scopus (408) Google Scholar,8Wan YY Regulatory T cells: immune suppression and beyond.Cell Mol Immunol. 2010; 7: 204-210Crossref PubMed Scopus (60) Google Scholar Recent reports indicate that additional important guardian cells for modulating inflammation are mesenchymal stem/stromal cells (MSCs). The interest in the guardian role of MSCs is in part related to their presence as adventitial reticular cells9Bianco P Sacchetti B Riminucci M Osteoprogenitors and the hematopoietic microenvironment.Best Pract Res Clin Haematol. 2011; 24: 37-47Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar that participate in normal wound repair and in regulation of hematopoietic cells in bone marrow.10Méndez-Ferrer S Michurina TV Ferraro F Mazloom AR Macarthur BD Lira SA et al.Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.Nature. 2010; 466: 829-834Crossref PubMed Scopus (2468) Google Scholar The interest in MSCs has been further enhanced by their potential use for therapies of various diseases, because the cells can be readily obtained from patients, they are easily expanded in culture, and they are generally not tumorigenic. Recent reports have demonstrated that many, but not all, of the therapeutic effects of the cells seen in animal models are explained by MSCs being activated by signals from injured tissues to secrete anti-inflammatory factors. In some instances, direct administration of the same factors replicates the anti-inflammatory effects of the MSCs. Therefore, the factors secreted by activated MSCs may replace the use of the cells for some therapeutic applications. The role of MSCs as guardians of inflammation has gradually emerged from research on the cells over the past several decades. The evolving data have prompted dramatic shifts in the hypotheses or paradigms for the research.11Prockop DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar Initially, the cells were explored as feeder layers that provided a niche for culture of hematopoietic cells (paradigm I). Then the cells were explored as reparative cells that can engraft in injured tissues and differentiate to replace damaged cells (paradigm II). More recently, the data demonstrate that the cells only transiently appear in injured tissues under most conditions, but during their brief appearance they respond to crosstalk with injured cells to limit tissue destruction or enhance repair by a variety of mechanisms (paradigm III). The mechanisms include (a) upregulation of genes that modulate excessive inflammatory and immune reactions; (b) providing a niche to enhance proliferation and differentiation of tissue-endogenous stem/progenitor cells (as in paradigm I); and (c) transfer of vesicular components that contain mitochondria and microRNAs. The role of MSCs as guardians of inflammation became more apparent as the events initiating inflammation have been defined in greater detail.4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,13Eigenbrod T Park JH Harder J Iwakura Y Núñez G Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells.J Immunol. 2008; 181: 8194-8198Crossref PubMed Scopus (187) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar The events include (a) both passive and active release from injured cells or macrophages of intracellular cytokines such as interleukin (IL)-1α that stimulate parenchymal cells to produce chemokines that recruit neutrophils; (b) classical activation of resident macrophages by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) that interact with pattern recognition receptors to produce high levels of proinflammatory cytokines as well as reactive nitrogen and reactive oxygen species that induce the acute phase response of inflammation. The literature on the anti-inflammatory effects of MSCs is continuing to expand at a rapid rate with over 500 entries in PubMed under “MSCs and inflammation.” We are unable to review all the entries in detail, and therefore we elected to focus here on several examples in which the anti-inflammatory effects of MSCs appear to be best explained at the cellular and molecular levels. The examples deal with inflammation of tissues as a discrete process and not as a component of adaptive immunity, a topic that has been covered in other recent reviews.15Uccelli A Prockop DJ Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?.Curr Opin Immunol. 2010; 22: 768-774Crossref PubMed Scopus (121) Google Scholar,16Tolar J Villeneuve P Keating A Mesenchymal stromal cells for graft-versus-host disease.Hum Gene Ther. 2011; 22: 257-262Crossref PubMed Scopus (48) Google Scholar,17English K Mahon BP Allogeneic mesenchymal stem cells: agents of immune modulation.J Cell Biochem. 2011; 112: 1963-1968Crossref PubMed Scopus (111) Google Scholar,18Singer NG Caplan AI Mesenchymal stem cells: mechanisms of inflammation.Annu Rev Pathol. 2011; 6: 457-478Crossref PubMed Scopus (641) Google Scholar One series of experiments were with a model of bleomycin-induced lung injury.19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar,20Ortiz LA Gambelli F McBride C Gaupp D Baddoo M Kaminski N et al.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci USA. 2003; 100: 8407-8411Crossref PubMed Scopus (1200) Google Scholar In the model, intravenous (i.v.) infusion of minimally expanded murine bone marrow-derived MSCs (500,000 cells per mouse) decreased the inflammatory response to bleomycin and prevented the lungs from developing fibrosis.19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar,20Ortiz LA Gambelli F McBride C Gaupp D Baddoo M Kaminski N et al.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci USA. 2003; 100: 8407-8411Crossref PubMed Scopus (1200) Google Scholar The beneficial effects of the MSCs were largely explained by the cells being activated to secrete IL-1 receptor antagonist (IL-1ra). The MSCs were effective only when administered at the same time as the bleomycin and not at later time points. This observation suggests that the action of MSCs in this model was exerted in the initial phases of the injury in which there is extensive apoptosis of macrophages.21Ortiz LA Moroz K Liu JY Hoyle GW Hammond T Hamilton RF et al.Alveolar macrophage apoptosis and TNF-α, but not p53, expression correlate with murine response to bleomycin.Am J Physiol. 1998; 275: L1208-L1218PubMed Google Scholar The observations were consistent with demonstrations that the IL-1 pathway plays a role in the of sterile T Park JH Harder J Iwakura Y Núñez G Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells.J Immunol. 2008; 181: 8194-8198Crossref PubMed Scopus (187) Google Kono H D G S KL of a pathway for the sterile inflammatory response by dying Med. 2007; PubMed Scopus Google Scholar and its effects are to the effects of tumor necrosis factor-α (TNF-α) in GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google and of 2008; PubMed Scopus Google Scholar and MSCs from the bone marrow express high levels of LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar and experiments in culture demonstrated that secreted from MSCs the of TNF-α by macrophages However, infusion of MSCs in the model of bleomycin-induced lung injury was more effective or The that one in which MSCs can modulate the phases of inflammation is to secrete and thereby the effects of IL-1 and TNF-α in both sterile and and of 2008; PubMed Scopus Google Scholar mechanism was provided by the H A N Y Y Y et bone marrow stromal cells inflammation Ther. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar that MSCs inflammation in of by for which to TNF-α and the of the One of the observations with MSCs is that of MSCs beneficial effects in tissues in such as and most MSCs are in the DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar The was at in part by experiments with were in a model for Kota DJ J et myocardial infarction in because cells in lung are activated to secrete the anti-inflammatory protein 2009; Full Text Full Text PDF PubMed Scopus Google Scholar The of cells per mouse) the inflammatory response to of the and the of the myocardial was in the of the as by However, for and for as a for live that only a small of the MSCs were in the the appearance of the in the was of the were at and they by of the cells were in the lungs as Kota DJ J et myocardial infarction in because cells in lung are activated to secrete the anti-inflammatory protein 2009; Full Text Full Text PDF PubMed Scopus Google J Prockop DJ The protein and MSCs with and to in 2009; PubMed Scopus Google Scholar and they with a of In an to the beneficial effects of the was from lungs of the infusion of the and was on for with the data that the in the lungs as were activated to the expression of over the the most was the for the anti-inflammatory protein to as TNF-α stimulated gene/protein 6 (TSG-6). The with an of the TSG-6 or effect in the the administration of TSG-6 the same beneficial effect as The were explained by a in which the were activated by being as to secrete and the TSG-6 decreased the and excessive inflammatory response in the that destruction of tissue In by being activated to secrete the MSCs at a to injury to the administration of was also to at a to inflammation in a model of sterile injury to the in The were injured by brief exposure to by of the and that the stem cells in the cells per decreased of proinflammatory and of the in the GW JY JH K et at a administered adult stem/progenitor cells (MSCs) inflammatory damage to the engraftment and by of 2011; PubMed Scopus Google Scholar infusion of the was also effective in inflammation and the in the A for for demonstrated that were in the of 1 and or administration of 1 However, the with an of the TSG-6 were not the beneficial effects of were largely by administration of Therefore, the data demonstrated that administered inflammatory damage to the engraftment in the tissue and that the anti-inflammatory effects of the cells were explained by their of A related series of experiments demonstrated that direct of the of the also decreased excessive inflammation in injured The anti-inflammatory effects of the were JY GW H JH et protein TSG-6 reduces inflammatory damage to the and injury.Proc Natl Acad Sci USA. 2010; PubMed Scopus Google Scholar The effective suppression of excessive inflammation in the phase of injury to a in of and of the at of data indicate that MSCs protect the or from injury and tissue by modulating acute excessive inflammation by The anti-inflammatory action of MSCs through of TSG-6 was further demonstrated in a model in which was in by of a from the cell of H Bazhanov N JY Prockop DJ protein TSG-6 secreted by activated MSCs by signaling in resident 2011; PubMed Scopus Google Scholar cells per mouse) were there was a in and in the in the with the TSG-6 were not and infusion of largely the anti-inflammatory effects of The anti-inflammatory effects of the were explained by their effects on resident the cell for inflammatory in most GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar In of murine macrophages that were stimulated with both and decreased the of the proinflammatory TNF-α and They also the activation and of the nuclear factor-κB (NF-κB) to the effect the TSG-6 was with an The effects of and TSG-6 were on the expression of because they not signaling in cells or in that not express signaling through the receptor The action of TSG-6 was on the of with and not on the of TSG-6 not the pathway in cells of and that interact with the of The effect was that the a negative feedback loop the inflammatory response in which MSCs and TSG-6 the initial of proinflammatory cytokines from They thereby the of the proinflammatory signals by mesothelial cells that produce high levels of and to recruit H Bazhanov N JY Prockop DJ protein TSG-6 secreted by activated MSCs by signaling in resident 2011; PubMed Scopus Google Scholar on resident macrophage critical in initiating inflammation in most GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google P an damage-associated molecular pattern that immune Rev Immunol. 4: PubMed Scopus Google G A K D et edge: pattern recognition and receptors activation by Immunol. 2009; PubMed Scopus Google Scholar The negative feedback loop by MSCs and TSG-6 on the pathway in macrophages may therefore largely for the beneficial effects of MSCs in other models in which excessive inflammatory to tissue A for the anti-inflammatory effects of MSCs was demonstrated in a model of by and K A B A K et marrow stromal cells prostaglandin of macrophages to their Med. 2009; PubMed Scopus Google Scholar et that there was a in the of that 1 MSCs at the time of or 1 the levels of TNF-α and proinflammatory cytokines that have a role in L The a for Mol Med. Full Text Full Text PDF PubMed Scopus Google Scholar were by administration of the most of the were in the and they over time but were the of an anti-inflammatory secreted by was at 6 and in MSCs. of macrophages or administration of to beneficial effects of MSCs in with MSCs from were effective in the of with the data that MSCs were not the of but they by in The MSCs the of in the macrophages by nitric oxide, but some of the data that the macrophages also nitric A series of in and in experiments demonstrated that and activation of in the expression of and thereby of prostaglandin E2 (PGE2). PGE2 in to and receptors on macrophages and macrophages to the phenotype that secretes IL-10. 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There are several for the including in when the MSCs were in when the was and in the of cells et that were and obtained from an Therefore, they the of that are easily by in DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google DJ M E K et the of mesenchymal stromal cell 2010; Full Text Full Text PDF PubMed Scopus Google Scholar The by et K A B A K et marrow stromal cells prostaglandin of macrophages to their Med. 2009; PubMed Scopus Google Scholar that MSCs can macrophages from a proinflammatory phenotype to the alternatively activated or anti-inflammatory M2 phenotype was by several other et J P Mesenchymal stem macrophages: a of alternatively activated 2009; Full Text Full Text PDF PubMed Scopus Google Scholar that macrophages with bone marrow-derived MSCs high levels of a of alternatively activated M2 macrophages a high levels of and and levels of and They In observations with et J G J et bone marrow-derived mesenchymal stromal cells activated macrophages a 2010; PubMed Scopus Google Scholar also that bone marrow-derived MSCs macrophages to a regulatory phenotype by decreased expression of inflammatory of and to by intracellular The effects were by of PGE2 by the MSCs a the of MSCs to the phenotype of the In experiments with et P A et mesenchymal stem cells of macrophages and enhance wound 2010; 28: PubMed Scopus Google Scholar also that the MSCs or from the MSCs macrophages to the M2 and because of the they enhanced wound repair in In they that the MSCs TNF-α by macrophages in a that with activation of Therefore, there is a of that MSCs inflammation and enhance tissue repair by modulating the phenotype of The observations that of the anti-inflammatory effects of MSCs can be by factors the cells produce an can therapies with the factors replace therapies with of the factors are not with has been to have because were seen in a small of with A T S J A of IL-1 by in acute Res Ther. 2007; PubMed Scopus Google Scholar but there was in with and C C G IL-1 in inflammation and Rev 2010; 6: PubMed Scopus Google Scholar factors by such as nitric oxide, or PGE2 are not because they have or they have effects when administered However, there appear to be for the protein TSG-6 for therapeutic The protein was to have multiple anti-inflammatory effects in to its of signaling in H Bazhanov N JY Prockop DJ protein TSG-6 secreted by activated MSCs by signaling in resident 2011; PubMed Scopus Google Scholar apparent in the J expression at the of immunity, inflammation and TSG-6 and Full Text Full Text PDF PubMed Scopus Google a inflammatory PubMed Scopus Google Scholar of the beneficial effects of MSCs in models may additional factors that can be the factors of therapeutic interest is that is secreted by MSCs in response to signals from S F J C et stromal cells are activated to apoptosis in part by upregulation and of 2009; 27: PubMed Scopus Google Scholar and that reduces reactive oxygen species by the expression of of Y L M A et in macrophages through of 2009; PubMed Scopus Google Scholar levels of reactive oxygen species are proinflammatory and high levels are may be both anti-inflammatory and The role of MSCs as guardians against excessive inflammation of the beneficial effects with administration of the cells in animal models for a of diseases, including models for lung diabetes, sterile injury to the and The recent that has defined the anti-inflammatory factors by the cells in the of one or more of the factors to therapies that may be and more therapies with the cells However, MSCs modulate their anti-inflammatory effects in multiple that appear to be to the by tissue Therefore, MSCs may be the of for some

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

OBJECTIVE: To prospectively determine risk factors for foot infection in a cohort of people with diabetes. RESEARCH DESIGN AND METHODS: We evaluated then followed 1,666 consecutive diabetic patients enrolled in a managed care-based outpatient clinic in a 2-year longitudinal outcomes study. At enrollment, patients underwent a standardized general medical examination and detailed foot assessment and were educated about proper foot care. They were then rescreened at scheduled intervals and also seen promptly if they developed any foot problem. RESULTS: During the evaluation period, 151 (9.1%) patients developed 199 foot infections, all but one involving a wound or penetrating injury. Most patients had infections involving only the soft tissue, but 19.9% had bone culture-proven osteomyelitis. For those who developed a foot infection, compared with those who did not, the risk of hospitalization was 55.7 times greater (95% CI 30.3-102.2; P < 0.001) and the risk of amputation was 154.5 times greater (58.5-468.5; P < 0.001). Foot wounds preceded all but one infection. Significant (P < 0.05) independent risk factors for foot infection from a multivariate analysis included wounds that penetrated to bone (odds ratio 6.7), wounds with a duration >30 days (4.7), recurrent wounds (2.4), wounds with a traumatic etiology (2.4), and presence of peripheral vascular disease (1.9). CONCLUSIONS: Foot infections occur relatively frequently in individuals with diabetes, almost always follow trauma, and dramatically increase the risk of hospitalization and amputation. Efforts to prevent infections should be targeted at people with traumatic foot wounds, especially those that are chronic, deep, recurrent, or associated with peripheral vascular disease.

BACKGROUND: Caring for a family member with dementia is extremely stressful, contributes to psychiatric and physical illness among caregivers, and increases the risk for caregiver death. Finding better ways to support family caregivers is a major public health challenge. OBJECTIVE: To test the effects of a structured multicomponent intervention on quality of life and clinical depression in caregivers and on rates of institutional placement of care recipients in 3 diverse racial or ethnic groups. DESIGN: Randomized, controlled trial. SETTING: In-home caregivers in 5 U.S. cities. PARTICIPANTS: 212 Hispanic or Latino, 219 white or Caucasian, and 211 black or African-American caregivers and their care recipients with Alzheimer disease or related disorders. INTERVENTION: Caregivers within each racial or ethnic group were randomly assigned to an intervention or to a control group. The intervention addressed caregiver depression, burden, self-care, and social support and care recipient problem behaviors through 12 in-home and telephone sessions over 6 months. Caregivers in the control group received 2 brief "check-in" telephone calls during the 6-month intervention. MEASUREMENTS: The primary outcome was a quality-of-life indicator comprising measures of 6-month caregiver depression, burden, self-care, and social support and care recipient problem behaviors. Secondary outcomes were caregiver clinical depression and institutional placement of the care recipient at 6 months. RESULTS: Hispanic or Latino and white or Caucasian caregivers in the intervention group experienced significantly greater improvement in quality of life than those in the control group (P < 0.001 and P = 0.037, respectively). Black or African-American spouse caregivers also improved significantly more (P = 0.003). Prevalence of clinical depression was lower among caregivers in the intervention group (12.6% vs. 22.7%; P = 0.001). There were no statistically significant differences in institutionalization at 6 months. LIMITATIONS: The study used only a single 6-month follow-up assessment, combined heterogeneous cultures and ethnicities into a single group, and excluded some ethnic groups. CONCLUSIONS: A structured multicomponent intervention adapted to individual risk profiles can increase the quality of life of ethnically diverse dementia caregivers. ClinicalTrials.gov identifier: NCT00177489.

OBJECTIVE: Disagreement exists concerning the appropriate delivery room management of the airway of vigorous meconium-stained infants. Some suggest a universal approach to intubation and suctioning of the airway in all such neonates, whereas others advocate a selective approach. We performed this investigation: 1) to assess whether intubation and suctioning of apparently vigorous, meconium-stained neonates would reduce the incidence of meconium aspiration syndrome (MAS); and 2) to determine the frequency of complications from delivery room intubation and suctioning of such infants. METHODS: Inclusion criteria included: 1) gestational age >/=37 weeks; 2) birth through meconium-stained amniotic fluid of any consistency; and 3) apparent vigor immediately after birth. Subjects were randomized to be intubated and suctioned (INT) or to expectant management (EXP). Primary outcome measures included: 1) the incidence of respiratory distress, including MAS, and 2) the incidence of complications from intubation. RESULTS: A total of 2094 neonates were enrolled from 12 participating centers (1051 INT and 1043 EXP). Meconium-stained amniotic fluid consistency was similar in both groups. Of the 149 (7.1%) infants that subsequently demonstrated respiratory distress, 62 (3.0%) had MAS and 87 (4.2%) had findings attributed to other disorders. There were no significant differences between groups in the occurrence of MAS (INT = 3.2%; EXP = 2.7%) or in the development of other respiratory disorders (INT = 3.8%; EXP = 4.5%). Of 1098 successfully intubated infants, 42 (3.8%) had a total of 51 complications of the procedure. In all cases, the complications were mild and transient in nature. CONCLUSIONS: Compared with expectant management, intubation and suctioning of the apparently vigorous meconium-stained infant does not result in a decreased incidence of MAS or other respiratory disorders. Complications of intubation are infrequent and short-lived.

Diversity among executives is widely assumed to influence a firm's strategic decision processes, but empirical research on this linkage has been virtually nonexistent. To partially fill the void, we drew upon three separate studies to examine the impact of executive diversity on comprehensiveness of strategic decision-making and extensiveness of strategic planning. Contrary to common assumptions of researchers and executives, our results suggest that executive diversity inhibits rather than promotes comprehensive examinations of current opportunities and threats, and inhibits rather than promotes extensive long-range planning. In light of the cumulative research showing that firm performance is related to both comprehensiveness and extensiveness, our results provide evidence for an indirect connection between executive diversity and firm performance. © 1998 John Wiley & Sons, Ltd.

BACKGROUND: Health-related quality of life (HRQOL) measurement has emerged as an important health outcome in clinical trials, clinical practice improvement strategies, and healthcare services research and evaluation. While pediatric patient self-report should be considered the standard for measuring perceived HRQOL, there are circumstances when children are too young, too cognitively impaired, too ill or fatigued to complete a HRQOL instrument, and reliable and valid parent proxy-report instruments are needed in such cases. Further, it is typically parents' perceptions of their children's HRQOL that influences healthcare utilization. Data from the PedsQL DatabaseSM were utilized to test the reliability and validity of parent proxy-report at the individual age subgroup level for ages 2-16 years as recommended by recent FDA guidelines. METHODS: The sample analyzed represents parent proxy-report age data on 13,878 children ages 2 to 16 years from the PedsQL 4.0 Generic Core Scales DatabaseSM. Parents were recruited from general pediatric clinics, subspecialty clinics, and hospitals in which their children were being seen for well-child checks, mild acute illness, or chronic illness care (n = 3,718, 26.8%), and from a State Children's Health Insurance Program (SCHIP) in California (n = 10,160, 73.2%). RESULTS: The percentage of missing item responses for the parent proxy-report sample as a whole was 2.1%, supporting feasibility. The majority of the parent proxy-report scales across the age subgroups exceeded the minimum internal consistency reliability standard of 0.70 required for group comparisons, while the Total Scale Scores across the age subgroups approached or exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores. Construct validity was demonstrated utilizing the known groups approach. For each PedsQL scale and summary score, across age subgroups, healthy children demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition, with most effect sizes in the medium to large effect size range. CONCLUSION: The results demonstrate the feasibility, reliability, and validity of parent proxy-report at the individual age subgroup for ages 2-16 years. These analyses are consistent with recent FDA guidelines which require instrument development and validation testing for children and adolescents within fairly narrow age groupings and which determine the lower age limit at which reliable and valid responses across age categories are achievable. Even as pediatric patient self-report is advocated, there remains a fundamental role for parent proxy-report in pediatric clinical trials and health services research.

Human mesenchymal stem/progenitor cells (hMSCs) repair tissues and modulate immune systems but the mechanisms are not fully understood. We demonstrated that hMSCs are activated by inflammatory signals to secrete the anti-inflammatory protein, TNF-α-stimulated gene 6 protein (TSG-6) and thereby create a negative feedback loop that reduces inflammation in zymosan-induced peritonitis. The results demonstrate for the first time that TSG-6 interacts through the CD44 receptor on resident macrophages to decrease zymosan/TLR2-mediated nuclear translocation of the NF-κB. The negative feedback loop created by MSCs through TSG-6 attenuates the inflammatory cascade that is initiated by resident macrophages and then amplified by mesothelial cells and probably other cells of the peritoneum. Because inflammation underlies many pathologic processes, including immune responses, the results may explain the beneficial effects of MSCs and TSG-6 in several disease models.

This article reports the first randomized prospective multicenter evaluation of a bioabsorbable conduit for nerve repair. The study enrolled 98 subjects with 136 nerve transections in the hand and prospectively randomized the repair to two groups: standard repair, either end-to-end or with a nerve graft, or repair using a polyglycolic acid conduit. Two-point discrimination was measured by a blinded observer at 3, 6, 9, and 12 months after repair. There were 56 nerves repaired in the control group and 46 nerves repaired with a conduit available for follow-up. Three patients had a partial conduit extrusion as a result of loss of the initially crushed skin flap. The overall results showed no significant difference between the two groups as a whole. In the control group, excellent results were obtained in 43 percent of repairs, good results in 43 percent, and poor results in 14 percent. In those nerves repaired with a conduit, excellent results were obtained in 44 percent, good results in 30 percent, and poor results in 26 percent (p = 0.46). When the sensory recovery was examined with regard to length of nerve gap, however, nerves with gaps of 4 mm or less had better sensation when repaired with a conduit; the mean moving two-point discrimination was 3.7 +/- 1.4 mm for polyglycolic acid tube repair and 6.1 +/- 3.3 mm for end-to-end repairs (p = 0.03). All injured nerves with deficits of 8 mm or greater were reconstructed with either a nerve graft or a conduit. This subgroup also demonstrated a significant difference in favor of the polyglycolic acid tube. The mean moving two-point discrimination for the conduit was 6.8 +/- 3.8 mm, with excellent results obtained in 7 of 17 nerves, whereas the mean moving two-point discrimination for the graft repair was 12.9 +/- 2.4 mm, with excellent results obtained in none of the eight nerves (p < 0.001 and p = 0.06, respectively). This investigation demonstrates improved sensation when a conduit repair is used for nerve gaps of 4 mm or less, compared with end-to-end repair of digital nerves. Polyglycolic acid conduit repair also produces results superior to those of a nerve graft for larger nerve gaps and eliminates the donor-site morbidity associated with nerve-graft harvesting.

BACKGROUND: Intrahepatic cholangiocarcinomas are malignant tumors arising from the intrahepatic biliary tract. The pathogenesis of these tumors remains unknown. Although there is a marked global variation in prevalence, some recent studies have suggested an increase in mortality from intrahepatic cholangiocarcinoma in several regions of low endemicity. As the study of mortality trends may yield clues to possible etiological factors, we analyzed worldwide time trends in mortality from biliary tract malignancies. METHODS: Annual age-standardized rates for individual countries were compiled for deaths from biliary tract malignancies using the WHO database. These data were used to analyze gender and site-specific trends in mortality rates. RESULTS: An increasing trend for mortality from intrahepatic cholangiocarcinoma was noted in most countries. The average estimated annual percentage change (EAPC) in mortality rates for males was 6.9 +/- 1.5, and for females was 5.1 +/- 1.0. Increased mortality rates were observed in all geographic regions. Within Europe, increases were higher in Western Europe than in Central or Northern Europe. In contrast, mortality rates for extrahepatic biliary tract malignancies showed a decreasing trend in most countries, with an overall average EAPC of -0.3 +/- 0.4 for males, but -1.3 +/- 0.4 for females. CONCLUSIONS: There has been a marked global increase in mortality from intrahepatic, but not extra-hepatic, biliary tract malignancies.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of a temperature monitoring instrument to reduce the incidence of foot ulcers in individuals with diabetes who have a high risk for lower extremity complications. RESEARCH DESIGN AND METHODS: In this physician-blinded, randomized, 15-month, multicenter trial, 173 subjects with a previous history of diabetic foot ulceration were assigned to standard therapy, structured foot examination, or enhanced therapy groups. Each group received therapeutic footwear, diabetic foot education, and regular foot care. Subjects in the structured foot examination group performed a structured foot inspection daily and recorded their findings in a logbook. If standard therapy or structured foot examinations identified any foot abnormalities, subjects were instructed to contact the study nurse immediately. Subjects in the enhanced therapy group used an infrared skin thermometer to measure temperatures on six foot sites each day. Temperature differences >4 degrees F (>2.2 degrees C) between left and right corresponding sites triggered patients to contact the study nurse and reduce activity until temperatures normalized. RESULTS: The enhanced therapy group had fewer foot ulcers than the standard therapy and structured foot examination groups (enhanced therapy 8.5 vs. standard therapy 29.3%, P = 0.0046 and enhanced therapy vs. structured foot examination 30.4%, P = 0.0029). Patients in the standard therapy and structured foot examination groups were 4.37 and 4.71 times more likely to develop ulcers than patients in the enhanced therapy group. CONCLUSIONS: Infrared temperature home monitoring, in serving as an "early warning sign," appears to be a simple and useful adjunct in the prevention of diabetic foot ulcerations.

Human mesenchymal stromal cells (hMSCs) were injected into the hippocampus of adult mice 1 day after transient global ischemia. The hMSCs both improved neurologic function and markedly decreased neuronal cell death of the hippocampus. Microarray assays indicated that ischemia up-regulated 586 mouse genes. The hMSCs persisted for <7 days, but they down-regulated >10% of the ischemia-induced genes, most of which were involved in inflammatory and immune responses. The hMSCs also up-regulated three mouse genes, including the neuroprotective gene Ym1 that is expressed by activated microglia/macrophages. In addition, the transcriptomes of the hMSC changed with up-regulation of 170 human genes and down-regulation of 54 human genes. Protein assays of the hippocampus demonstrated increased expression in microglia/macrophages of Ym1, the cell survival factor insulin-like growth factor 1, galectin-3, cytokines reflective of a type 2 T cell immune bias, and the major histocompatibility complex II. The observed beneficial effects of hMSCs were largely explained by their modulation of inflammatory and immune responses, apparently by alternative activation of microglia and/or macrophages.

In this longitudinal study of 1666 persons with diabetes, there was an observed trend toward an increased risk for amputation (chi(2) test for trend, 108.0; P<.001), higher-level amputation (chi(2) test for trend, 113.3; P<.001), and lower extremity-related hospitalization (chi(2) test for trend, 118.6; P<.001) with increasing infection severity. The Infectious Diseases Society of America's foot infection classification system may be a useful tool for grading foot infections.

OBJECTIVE: To evaluate the effectiveness of at-home infrared temperature monitoring as a preventative tool in individuals at high risk for diabetes-related lower-extremity ulceration and amputation. RESEARCH DESIGN AND METHODS: Eighty-five patients who fit diabetic foot risk category 2 or 3 (neuropathy and foot deformity or previous history of ulceration or partial foot amputation) were randomized into a standard therapy group (n = 41) or an enhanced therapy group (n = 44). Standard therapy consisted of therapeutic footwear, diabetic foot education, and regular foot evaluation by a podiatrist. Enhanced therapy included the addition of a handheld infrared skin thermometer to measure temperatures on the sole of the foot in the morning and evening. Elevated temperatures (>4 degrees F compared with the opposite foot) were considered to be "at risk" of ulceration due to inflammation at the site of measurement. When foot temperatures were elevated, subjects were instructed to reduce their activity and contact the study nurse. Study subjects were followed for 6 months. RESULTS: The enhanced therapy group had significantly fewer diabetic foot complications (enhanced therapy group 2% vs. standard therapy group 20%, P = 0.01, odds ratio 10.3, 95% CI 1.2-85.3). There were seven ulcers and two Charcot fractures among standard therapy patients and one ulcer in the enhanced therapy group. CONCLUSIONS: These results suggest that at-home patient self-monitoring with daily foot temperatures may be an effective adjunctive tool to prevent foot complications in individuals at high risk for lower-extremity ulceration and amputation.

CONTEXT: Despite the widespread use of percutaneous coronary intervention (PCI), the appropriateness of these procedures in contemporary practice is unknown. OBJECTIVE: To assess the appropriateness of PCI in the United States. DESIGN, SETTING, AND PATIENTS: Multicenter, prospective study of patients within the National Cardiovascular Data Registry undergoing PCI between July 1, 2009, and September 30, 2010, at 1091 US hospitals. The appropriateness of PCI was adjudicated using the appropriate use criteria for coronary revascularization. Results were stratified by whether the procedure was performed for an acute (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, or unstable angina with high-risk features) or nonacute indication. MAIN OUTCOME MEASURES: Proportion of acute and nonacute PCIs classified as appropriate, uncertain, or inappropriate; extent of hospital-level variation in inappropriate procedures. RESULTS: Of 500,154 PCIs, 355,417 (71.1%) were for acute indications (ST-segment elevation myocardial infarction, 103,245 [20.6%]; non-ST-segment elevation myocardial infarction, 105,708 [21.1%]; high-risk unstable angina, 146,464 [29.3%]), and 144,737 (28.9%) for nonacute indications. For acute indications, 350,469 PCIs (98.6%) were classified as appropriate, 1055 (0.3%) as uncertain, and 3893 (1.1%) as inappropriate. For nonacute indications, 72,911 PCIs (50.4%) were classified as appropriate, 54,988 (38.0%) as uncertain, and 16,838 (11.6%) as inappropriate. The majority of inappropriate PCIs for nonacute indications were performed in patients with no angina (53.8%), low-risk ischemia on noninvasive stress testing (71.6%), or suboptimal (≤1 medication) antianginal therapy (95.8%). Furthermore, although variation in the proportion of inappropriate PCI across hospitals was minimal for acute procedures, there was substantial hospital variation for nonacute procedures (median hospital rate for inappropriate PCI, 10.8%; interquartile range, 6.0%-16.7%). CONCLUSIONS: In this large contemporary US cohort, nearly all acute PCIs were classified as appropriate. For nonacute indications, however, 12% were classified as inappropriate, with substantial variation across hospitals.