Texas A&M Health Science Center

Evidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations including long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergency medicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics.

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

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.).

The novel coronavirus disease 2019 (COVID-19) has become a pandemic affecting health and wellbeing globally. In addition to the physical health, economic, and social implications, the psychological impacts of this pandemic are increasingly being reported in the scientific literature. This narrative review reflected on scholarly articles on the epidemiology of mental health problems in COVID-19. The current literature suggests that people affected by COVID-19 may have a high burden of mental health problems, including depression, anxiety disorders, stress, panic attack, irrational anger, impulsivity, somatization disorder, sleep disorders, emotional disturbance, posttraumatic stress symptoms, and suicidal behavior. Moreover, several factors associated with mental health problems in COVID-19 are found, which include age, gender, marital status, education, occupation, income, place of living, close contact with people with COVID-19, comorbid physical and mental health problems, exposure to COVID-19 related news and social media, coping styles, stigma, psychosocial support, health communication, confidence in health services, personal protective measures, risk of contracting COVID-19, and perceived likelihood of survival. Furthermore, the epidemiological distribution of mental health problems and associated factors were heterogeneous among the general public, COVID-19 patients, and healthcare providers. The current evidence suggests that a psychiatric epidemic is cooccurring with the COVID-19 pandemic, which necessitates the attention of the global health community. Future epidemiological studies should emphasize on psychopathological variations and temporality of mental health problems in different populations. Nonetheless, multipronged interventions should be developed and adopted to address the existing psychosocial challenges and promote mental health amid the COVID-19 pandemic.

It is now 10 years since the last technical review on preventative foot care was published (1), which was followed by an American Diabetes Association (ADA) position statement on preventive foot care in diabetes (2). Many studies have been published proposing a range of tests that might usefully identify patients at risk of foot ulceration, creating confusion among practitioners as to which screening tests should be adopted in clinical practice. A task force was therefore assembled by the ADA to address and concisely summarize recent literature in this area and then recommend what should be included in the comprehensive foot exam for adult patients with diabetes. The committee was cochaired by the immediate past and current chairs of the ADA Foot Care Interest Group (A.J.M.B. and D.G.A.), with other panel members representing primary care, orthopedic and vascular surgery, physical therapy, podiatric medicine and surgery, and the American Association of Clinical Endocrinologists. The lifetime risk of a person with diabetes developing a foot ulcer may be as high as 25%, whereas the annual incidence of foot ulcers is ∼2% (3–7). Up to 50% of older patients with type 2 diabetes have one or more risk factors for foot ulceration (3,6). A number of component causes, most importantly peripheral neuropathy, interact to complete the causal pathway to foot ulceration (1,3–5). A list of the principal contributory factors that might result in foot ulcer development is provided in Table 1. View this table: Table 1— Risk factors for foot ulcers The most common triad of causes that interact and ultimately result in ulceration has been identified as neuropathy, deformity, and trauma (5). As identification of those patients at risk of foot problems is the first step in preventing such complications, this report will focus on key components of the …

BACKGROUND: Previous trials suggesting that high-frequency oscillatory ventilation (HFOV) reduced mortality among adults with the acute respiratory distress syndrome (ARDS) were limited by the use of outdated comparator ventilation strategies and small sample sizes. METHODS: In a multicenter, randomized, controlled trial conducted at 39 intensive care units in five countries, we randomly assigned adults with new-onset, moderate-to-severe ARDS to HFOV targeting lung recruitment or to a control ventilation strategy targeting lung recruitment with the use of low tidal volumes and high positive end-expiratory pressure. The primary outcome was the rate of in-hospital death from any cause. RESULTS: On the recommendation of the data monitoring committee, we stopped the trial after 548 of a planned 1200 patients had undergone randomization. The two study groups were well matched at baseline. The HFOV group underwent HFOV for a median of 3 days (interquartile range, 2 to 8); in addition, 34 of 273 patients (12%) in the control group received HFOV for refractory hypoxemia. In-hospital mortality was 47% in the HFOV group, as compared with 35% in the control group (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005). This finding was independent of baseline abnormalities in oxygenation or respiratory compliance. Patients in the HFOV group received higher doses of midazolam than did patients in the control group (199 mg per day [interquartile range, 100 to 382] vs. 141 mg per day [interquartile range, 68 to 240], P<0.001), and more patients in the HFOV group than in the control group received neuromuscular blockers (83% vs. 68%, P<0.001). In addition, more patients in the HFOV group received vasoactive drugs (91% vs. 84%, P=0.01) and received them for a longer period than did patients in the control group (5 days vs. 3 days, P=0.01). CONCLUSIONS: In adults with moderate-to-severe ARDS, early application of HFOV, as compared with a ventilation strategy of low tidal volume and high positive end-expiratory pressure, does not reduce, and may increase, in-hospital mortality. (Funded by the Canadian Institutes of Health Research; Current Controlled Trials numbers, ISRCTN42992782 and ISRCTN87124254, and ClinicalTrials.gov numbers, NCT00474656 and NCT01506401.).

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. The by macrophages inflammation in with is an component of a negative feedback loop in because the response that its and on macrophages and other cells that produce inflammatory of an 2010; 140: Full Text Full Text PDF PubMed Scopus Google Scholar The observations 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 create negative feedback loop of one that not One the K A B A K et marrow stromal cells prostaglandin of macrophages to their Med. 2009; PubMed Scopus Google Scholar was in a experiments with and in et Y et al.Mesenchymal stem cells inflammation and in J Med. 2010; PubMed Scopus Google Scholar that the beneficial effects but their data a of an K A B A K et marrow stromal cells prostaglandin of macrophages to their Med. 2009; PubMed Scopus Google Scholar in levels of that were infusion of MSCs. 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

BACKGROUND: Both targeted decolonization and universal decolonization of patients in intensive care units (ICUs) are candidate strategies to prevent health care-associated infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: We conducted a pragmatic, cluster-randomized trial. Hospitals were randomly assigned to one of three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carriers); and group 3, universal decolonization (i.e., no screening, and decolonization of all patients). Proportional-hazards models were used to assess differences in infection reductions across the study groups, with clustering according to hospital. RESULTS: A total of 43 hospitals (including 74 ICUs and 74,256 patients during the intervention period) underwent randomization. In the intervention period versus the baseline period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screening and isolation (crude rate, 3.2 vs. 3.4 isolates per 1000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1000 days), and 0.63 for universal decolonization (2.1 vs. 3.4 isolates per 1000 days) (P=0.01 for test of all groups being equal). In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1000 days), 0.78 (3.7 vs. 4.8 infections per 1000 days), and 0.56 (3.6 vs. 6.1 infections per 1000 days), respectively (P<0.001 for test of all groups being equal). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isolation. One bloodstream infection was prevented per 54 patients who underwent decolonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not significant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine. CONCLUSIONS: In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infection from any pathogen. (Funded by the Agency for Healthcare Research and the Centers for Disease Control and Prevention; REDUCE MRSA ClinicalTrials.gov number, NCT00980980).

Abstract Rationale Evidence concerning the acute health effects of air pollution caused by fine particulate matter (PM2.5) in developing countries is quite limited. Objectives To evaluate short-term associations between PM2.5 and daily cause-specific mortality in China. Methods A nationwide time-series analysis was performed in 272 representative Chinese cities from 2013 to 2015. Two-stage Bayesian hierarchical models were applied to estimate regional- and national-average associations between PM2.5 concentrations and daily cause-specific mortality. City-specific effects of PM2.5 were estimated using the overdispersed generalized additive models after adjusting for time trends, day of the week, and weather conditions. Exposure–response relationship curves and potential effect modifiers were also evaluated. Measurements and Main Results The average of annual mean PM2.5 concentration in each city was 56 μg/m3 (minimum, 18 μg/m3; maximum, 127 μg/m3). Each 10-μg/m3 increase in 2-day moving average of PM2.5 concentrations was significantly associated with increments in mortality of 0.22% from total nonaccidental causes, 0.27% from cardiovascular diseases, 0.39% from hypertension, 0.30% from coronary heart diseases, 0.23% from stroke, 0.29% from respiratory diseases, and 0.38% from chronic obstructive pulmonary disease. There was a leveling off in the exposure–response curves at high concentrations in most, but not all, regions. The associations were stronger in cities with lower PM2.5 levels or higher temperatures, and in subpopulations with elder age or less education. Conclusions This nationwide investigation provided robust evidence of the associations between short-term exposure to PM2.5 and increased mortality from various cardiopulmonary diseases in China. The magnitude of associations was lower than those reported in Europe and North America.

The coronavirus disease 2019 (COVID-19) pandemic has not only caused significant challenges for health systems all over the globe but also fueled the surge of numerous rumors, hoaxes, and misinformation, regarding the etiology, outcomes, prevention, and cure of the disease. Such spread of misinformation is masking healthy behaviors and promoting erroneous practices that increase the spread of the virus and ultimately result in poor physical and mental health outcomes among individuals. Myriad incidents of mishaps caused by these rumors have been reported globally. To address this issue, the frontline healthcare providers should be equipped with the most recent research findings and accurate information. The mass media, healthcare organization, community-based organizations, and other important stakeholders should build strategic partnerships and launch common platforms for disseminating authentic public health messages. Also, advanced technologies like natural language processing or data mining approaches should be applied in the detection and removal of online content with no scientific basis from all social media platforms. Furthermore, these practices should be controlled with regulatory and law enforcement measures alongside ensuring telemedicine-based services providing accurate information on COVID-19.

The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors.

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.

OBJECTIVES: Transmission of infectious diseases is often prevented by quarantine and isolation of the populations at risk. These approaches restrict the mobility, social interactions, and daily activities of the affected individuals. In recent coronavirus disease 2019 (COVID-19) pandemic, quarantine and isolation are being adopted in many contexts, which necessitates an evaluation of global evidence on how such measures impact the mental health outcomes among populations. This umbrella review aimed to synthesize the available evidence on mental health outcomes of quarantine and isolation for preventing infectious diseases. METHODS: We searched nine major databases and additional sources and included articles if they were systematically conducted reviews, published as peer-reviewed journal articles, and reported mental health outcomes of quarantine or isolation in any population. RESULTS: Among 1,364 citations, only eight reviews met our criteria. Most of the primary studies in those reviews were conducted in high-income nations and in hospital settings. These articles reported a high burden of mental health problems among patients, informal caregivers, and healthcare providers who experienced quarantine or isolation. Prevalent mental health problems among the affected individuals include depression, anxiety, mood disorders, psychological distress, posttraumatic stress disorder, insomnia, fear, stigmatization, low self-esteem, lack of self-control, and other adverse mental health outcomes. CONCLUSIONS: This umbrella review found severe mental health problems among individuals and populations who have undergone quarantine and isolation in different contexts. This evidence necessitates multipronged interventions including policy measures for strengthening mental health services globally and promoting psychosocial wellbeing among high-risk populations.

Traditionally, the success of a researcher is assessed by the number of publications he or she publishes in peer-reviewed, indexed, high impact journals. This essential yardstick, often referred to as the impact of a specific researcher, is assessed through the use of various metrics. While researchers may be acquainted with such matrices, many do not know how to use them to enhance their careers. In addition to these metrics, a number of other factors should be taken into consideration to objectively evaluate a scientist's profile as a researcher and academician. Moreover, each metric has its own limitations that need to be considered when selecting an appropriate metric for evaluation. This paper provides a broad overview of the wide array of metrics currently in use in academia and research. Popular metrics are discussed and defined, including traditional metrics and article-level metrics, some of which are applied to researchers for a greater understanding of a particular concept, including varicocele that is the thematic area of this Special Issue of Asian Journal of Andrology. We recommend the combined use of quantitative and qualitative evaluation using judiciously selected metrics for a more objective assessment of scholarly output and research impact.

Compelling evidence from basic molecular biology has demonstrated the dual roles of microglia in the pathogenesis of Alzheimer's disease (AD). On one hand, microglia are involved in AD pathogenesis by releasing inflammatory mediators such as inflammatory cytokines, complement components, chemokines, and free radicals that are all known to contribute to beta-amyloid (Aβ) production and accumulation. On the other hand, microglia are also known to play a beneficial role in generating anti-Aβ antibodies and stimulating clearance of amyloid plaques. Aβ itself, an inducer of microglia activation and neuroinflammation, has been considered as an underlying and unifying factor in the development of AD. A vicious cycle of inflammation has been formed between Aβ accumulation, activated microglia, and microglial inflammatory mediators, which enhance Aβ deposition and neuroinflammation. Thus, inhibiting the vicious cycle seems to be a promising treatment to restrain further development of AD. With increasing research efforts on microglia in AD, intervention of microglia activation and neuroinflammation in AD may provide a potential target for AD therapy in spite of the provisional failure of nonsteroidal antiinflammatory drugs in clinical trials.

Our goal was to gain a better understanding of the contribution of the burial of polar groups and their hydrogen bonds to the conformational stability of proteins. We measured the change in stability, Δ(ΔG), for a series of hydrogen bonding mutants in four proteins: villin headpiece subdomain (VHP) containing 36 residues, a surface protein from Borrelia burgdorferi (VlsE) containing 341 residues, and two proteins previously studied in our laboratory, ribonucleases Sa (RNase Sa) and T1 (RNase T1). Crystal structures were determined for three of the hydrogen bonding mutants of RNase Sa: S24A, Y51F, and T95A. The structures are very similar to wild type RNase Sa and the hydrogen bonding partners form intermolecular hydrogen bonds to water in all three mutants. We compare our results with previous studies of similar mutants in other proteins and reach the following conclusions. (1) Hydrogen bonds contribute favorably to protein stability. (2) The contribution of hydrogen bonds to protein stability is strongly context dependent. (3) Hydrogen bonds by side chains and peptide groups make similar contributions to protein stability. (4) Polar group burial can make a favorable contribution to protein stability even if the polar groups are not hydrogen bonded. (5) The contribution of hydrogen bonds to protein stability is similar for VHP, a small protein, and VlsE, a large protein.

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell–mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P &lt;0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell–mediated types ≥IB), 0.2% (T cell–mediated type IA), and 0.3% in controls ( P =0.05 for T cell–mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels &lt;1% reflect the absence of active rejection (T cell–mediated type ≥IB or ABMR) and levels &gt;1% indicate a probability of active rejection.

BACKGROUND: Diseases such as tuberculosis (TB) have always had a large impact on human health. Bacillus Calmette-Guérin (BCG) is used as a surrogate for TB during the development of anti-TB drugs. Nanoparticles (NPs) have attracted great interest in drug development. The purpose of this study was to examine the potential of NPs as anti-TB compounds by studying the interacting mechanisms between NPs and bacteria. RESULTS: We investigated effects of gold and silver NPs on BCG and Escherichia coli. Experimentally, particle size and shape were characterized using transmission electron microscopy (TEM). Different concentrations of NPs were applied in bacterial culture. The growth of E. coli was monitored through colony forming units (CFU). The mechanism of interaction between NPs and bacteria was analyzed through bacterial thin sections followed by TEM and scanning electron microscopy. Antibacterial effects on BCG were observed by recording fluorescent protein expression levels. CONCLUSIONS: The results suggest NPs have potential applications as anti-TB compounds. The antibacterial effects and mechanism of action for NPs were dependent upon composition and surface modifications.

Evidence is provided that proteolytic cleavage of collagen type IV results in the exposure of a functionally important cryptic site hidden within its triple helical structure. Exposure of this cryptic site was associated with angiogenic, but not quiescent, blood vessels and was required for angiogenesis in vivo. Exposure of the HUIV26 epitope was associated with a loss of alpha1beta1 integrin binding and the gain of alphavbeta3 binding. A monoclonal antibody (HUIV26) directed to this site disrupts integrin-dependent endothelial cell interactions and potently inhibits angiogenesis and tumor growth. Together, these studies suggest a novel mechanism by which proteolysis contributes to angiogenesis by exposing hidden regulatory elements within matrix-immobilized collagen type IV.

abstract Firm ownership is an increasingly influential form of corporate governance. Although firms might be owned by different types of owners, most studies examine owner influence on a particular firm outcome in isolation. This study synthesizes research from multiple disciplines on different types of owners and offers a unifying framework of governance through ownership. Using this framework, we describe the motivations of various types of owners, the tactics owners use to affect firms in which they are invested, and the dominant firm outcomes these owners seek to influence. We note how heightened managerial awareness of heterogeneous owner interests increases owner influence on firm‐level outcomes. We also provide a roadmap for future study and offer research questions about where scholars might turn their attention to better understand the role of owners in directing firm actions. Our study draws attention to emerging forms of ownership, such as hedge funds and sovereign wealth funds, and highlights the changing (and often competing) interests of shareholders and how this impacts theories of governance.