IgG4-related disease was only recently discovered, so its description, management, and new discoveries related to its etiology are rapidly evolving. Because IgG4 itself is a unique antibody which is intimately related to the diagnosis of the disease, the role of plasmablasts in the pathophysiology remains an active area of discussion. Recent studies have uncovered a possible role for CD4-positive cytotoxic T lymphocytes, T follicular helper cells, and M2 macrophages. The clinical presentation is variable and can be vague, as this disease affects many organs and new presentations are continuing to be described. The diagnosis depends on clinical and histopathological assessment. The mainstay of treatment is with glucocorticoids, but rituximab has recently shown promise. Monitoring disease activity using imaging modalities (including positron emission tomography) and serum markers is imperative, as relapses are common. IgG4-related disease spans many medical disciplines but is a treatable condition with which all clinicians should be familiar. IgG4-related disease is a recently described entity which is quite rare. Descriptions and recognition of the disease are advancing rapidly. Certainly, the fact that it closely resembles malignancy is one of the many reasons why recognizing this disease is important. Furthermore, it is generally very treatment-responsive, so early diagnosis can contribute to a significant improvement in morbidity for patients. The underlying disease mechanisms are an area of active research, and further understanding will aid in the treatment of patients.1, but prevalence data for other organs involved in IgG4-related disease are not well characterized. In Japanese patients with autoimmune pancreatitis as well as Japanese patients with IgG4-related disease of other organ types2, the patients are predominantly male; there are 3 to 4 males to every 1 female patient. The mean age in both studies was late 60s. In a cohort from Spain with IgG4-related disease, 69.1% of patients were male and the median age at diagnosis was 53 years3.Because IgG4-related disease was only recently described and mimics other diseases, recognition remains low and a true estimation of prevalence remains elusive. In 2011, the prevalence of autoimmune pancreatitis in Japan was 4.6 per 100,000 population4.Interestingly, a recent review analyzed published pediatric cases of IgG4-related disease and found 25 cases with an average age of 13 and a mild female predominance (64%)5.In one small cohort of 25 patients with IgG4-associated cholangitis and autoimmune pancreatitis, 88% reported a history of “blue collar” work, often with exposures to occupational chemicals6. In the study by Chenet al., the mean number of organs involved was 3.0 ± 1.6 (range of 1–10)7. If the disease has progressed, organ failure can occur. Ruling out malignancy is crucial when the diagnosis of IgG4-related disease is considered. The differential is broad and is largely organ-specific, but multi-centric Castleman’s disease and other multi-organ autoimmune diseases such as granulomatosis with polyangiitis, Sjögren’s syndrome, eosinophilic granulomatosis with polyangiitis, and sarcoidosis should be considered.Patients classically present with subacute, non-specific complaints, which can be general, such as weight loss, or organ-specific complaints. The classic finding is a tumefactive lesion in at least one organ, but the disease can develop over years, adding new organs one at a time, so patients may present with multi-organ disease8; involving the sinuses, which in some cases can be invasive11; involving the esophagus presenting with dysphagia12; involving the prostate presenting with urinary retention13; or involving the testes presenting with scrotal pain14. Skin manifestations were rare in the series reported by Chenet al.7. A review of the dermatological literature showed that the most common skin presentations are papules, plaques, and nodules of the head and neck15. Clinical symptoms of patients were well summarized by Chenet al. , but the greater the number of organs involved in the disease, the higher the elevation in the serum IgG4 level24. An elevated IgG4 level is also not specific for the disease, as there are many diseases associated with this laboratory abnormality; it similarly does not have a good positive predictive value25. Importantly, Oseiniet al. showed that elevated IgG4 can be seen in patients with cholangiocarcinoma24, and Ghazaleet al. showed that elevated IgG4 cannot be used to distinguish autoimmune pancreatitis from pancreatic cancer, thus elevated serum IgG4 levels do not exclude these deadly differential diagnoses26. Patients with primary sclerosing cholangitis can also have elevated IgG4 levels28. However, 65 out of 72 patients with IgG4-related disease had elevated IgG4 levels, yielding a sensitivity of 90% according to a study by Carrutherset al.25.Although IgG4 levels are classically elevated in IgG4-related disease (Japanese criterion is more than 135 mg/dL), this finding is not necessary to make the diagnosis—which is based on histopathological findings when histopathology is available, as obtaining specimens  is not without risk—and is not specific to the disease23. In one study of the treatment of autoimmune pancreatitis, the IgG4 level remained above the upper limit of normal in 115 out of 182 patients (63%) treated with glucocorticoids29. Furthermore, despite elevated levels, patients may remain in remission; in this study, only 30% of patients with persistent elevation of serum IgG4 had a relapse29. Although an increase in IgG4 level may be a marker of relapse in some patients, for 10% of the patients in this study, relapses also occurred without an increase in the serum concentration of IgG429.With glucocorticoid treatment, elevated IgG4 levels can decrease but may remain above the upper limit of normal31.Although it is not yet clinically available, quantitation of circulating plasmablasts using flow cytometry is more sensitive than serum IgG4 levels, so this measurement could emerge as a better test for the diagnosis and monitoring of IgG4-related disease in the future32. The clinician should be aware that very high serum IgG4 levels may lead to errors in the measurement of IgG4 serum concentrations, resulting in reporting of spuriously low values, a type of “prozone” effect33.IgG4/IgG RNA ratio is a novel, highly accurate marker for IgG4-related disease and has been validated for IgG4-associated cholangitis and autoimmune pancreatitis6.In conclusion, IgG4 levels alone are insufficient to make a diagnosis of IgG4-related disease or to monitor patients in follow-up. Elevations in eosinophils and C-reactive protein can also be observed in patients with IgG4-related disease, but these are non-specific34. In this study, Zhanget al. reported that 9 out of 10 patients initially enrolled in the study with single-organ disease were ultimately found to have multi-organ disease34. PET/CT is also useful for monitoring disease progression and identifying sites for biopsy35. CT and magnetic resonance imaging (MRI) can also be used to identify organ enlargement, and lesions identified by CT typically generate low signal intensity in T2-weighted MRI37.As already stated, histopathology is an integral part of the diagnosis, but imaging can aid in defining the disease involvement and in follow-up. A recent study showed the efficacy of using positron emission tomography/computed tomography (PET/CT) with the glucose analogue 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) in patients diagnosed with one-organ involvement of IgG4-related disease to assess for the involvement of other organs38.The presence of at least two of these findings in combination with infiltration of IgG4-positive plasma cells is highly suggestive of a diagnosis of IgG4-related disease, with the cutoff value for the number of IgG4-positive plasma cells being defined for each organ. Eosinophils are commonly present. IgG4-positive plasma cells are distributed diffusely throughout the tissue, even in patients who have normal levels of serum IgG4. This finding can help to differentiate IgG4-related disease from other diseases characterized by plasma cell infiltration but is not sufficient to make the diagnosis. The cutoff value for the number of IgG4-positive plasma cells required to make a diagnosis is specific to the organ, but the ratio of IgG4 to IgG cells must be greater than 40%38.Histopathology is the gold standard for diagnosis of IgG4-related disease, since the disease cannot be diagnosed on the basis of IgG4 levels in the serum or in tissue samples on pathology, although these findings are suggestive of the disease. The classic findings are dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis et al. highlighted this nicely: they analyzed 121 randomly selected pathology specimens with lymphoplasmacytic infiltrates39. Interestingly, variably high numbers of IgG4-positive plasma cells were found in diverse samples, particularly in rheumatoid synovitis, carcinoma-associated inflammation, and sclerosing sialadenitis39. This article thus highlights the fact that IgG4 can be elevated in inflammation unrelated to IgG4-related disease39. Cheuk and Chan also warned of the danger of over-interpretation of lymphadenopathy with positive immunostaining for IgG4 in a patient with no other clinical or laboratory signs of IgG4-related disease40.It is worth mentioning that the clinician must be cautious to not over-emphasize the role of histopathology, especially IgG4 immunostaining, when making a diagnosis of IgG4-related disease. StrehlAlthough organ involvement in IgG4-related disease requires treatment, less aggressive management is appropriate if this is not the case. For example, in asymptomatic lymphadenopathy, watchful waiting is acceptable.29, and the first prospective, randomized, placebo-controlled trial examining their efficacy for the treatment of autoimmune pancreatitis was just published by Masamuneet al.41. In this study, remission was induced with prednisolone in both groups and then withdrawn at 26 weeks in 19 of the patients versus continued for 3 years in 30 patients41. The authors found that the relapse rate was significantly lower in the maintenance group, where 7 out of 30 patients (23.3%) relapsed compared with the cessation group, where 11 out of 19 (57.9%) relapsed (P = 0.011)41.The first-line treatment of IgG4-related disease is glucocorticoids43. Notably, low doses of prednisone may be as effective as higher doses for induction therapy: a retrospective review found that outcomes were not significantly different in patients who received prednisone in the range of 10 to 60 mg per day44. Clinical symptoms, imaging, and blood tests are used to guide the taper42. Many patients have an effective, rapid response to glucocorticoids, and an alternative diagnosis should be considered if this rapid response is not seen45. Advanced fibrosis, however, is a poor prognostic sign42.The initial treatment for autoimmune pancreatitis is typically prednisolone 0.6 mg/kg for 2 to 4 weeks, which is then tapered every 2 to 4 weeks to 5 mg/day over the subsequent 3 to 6 months, and then 2.5 to 5 mg/day is continued for 3 yearset al. reflects the common paradigm with treatment with glucocorticoids: 1,186 out of 1,220 patients (97%) who received monotherapy with glucocorticoids as their first-line drug had a therapeutic response, but the response was classified as complete in only 84 out of 130 patients (65%) in whom this information could be extracted45. This study also discussed the management of relapses, where glucocorticoids were most commonly used but immunosuppressive agents were used in 149 cases (39%) (azathioprine in 126 out of these 149 cases) and rituximab in 9 cases (2%)45. The treatment was reported to be effective to treat the relapses for 219 out of 231 cases (95%) treated with glucocorticoids, 56 out of 69 patients (81%) treated with azathioprine, 16 out of 22 patients (72%) treated with other immunosuppressives, and 9 out of 9 patients (100%) treated with rituximab45.A recent systematic review by Brito-Zeron42. A more recent, promising option is treatment with rituximab; the mechanism is via the depletion of CD20-positive plasmablast precursors— with fewer plasmablasts, IgG4 production decreases46. Yamamotoet al. recently published a case report of successful treatment with abatacept (an inhibitor of T-cell activation), but treatment with this is in its infancy47.Steroid-sparing treatments, such as azathioprine, mycophenolate mofetil, and methotrexate, are used to allow respite from the side effects of glucocorticoids and in order to maintain remission, but evidence for their effectiveness is lacking45. Surgery was considered effective in 14 out of 17 patients (82%), and radiation was considered effective in 9 out of 12 patients (75%)45. Combination surgery and glucocorticoids were effective in 20 out of 22 patients (91%)45.Surgery and radiotherapy have been reported to treat tumefactive masses in the pancreas, kidneys, or other organs in cases where the diagnosis of IgG4-RD may not have occurred until after histopathologic analysis was performed. However, these modalities have had some role in treating patients with specific involvements, such as infiltrative masses of tubular structures, such as the biliary tract, lymphadenopathy, or masses in other solid organs. In the recent systematic review of treatment of IgG4-related disease, out of 1,952 patients, 1,437 (74%) were treated with glucocorticoids as first-line, but 213 patients (11%) were treated with surgery or radiotherapy and 38 (2%) were treated with other optionset al. compiled the mortality data from 7 studies for 294 patients and a mean follow-up of 29.2 months45. In this group, mortality was reported in 26 patients (8.8%). Four patients died of pulmonary disease, 1 died of an aneurysm, 1 of cholangitis, 1 of renal failure, 7 of cancer, 4 of cardiovascular disease, 3 of infection, and 5 of unknown or other causes45.In a recent systematic review of treatment of IgG4-related disease, Brito-Zeron48. It is unique among the immunoglobulin isotypes in that it undergoes a process known as fragment antigen-binding (Fab)-arm exchange. The disulfide bonds between the heavy chains of the IgG4 molecules are unstable, so dissociation of the heavy chains occurs, leading to random recombination. The result is antibodies with two different antigen-binding specificities that are unable to cross-link antigen or form immune complexes in a manner similar to that of IgG1, IgG2, and IgG3 antibodies. IgG4 antibodies are also unable to fix complement49. IgG4 has traditionally been regarded as anti-inflammatory.The immunoglobulin IgG4 isotype accounts for less than 5% of the total IgG in healthy patients and is the least abundant of the IgG subclasses50. RF was reported to be positive in 20% of patients (50 out of 255) with IgG4-related disease6. The question of whether IgG4 itself is pathogenic remains to be fully elucidated. Shiokawaet al. injected Balb/c mice with IgGs from patients with IgG4-related disease in order to explore this question51. Pancreatic injury was seen with both IgG1 and IgG4, but more so from IgG1. Interestingly, patient IgG1-induced damage to the mouse pancreas was somewhat attenuated with the addition of patient IgG4.Another unique property of IgG4 is that it sometimes binds the Fc region of IgG, producing a rheumatoid factor (RF), but the physiologic relevance of this is unclear49. More recent studies have identified genes involved in pancreatic cell injury52, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene polymorphisms have been associated with IgG4-related disease in the pancreas53.There is much still to be learned about the genes involved in IgG4-related disease. Genetic susceptibility has been associated with certain human leukocyte antigen (HLA) haplotypes in Japanese and Korean populations49. It stands to reason that the target of the antibody would be specific to the organs commonly affected in IgG4-related disease. Indeed, a recent study which sought to identify autoantigens in IgG4-related disease identified only one candidate: prohibitin54. As prohibitin is involved in anti-proliferation, the authors hypothesize that antibodies against prohibitin would result in tissue growth and the presentation of IgG4-related disease54. Another recent study showed that anti-nuclear antibody (ANA) in IgG4-related disease was not of the IgG4 subclass55. ANA was reported to be positive in 32% of patients (168 out of 524 patients)6.Autoimmunity has long been hypothesized as a pathologic mechanism in IgG4-related disease, but studies have failed to identify a clear autoantigen specific to the disease that selectively induces the production of IgG4 autoantibodieset al. used DNA microarray analysis to show that the expression of genes associated with allergy or innate immunity is lower in the peripheral blood mononuclear cells of patients with IgG4-related disease compared with healthy controls (HCs) and that these levels were increased with steroid therapy56. Furthermore, Watanabeet al. recently postulated that since activation of the innate immune system leads to the production of IgG4, this pathway could be the target of future treatments for IgG4-related disease57.Evidence is beginning to accumulate that there is a role for innate immunity in the mechanism of IgG4-related disease. Nakajimaet al., who showed that patients with hypocomplementemia in IgG4-related disease have a high serum level of C1q-binding IgG4, thus implying that IgG4 participates in the activation of complement in these patients by an unknown mechanism58.A feature that is important in IgG4-related disease is hypocomplementemia. The etiology of this was studied by Sugimoto60. The peripheral blood lymphocytes of patients with IgG4-related disease also express elevated levels of Th2 cytokines60. A subset of patients also has elevated eosinophils and IgE, suggestive of an underlying disease mediated by Th2 cytokines.It has been observed that CD4 T cells are present at the sites of inflammation in IgG4-related disease. Similar to IgE, class switching to IgG4 depends on interleukin-4 (IL-4) and IL-13. These interleukins are considered part of the type 2 helper T (Th2) immune response. Messenger RNA levels of these Th2 cytokines are higher in organs affected by IgG4-related disease in comparison with other classic autoimmune conditions48. Allergen-specific IgG4 antibodies are also induced during allergen immunotherapy and accompany clinical improvement61.Allergens and nematodes that induce IgE also induce IgG4. However, a so-called “modified Th2 response” refers to the scenario in which IgG4 antibody is produced without IgE antibody production, which seems to be the desired, healthy response to innocuous antigens, as it occurs during occupational exposures to antigens such as in beekeepers62. This is in contrast to most autoimmune conditions, in which a deficiency in Treg cells is present and thought to promote autoimmunity. In IgG4-related disease, it has been hypothesized that collagen deposition occurs through the production of cytokines produced by Th2 and Treg cells and thus that these cells could act synergistically to induce tissue fibrosis, a prominent feature of the disease63.A role for elevated levels of regulatory T (Treg) cells in IgG4-related disease has also been suggested65 suggest that the role of Th2 immune responses in IgG4-related disease may be overstated and may, in fact, be a reflection of atopy, which affects approximately 40%66 of patients with IgG4-related disease, which is similar to the prevalence in the general US population. Instead, evidence is accumulating for a role of CD4-positive cytotoxic T lymphocytes (CTLs). Maeharaet al. have shown over-expression of genes associated with CD4-positive CTLs in the salivary glands of patients with IgG4-related disease compared with HCs and compared with patients with Sjögren’s syndrome and chronic sialoadenitis65. Furthermore, CD4-positive CTLs, which produce IL-1β, transforming growth factor-beta 1 (TGF-β1), and interferon-gamma (IFN-γ), are found in affected tissue. IL-1β and TGF-β1 have been shown to be involved in the pathology of fibrosis67, an integral feature of IgG4-related disease, thus further strengthening the putative role of CD4-positive CTLs. Finally, rituximab-mediated B-cell depletion results in both clinical improvement of patients’ IgG4-related disease and a decrease in the number of CD4-positive CTLs64. This new research is exciting, as CD4-positive CTLs may ultimately prove to be the major mechanism of pathogenesis of IgG4-related disease.Recent studieset al. have published two articles implicating a role for these cells in IgG4-related disease69. They showed that in patients with untreated IgG4-RD compared with those with primary Sjögren’s syndrome, those with multi-centric Castleman’s disease, and HCs, the number of circulating Tfh2 cells (defined as CD3+CD4+CD45RA−CXCR5+CXCR3−CCR6−) was significantly increased. Furthermore, “activated” Tfh2 cells  were shown to induce IgG4 production and to decrease in response to treatment with glucocorticoids in parallel with decreased disease activity68. Activated circulating Tfh1 cells were also found to correlate with disease activity but not with serum IgG4 levels68.The role of circulating follicular helper T (Tfh) cells in IgG4-related disease is an active area of research. Akiyamaet al. showed that IgG4-positive B cells were clonally expanded in patients with IgG4-associated cholangitis and decreased when the patients were treated with glucocorticoids70. The role of the B cells in IgG4-related disease is especially interesting given the utility of rituximab-mediated CD20+ B-cell depletion in treating these patients46. Recent studies have shown that circulating plasmablasts are increased in patients with IgG4-related disease and that their levels reflect disease activity31. The plasmablasts are oligoclonal, which suggests that specific antigen(s) may be driving their production30. In B-cell development, plasmablast differentiation occurs between activated B cells and plasma cells.Maillette de Buy Wenniger71 showed that there are increased numbers of M2 macrophages in submandibular glands affected by IgG4-related dacryoadenitis and sialoadenitis and that fibrosis is associated with an increased number of M2 macrophages. Macrophage receptor with collagenous structure (MARCO) is a pattern-recognition receptor with an expression pattern similar to that of the M2 macrophage marker CD163. It has been speculated that MARCO may be involved in the initiation of IgG4-related disease72. Future research is needed to ascertain whether there is any interaction between CD4-positive CTL or Th2 Tfh cells and M2 macrophages in promoting IgG4-related disease.Returning to the issue of the IgG4-related disease being mainly a Th2-mediated disease, a possible disease mechanism could be mediated by M2 macrophages, which are defined as alternatively activated macrophages stimulated by Th2 response. IL-10, IL-13, and CCL18 produced by M2 macrophages induce fibrosis, and a recent studyIgG4-related disease, though uncommon, is an important disease entity to consider in the differential of a patient presenting with tumefactive lesions. Current research into the underlying pathophysiology is focused on improved understanding of the T-cell and B-cell compartments. Future studies to improve the prognosis of this condition will focus not only on arresting the abnormal immunologic response but also on treating fibrosis.


Salmonella and Chlamydia infection also demonstrate that early antibiotic intervention reduces host protective immunity to subsequent infection. This heightened susceptibility to reinfection correlates with poor development of Th1 and antibody responses in antibiotic-treated mice but can be overcome by delayed antibiotic intervention, thus suggesting a requirement for sustained T cell stimulation for protection. Although the contribution of memory T cell subsets is imperfectly understood in both of these infection models, a protective role for noncirculating memory cells is suggested by recent studies. Together, these data propose a model where antibiotic treatment specifically interrupts tissue-resident memory T cell formation. Greater understanding of the mechanistic basis of this phenomenon might suggest therapeutic interventions to restore a protective memory response in antibiotic-treated patients, thus reducing the incidence of reinfection.Antibiotic intervention is an effective treatment strategy for many bacterial infections and liberates bacterial antigens and stimulatory products that can induce an inflammatory response. Despite the opportunity for bacterial killing to enhance the development of adaptive immunity, patients treated successfully with antibiotics can suffer from reinfection. Studies in mouse models of  Since the discovery of penicillin in 1928, antibiotics have been widely used to treat bacterial infections, and as a result, bacteria have rapidly developed antibiotic resistance –6. Despi–Salmonella and Chlamydia infection, since both models show a detrimental effect of antibiotics upon the development of immune memory.An adaptive immune response to infection is initiated by recognition of foreign protein antigens in the presence of local inflammation . The con11–Salmonella bacteria cause a variety of clinical diseases, depending on the bacterial serovar and the underlying susceptibility of the infected host . Thus, appropriate protective mechanisms appear to be engaged in antibiotic-treated mice, but the overall response is reduced, preventing a robust response to secondary infection  T cells have been identified as an essential component of protection at mucosal surfaces (–Chlamydia model is not trivial to complete (Chlamydia infection induces effector memory CD4 T cells in local draining lymph nodes (Chlamydia vaccine (Chlamydia (Chlamydia-specific TRM within the reproductive tract, but this issue has yet to be examined experimentally.While CD4 T cells are essential for immunity to genital surfaces . Cells osurfaces –79. Howecomplete . Recent ph nodes , but the vaccine . Thus, nhlamydia . TherefoSalmonella and Chlamydia infection models suggest that early antibiotic intervention impedes the development of effective protective memory, which is largely mediated by Th1 CD4 cells. The duration of antigen presentation and inflammatory stimulation are known to be key variables in the generation of CD4 T cell memory, and both of these variables are likely to be adversely affected by antibiotic administration. It is not yet clear whether this deficiency in CD4 T cell responses could be overcome by administering additional antigen or adjuvants during the period of antibiotic administration. Using the Salmonella infection model, we administered purified bacterial flagellin to mice being treated with antibiotic and detected the recovery of robust protective immunity to secondary infection (A number of experiments from nfection . This exnfection , 83, it


Hepatocyte growth factor (HGF) is the ligand for this receptor. The binding of HGF to c-Met initiates a series of intracellular signals that mediate embryogenesis and wound healing in normal cells. However, in cancer cells, aberrant HGF/c-Met axis activation, which is closely related to c-Met gene mutations, overexpression, and amplification, promotes tumor development and progression by stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/β-catenin, and other signaling pathways. Thus, c-Met and its associated signaling pathways are clinically important therapeutic targets. In this review, we elaborate on the molecular structure of c-Met and HGF and the mechanism through which their interaction activates the PI3K/AKT, Ras/MAPK, and Wnt signaling pathways. We also summarize the connection between c-Met and RON and EGFR, which are also receptor tyrosine kinases. Finally, we introduce the current therapeutic drugs that target c-Met in primary tumors, and their use in clinical research. HGF However, as a type of proto-oncogene, abnormal activation of c-Met can promote the development and progression of multiple cancers such as liver, lung, colon, breast, pancreatic, ovarian, prostate, and gastric carcinomas, in addition to cancers of the nervous system such as glioblastoma –9. The HMET (c-Met encoding) gene is located on human chromosome 7 (7q21-q31), includes 21 exons and 20 introns, and encodes a protein that is approximately 120 kDa in size , an, an80], Crizotinib , an effective small molecule inhibitor of c-Met, was derived from the first-generation series c-Met inhibitor, PHA-66752 (3-benzyloxy-2-amino). PF-22341066 targets the TK domain of c-Met, and after a series of reactions, some residues cause a conformational change, which interferes with the ATP binding site. One clinical trial (phase I) for the treatment of NSCLC with enhanced Met amplification, performed in 2014 , showed Cabozantinib (XL184) is a small molecule inhibitor of Met and AXL , 87, andForetinib (GSK1363089) is an ATP-competitive c-Met inhibitor, and its therapeutic potential has been assessed for different tumors including head and neck cancer, gastric cancer, and liver cancer , 91, 92.LY280163 is an ATP competitive Met tyrosine kinase inhibitor developed by Lilly. Cheng et al.  showed tMK2461 is an ATP competitive small molecule multi-target inhibitor developed by Merck Sharp & Dohme Corp. It is effective in inhibiting the proto-oncogene c-Met mutants N1100Y, Y1230C, Y1230H, Y1235D, and M1250Tn1100y. Currently, this drug is in experimental stage I clinical trials for advanced cancer.Capmatinib (INC280) blocks c-Met phosphorylation and the activation of key downstream molecules in c-Met-dependent tumor cell lines, causing mitochondrial membrane depolarization and DNA repair , 97. TheTivantinib (ARQ197), developed by American ArQule Corporation and Japan’s Daiichi Sankyo and Kyowa Hakko Kogyo, is a non-ATP competitive inhibitor that blocks receptor activation and downstream signaling by binding to unactivated receptors , 98. ARQDespite research on c-Met over the past 30 years, the structure and function of this tyrosine kinase has not been well established. HGF/c-Met mediates cascades that play a key role in tumorigenesis; extensive research on those pathways is not only beneficial for enhancing our understanding of the mechanisms associated with carcinoma, but also suggest promising targets for the development of novel cancer treatments. Considering the complexity of the HGF/c-Met axis, further exploration of the mechanism through which blocking c-Met activation modulates downstream pathways is required.Recently, many clinical trials have found that drug resistance is more easily acquired with single drug therapy; therefore, research on combining c-Met inhibitors with other drugs (e.g. EGFR-TKI) will lead to the rapid discovery of effective treatment options. One study showed that in a nude mouse model of treatment-sensitive NSCLC, erlotinib resistance could be effectively reversed by the administration of SU1274. Meanwhile, Klempner et al.  found thRecently, phase II/III clinical trials for c-Met inhibitors have been initiated, and many of these drugs are regarded as second-line drugs. The main problem is that in most c-Met-overexpressing cancer cells, this receptor is not always the only driver of carcinoma, as it often interacts with other tyrosine kinase receptors. For example, the cytotoxic effect of tivantinib is not due solely to c-Met inhibition. Meanwhile, non-specific reactions are also a major problem when using c-Met inhibitors. For example, the c-Met monoclonal antibody Metmab is associated with several adverse events including rash, diarrhea, fatigue, and nausea/vomiting.Under these circumstances, more precise information regarding how the drug functions and its relationship with c-Met and other tyrosine kinase receptors is required. In fact, as mentioned previously, the relationship between c-Met and its family member RON is being extensively studied, whereas the mechanism underlying the crosstalk between c-Met and RON is still not fully understood. One study showed that in pancreatic cancer, silencing RON might modulate the c-Met signaling pathway, resulting in a compensatory reaction during the downregulation of either tyrosine kinase receptor –59. As sMeanwhile, the initiation of carcinoma can be induced by multiple factors including genome backgrounds, environmental factors , microenHowever, based on the fact that c-Met has an intimate association with cancer, targeting this receptor for the treatment of tumorigenesis is still thought to be associated with vast clinical significance.


Ac-(KIAALKE)3-GW-NH2) and E (Ac-(EIAALEK)3-GY-NH2) peptides, components of the zipper of an artificial membrane fusion system  is investigated by electron paramagnetic resonance (EPR). By frozen solution continuous-wave EPR and double electron-electron resonance (DEER), the distance between spin labels attached to the K- and to the E-peptide is measured. Three constructs of spin-labelled K- and E-peptides are used in five combinations for low temperature investigations. The K/E heterodimers are found to be parallel, in agreement with previous studies. Also, K homodimers in parallel orientation were observed, a finding that was not reported before. Comparison to room-temperature, solution EPR shows that the latter method is less specific to detect this peptide-peptide interaction. Combining frozen solution cw-EPR for short distances (1.8 nm to 2.0 nm) and DEER for longer distances thus proves versatile to detect the zipper interaction in membrane fusion. As the methodology can be applied to membrane samples, the approach presented suggests itself for in-situ studies of the complete membrane fusion process, opening up new avenues for the study of membrane fusion.The interaction of the complementary K ( N-ethylmaleimide-sensitive factor). Membrane fusion induced by SNARE involves the coiled-coil interaction between three complementary SNARE proteins , in which 2D represents the parallel component of the dipolar tensor, was used. The value of D (in MHz) was varied until the simulation agrees with the experimental spectrum. By doing this we were able to obtain the dipolar frequency (in MHz), from which the corresponding inter-spin distance is calculated.The spectral simulation was performed using Matlab  and the EasySpin package . For all1 values spaced by 8 ns starting at τ1 = 200 ns were added to suppress proton modulations. Typical accumulation times per sample were 16–20 hours.All DEER experiments were done at 9.7 GHz on an ELEXSYS E680 spectrometer  using a 3 mm split-ring resonator (ER 4118XMS-3-W1). We performed the measurements at 40 K with a helium gas flow using a CF935 cryostat . The pump and observer frequencies were separated by 70 MHz and adjusted as reported before . The powIn order to analyze the DEER traces and extract the distance distributions, the software package “DeerAnalysis 2011” was used . All theIn order to visualize the dimer of E-SL: SL-K, a model of the dimer was created using VMD software (Molecular Simulations). VMD software is owned by the Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, at the Beckman Institute, University of Illinois at Urbana-Champaign.E-SL, K-SL, and of E-SL: K-SL are broadened with respect to MTSL, whereas spectra of SL-K and E-SL: SL-K are not.. These observations are summarized in In K-SL and the 1: 1 mixture of E-SL: K-SL  and a short distance in the range of 1.8 to 2.0 nm (obtained from cw-EPR) suggesting a broad range of distances, as we will discuss in detail below. Room temperature cw-EPR was performed to test, if under those conditions dimer formation can be detected. Overall the effects were weak, and are described in Combining the results of cw-EPR and DEER in In this study, we determine the interactions between the K- and the E-peptides by EPR using two complementary methods: Short distances (up to 2 nm) are detected by cw-EPR and longer distances by DEER. For these experiments, the peptides are investigated in frozen solution using the same sample for both types of measurements. E-SL, K-SL and E-SL: K-SL corresponds to distances in the range of 1.8 to 2.0 nm, as derived from simulations of the EPR spectra under conditions described in Materials and methods.The broadening of the cw-EPR spectra for In the present samples, because of different spin-label linker conformations and the intermolecular nature of the interactions, cw-EPR line broadening most likely reflects not a single distance/conformation and therefore only a range of distances see  can be dTo facilitate the following discussion, long distance . A distance of 3.2 nm is observed, when the C-terminus of E and the N-terminus of K are labelled (E-SL: SL-K) (see E-SL: K-SL) and a longer one, when one peptide is labelled at the C-terminus and the other at the N-terminus (E-SL: SL-K) is in qualitative agreement with a parallel heterodimer situation as shown in E-SL: SL-K suggests more than a single conformation of the dimer. In order to visualize the dimer of E-SL: SL-K, a model of the dimer was created with the VMD software (Molecular Simulations) assuming standard φ and ψ angles for a regular α helix including cysteine (SH) (both Cys-K and E-Cys). We have built the S-S bond and included the atoms required to define the MTSL label. The molecules were arranged as close as possible and in a parallel orientation  see  section.shown in  to repreE-SL: SL-K with spin labels attached gives a distance of 3.5 nm between the nitroxide groups of the spin label in agreement with the results of the DEER experiments  and a distance of 2.6 nm when labelled at the N-terminus (SL-K). A distance of 1.8–2.0 nm for K-SL is only compatible with a parallel homodimer. The distance for SL-K, 2.6 nm, is consistent with a parallel homodimer in which the spin labels point away from each other and possibly indicate flared-out ends of the N-terminal region of the homodimer. The finding of a K homodimer based on EPR, in our study, was not described before. We attribute the longer distance between the spin labels at the N-terminus (SL-K) to fraying of the helix ends in combination with the spin labels pointing away from each other. On the other hand, the short distance at the C-terminus (K-SL), which contains a tryptophan residue, can be explained by the H-bond formation between the NO of the spin label with the NH proton of the indole group of the tryptophan. This interaction might stabilize the C-terminus and avoid fraying at this end of the peptide ,42.a and d must be sufficient to override this helix repulsion.The finding of a parallel homodimer for the K-peptide must be attributed to dominance of the knob-into-hole interaction  studies ,22 show 2 M-1 ,22. Under) are observed for K/E heterodimers, independent of which position is labelled  longer than that of monomeric peptide, explaining why K-SL has a longer τr than E-SL Click here for additional data file.S1 Text(PDF)Click here for additional data file.


Inappropriate antibiotic use significantly contributes to antibiotic-resistance, resulting in reduced antibiotic efficacy and increasing physical burden and cost of disease. The goal of this study was to explore antibiotic usage patterns in South Korea using 2007–2014 health insurance claims data.We used the Health Insurance Review & Assessment Service data, which represents nearly the entire population of South Korea, to discern patterns in antibiotic prescribing practices. The daily dose, as defined by the World Health Organization , was used as a measure of antibiotic use. Subgroup analyses were performed on the basis of patient characteristics  and provider characteristics .Antibiotic use in DID increased from 23.5 in 2007 to 27.7 in 2014. The ≤ 6 years old age group showed the highest level of usage at 59.21 DID in 2014, and showed an increasing trend each year. DIDs of beta-lactam antibacterials, penicillins (J01C), other beta-lactam antibacterials (J01D), lincosamides and streptogramins (J01F), quinolone antibacterials (J01M), and other antibacterials (J01X) increased over time.This study provides valuable statistics regarding antibiotic usage in South Korea; this is important for guiding health policy with regard to antibiotic usage. There is a need for further study exploring antibiotics use and resistance. Antibiotics are pivotal in the treatment of infectious diseases. However, the inappropriate use and overuse of antibiotics are emerging as major global issues because of the increased number of resistant bacteria, reduced antibiotic efficacy, multiple infections, and increased medical expenses . The devIn South Korea, antibiotic use has shown a decreasing trend since separating the prescribing and dispensing of drugs in 2000. However, the level of antibiotic usage in South Korea  is still much higher than the average for other Organisation for Economic Co-operation and Development (OECD) countries (18 DID) as of 2012 .To resolve this issue, since 2001, South Korea has implemented the Project to Assess the Appropriateness of Drug Provision, evaluating the antibiotic prescription rate for upper respiratory tract infections per each prescriber to assess prescribing habits . SpecifiStreptococcus pneumoniae, community-associated methicillin-resistant Staphylococcus aureus, and extended-spectrum β-lactamase producing Enterobacteriaceae are major issues in antibiotic resistance [S. aureus infections were methicillin-resistant in a survey of hospital samples in 2012 [S. pneumoniae showed penicillin resistance [The increase in antibiotic-resistant bacteria has been a major public health concern in South Korea. Multidrug-resistant sistance . Seventysistance , and 80.sistance . The Worsistance , 11.The aim of the present study was to investigate the epidemiological characteristics of antibiotic use at a national level in South Korea. The investigation of antibiotic usage patterns is important for detecting the inappropriate use of antibiotics and for designing public health intervention strategies to promote appropriate use. Although previous studies have investigating the use of antibiotics with claims data , 13, theThis analysis used the National Health Insurance claims database (HIRA claims data) from 2007–2014. This database is representative of the entire population of approximately 50 million South Koreans and includes compulsory beneficiaries of National Health Insurance or the Medical Aid for low-income members of the population. The HIRA claims data contain each patient’s unique encrypted identification number, age, sex, primary diagnosis, secondary diagnosis, surgical or medical treatment administered, whether the individual was an inpatient or outpatient, type of insurance , medical expenses, medical institution identification number, and prescriptions. The diagnoses were coded according to the International Classification of Disease, Tenth Revision (ICD-10). The drug names were coded according to the Korean national drug code system; almost all antibiotics are listed as reimbursable drugs under the National Health Insurance. Therefore, our data represent antibiotic use for nearly the entire South Korean population for the given period.Medical institutions included in this study were tertiary hospitals, secondary hospitals, hospitals, clinics, dental hospitals, dental clinics, and public health institutions. We analyzed claims for health care services submitted to HIRA by these medical institutions for patients treated between January 01, 2007 and December 31, 2014.Antibiotics were defined as drugs classified as J01  according to WHO’s Anatomic Therapeutic Chemical (ATC) classification . To measDrug use was assessed using drug consumption in units of DDD, which allows standard consumption to be calculated by adjusting variations in doses and units for each antibiotic product . DDD enaAnnual usage was calculated as DDD/1,000 inhabitants/day (hereafter DID) as shown in We analyzed antibiotic usage for the entire South Korean population and for various subgroups including groups based on patient demographics, utilization type, and prescribing practice setting. Patient age was defined as age on the date of the encounter and was grouped into four categories: ≤6 y, 7–19 y, 20–64 y, and date of the encounter and was grouped into four categories: ≤6 y, 7ups including groups based on patient demographics, utilization type, and fourth ATC classification level.t represents the time trend, and β, δ, and ζ are parameters to estimate, and εt is identically independently distributed stochastic error. Rejection of the null hypothesis H0: ρ = 1 in Eq yy−1+ϵtwhere t t is DID at time t, β is the size of the change in yt, ρ is the first-order autocorrelation parameter, θ is the first-order moving average parameter, and εt and ϵt are identically independently distributed white noise component of the ARMA model at time t.We used a structural autoregressive moving average (ARMA) model with the autoregressive process of order one (AR(1)) and moving average process of order one (MA(1)) as in Eq . The firSAS 9.1  STATA SE 14.0  were used for all analyses.The study design was approved by the Research Ethics Committees which is predecessor of Institutional Review Board of the HIRA.Total antibiotic usage increased by 4.2 DID from 2007 (23.5 DID) to 2014 (27.7 DID). For inpatient services, antibiotic usage increased from 2.4 DID in 2007 to 2.8 DID in 2012, but decreased to 2.6 DID in 2014. Outpatient usage fluctuated in a manner similar to total usage, although there was a downward trend in 2011 when various health policies were implemented. Age groups were categorized as ≤6 years old, 7–19 years old, 20–64 years old, and ≥65 years old. The ≤6 years old age group showed the highest level of usage at 59.21 DID in 2014 and showed an increasing trend each year and a particularly large increase in 2010 .Results by age and chemical subgroup level (ATC-4) are presented in The year-on year difference were slight, but in overall, antibiotic usage was highest in April, October, and November. In 2013, usage showed troughs in June (1.871 DID), July (1.882 DID), and August (1.872 DID), and was highest in December (2.309 DID), January (2.367 DID), and February (2.283 DID) .The aim of the present study was to investigate the epidemiological characteristics of antibiotic use at a national level using representative claims data of the entire population of South Korea from 2007 to 2014. In South Korea, antibiotics usage alone is far higher than in other OECD countries  and Europe  [The findings of the current study show a relatively high use of penicillin-class antibiotics in the outpatient setting, and a high use of aminoglycoside- and cephalosporin-class antibiotics in the inpatient setting. Women showed a slightly higher total antibiotic use than did men. In terms of age, antibiotics were most frequently used in children ≤6 years old, followed by patients ≥65 years old. Antibiotic usage was least frequent in the 7–19 year old age group. The most frequently prescribed antibiotics in the ≤6 years old age group, based on data from 2014, were combinations of penicillins, including beta-lactamase inhibitors (J01CR). In 2013, Sohn et al. reported that antibiotic use was higher in infants and children than in the elderly ; this isWith regard to the choice of antibiotics prescribed, broad-spectrum antibiotics were prescribed more frequently than other antibiotics usually recommended as first-line therapy. There is a large difference between the annual patterns of South Korean antibiotic usage and resistance for the individual ATC antibiotic classes when compared with those of Sweden . For exaThe high utilization of antibiotics in children ≤6 years old (59.21 DID) in South Korea is a significant problem. In contrast, antibiotic usage was 23.15 DID for 7–19 year olds and 37.32 DID for patients ≥ 65 years old. Sweden shows a completely different pattern of antibiotic use relative to age.The present study aimed to measure antibiotic usage as accurately as possible by using health insurance claims data, including almost all Koreans as beneficiaries. The data regarding the epidemiological characteristics of antibiotic use in the present study are particularly useful. Our findings identify the groups that most utilize antibiotics, and our results can be used as the basis for instituting control policies targeting these groups. It should be noted that there are a large number of drugs used in South Korea that have no DDD or ATC category, including traditional Korean medicines, new medications, and combination medications. These drugs were not included in the current study, and thus, estimates from the current study may underestimate the actual usage of certain drugs.Our study has some limitations. First, since we utilized the National Health Insurance claim database, utilization information regarding over-the-counter medicines and medications not listed in the database is not available, thus we might have underestimated the DID of antibiotics. However, all antibiotics are listed in the database, and patients should have access to antibiotics without physicians’ prescribing in Korea. In addition, we were not able to compare adverse effects such as antimicrobial resistance. Further study exploring antibiotics use and resistance is needed.In conclusion, this study provides valuable statistics regarding antibiotic usage in South Korea. Antibiotics use in the ≤6 years old age group showed the highest level of usage at 59.21 DID in 2014, and showed an increasing trend each year. DIDs of beta-lactam antibacterials, penicillins (J01C), other beta-lactam antibacterials (J01D), lincosamides and streptogramins (J01F), quinolone antibacterials (J01M), and other antibacterials (J01X) increased significantly over time. This result is important for guiding health policy with regard to antibiotic usage.S1 Table(PDF)Click here for additional data file.


The objective of this paper is to examine the possible use of new blended cements containing calcareous fly ash in structural concrete, potentially adequate for structural elements of nuclear power plants. The investigation included five new cements made with different contents of non-clinker constituents: calcareous fly ash, siliceous fly ash, ground granulated blastfurnace slag, and a reference cement—ordinary Portland cement. The influence of innovative cements on the resistance of concrete to chloride and carbonation exposure was studied. Additionally, an evaluation of the microstructure was performed using optical microscopy on concrete thin sections. Test results revealed a substantial improvement of the resistance to chloride ion penetration into concrete containing blended cements. The resistance was higher for increased clinker replacement levels and increased with curing time. However, concrete made with blended cements exhibited higher depth of carbonation than the Portland cement concrete, except the Portland-fly ash cement with 14.3% of calcareous fly ash. The thin sections analysis confirmed the values of the carbonation depth obtained from the phenolphthalein test. Test results indicate the possible range of application for new cements containing calcareous fly ash. Since most concrete shielding structures are massive, limits are imposed on the temperature development in the hardening of concrete in order to prevent early age cracking. Both for a decreased risk of thermal cracking during concrete hardening and for an increased chemical resistance of hardened concrete, the use of supplementary cementitious materials is encouraged, [Concrete design for long-term performance in structures requires a more sophisticated approach than the prescriptive approach used for buildings and less important structures. Nuclear reactor containments must maintain high durability since they restrict the spread of radiation and radioactive contamination to the general public, which could have signfiicant consequences . Among touraged, . The objA large amount of calcareous fly ash is generated by the European power industry but its use in construction materials is quite limited. This type of ash is generated when burning lignite or brown coal. Because of the increased content of CaO, usually above 20%, its properties do not conform to the requirements of the PN-EN 450-1 ,7,8 thatPossible use of calcareous fly ash as one of the major components of blended cements could result in several desired environmental and technical benefits, including a reduced carbon print and more consistent properties of binders. This is admissible following the common cements’ definition given in PN-EN 197-1  but not −16 m2 (low air permeability) regardless of the type of cement.In , the actThe reviewed studies related to the use of calcareous fly ash in blended cements indicate certain potential for its application in structural concrete. Therefore, this investigation was undertaken to study the influence of new blended cements containing calcareus fly ash from brown coal combustion in “Bełchatów” power plant in Poland on the resistance of concrete to chloride ingress and carbonation.3, the fineness 46.3% and the surface area was 2400 cm2/g. The content of SiO2 above 40% is high in comparison to other calcareous fly ashes. Following the rules given by PN-EN 197-1 [i.e., between 2 and 5 MPa. Considering the high content of active silica, this type of ash has both pozzolanic and self-hardening properties; the case when both reactive CaO and SiO2 are greater than 15% and 25%, respectively, seems to not be in line with the standard classification. Blended cements were manufactured by grinding Portland cement clinker together with gypsum, calcareous fly ash (W) and selected non-clinker major constituents  was adjusted to maintain the target slump. The composition of prepared concrete mixes is shown in Standard 150 mm cube specimens were cast for compressive strength testing and cylinders with dimensions of 100 × 200 mm for chloride ion migration testing. Prisms of 100 × 100 × 500 mm were cast for carbonation testing. Until the age of 28 days, the specimens were subjected to standard moist curing conditions in a climatic chamber at a temperature of 20 °C and a relative humidity of 95%.2 solution were placed between two chambers, one of which was filled with catholyte (10% NaCl solution) and the second with anolyte (0.3 molar solution of NaOH). Between the cathode and the anode, the electrical voltage was set to 30 V. After the measurement of current passing through the sample, the duration of the test was set. After finishing the ion migration process, the specimens were split into two parts in order to determine the depth of chloride ions’ penetration. For this purpose, the concrete section was sprayed with silver nitrate solution (0.1 M AgNO3) [The chloride penetration was determined with the rapid chloride migration test described in Nordtest Method NT Build 492 . ConcretM AgNO3) .nssmD, is calculated from Equation (1) derived from the Fick’s second law: The conformity criteria for concretes according to Non-Steady State Migration Test are based on the voltage magnitude, temperature of anolite measured at the beginning and end of the test and the depth of chloride ions’ penetration, and are presented in nssmD—non-steady-state migration coefficient, (×10−12 m2/s);U—absolute value of the applied voltage (V);T—average value of the initial and final temperatures in the anolyte solution (°C);L—thickness of the specimen (mm);x—average value of the penetration depths (mm);t—test duration (h).nssmD < 2 × 10−12 m2/s) to good (2–8 × 10−12 m2/s), acceptable (8–16 × 10−12 m2/s) and unacceptable (nssmD > 16 × 10−12 m2/s).The following evaluation of the concrete resistance to chloride ions’ penetration was applied : from ve2 concentration (1%) at a constant temperature (22 °C) and relative humidity (60%) in a computer-controlled CTS C −20/600/CO2 climatic chamber. After 0, 28, 56 and 90 days of exposure, the depth of carbonation was examined on the freshly broken surface with 1% of phenolphthalein in the solution of 70% ethyl alcohol according to PN-EN 13295:2005 [After 28 days of curing in water, the concrete prisms were stored in laboratory conditions at a temperature of 21 °C until they reached a constant weight. The specimens were exposed to the atmosphere of increased COperature  °C and rThe compressive strength was determined with 150 mm cube specimens following the standard procedure PN-EN 12390-3:2009.2. The fluorescent epoxy impregnated thin sections used for this study were prepared according to [Evaluation of the concrete microstructure was performed on thin sections made from concrete prisms both, before the placement in a carbonation chamber and after 56 days of exposure to 1% COrding to . The concf < 40 MPa were attained for concretes with the highest clinker substitution rate CEM V/A(S-W) and a (V-W) combination with limestone aggregate. Concrete specimens made with blended cements, which contained both calcareous fly ash and other mineral additives, showed lower compressive strength for limestone aggregate than for granodiorite aggregate. Such differences were within the limits of 3%–17%.The compressive strength of concrete specimens ranged from 34.3 to 52.4 MPa . The hignssmD after 28 and 90 days of curing are presented in The values of chloride migration coefficient nssmD value by 38% and 33% in comparison with the reference concrete after 28 days of curing, and by 41% and 38% after 90 days of curing, respectively. As a result, the level of the resistance to chloride ions’ penetration increased from unacceptable to acceptable.Beneficial effects of blended cements in concrete were observed—generally a reduction of the chloride migration coefficient was apparent. An application of cements made with calcareous fly ash and ground granulated blast furnace slag: CEM V/A(S-W) and CEM II/B-M(S-W) to concrete mixes with granodiorite aggregate was found to reduce the nssmD after 90 days was reduced by 34% and 64%, respectively. The value of chloride migration coefficient concrete with CEM II/B-W was 7.21 × 10−2 m2/s and it was assigned to the concrete with good chloride ion penetration resistance. Concrete specimens containing blended cements, except for CEM II/B-M(V-W), had a higher resistance to chloride migration, as compared to the reference concrete.In the case of concrete with limestone aggregate, the best results were obtained for 2D and 3D mixes made with CEM II/A-W and CEM II/B-W containing 14.3% and 28.9% calcareous fly ash. The chloride migration coefficient after 28 days decreased by 20% and 40%, respectively. This desirable effect has yet improved over the curing time—nssmD were higher for the limestone aggregate than for granodiorite aggregate for ternary cements contained slag (S). The reasons could be related to differences in porosity of the interfacial transition zone. According to manufacturer’s data, the porosity of limestone aggregate was twice as much as the porosity of granodiorite aggregate, 2.1% and 1.1%, respectively. Performed mercury intrusion porosimetry tests on aggregate grains revealed further differences in pore content and pore size distribution. The relative content of large pores in the range of 100–1000 μm was 46% and 32% for limestone and granodiorite aggregate, respectively. Such grain porosity characteristics could induce noticeable differences in interfacial transition zone porosity, which resulted in greater mobility of chloride ions in concrete.Comparing the two series of concretes with different coarse aggregate, it can be concluded that the resistance to chloride migration is approximately equal for reference concrete with ordinary Portland cement and it did not improve with V-W blend in cement. The values of the cK (mm/y1/2) were calculated using Equation (2), based on the measurements of cx and the age of the tested specimens. cx—the depth of concrete penetrated by CO2 in mm; t—time of exposure in years.The values of carbonation coefficient c vs.xt is approximately linear and the slope is related to the cK value. The results of the rate of carbonation are presented in The plot The lowest resistance to carbonation in concrete with granodiorite aggregate was achieved for cement containing the highest contents of non-clinker constituents—CEM V/A(S-W). The highest depth of carbonation in concretes with limestone aggregate was achieved by application of cement CEM II/B-M(V-W), with siliceous and calcareous fly ash.The use of ternary V-W cements in concrete resulted in a slight increase in carbonation depth for medium content of non-clinker constituents. However, when the sum of V and W constituents was high, almost 50%, a major increase in carbonation depth was recorded. The same increase of carbonation depth was observed for concrete containing binary cements CEM II/A-W and CEM II/B-W. A combination of siliceous and calcareous fly ash in cement resulted in a faster carbonation and a higher carbonation depth in concrete. The frequently cited statement—that fly ash reduces the amount of calcium hydroxide which may cause an increase in the carbonation rate Papadakis —is validet al. [2 concentration. According to this assumption, the predicted cK values for natural environmental conditions (CO2 concentration = 0.03%) are shown in The carbonation depth in concrete progresses with exposure duration. However, the rate of carbonation reduces with respect to time period, and is usually considered as proportional to the square root of exposure period. Even in the case of accelerated carbonation conditions, the depths of carbonation are in proportion to the square root of exposure time, as in the case of natural indoor exposure conditions and natural outdoor exposure conditions under a shelter . There aet al.  to predicK values for natural environmental conditions are in good agreement with other literature data. It is know that values cK found for real structures exposed to the atmosphere but protected from rain, vary from 2 to 15 mm/y1/2. Indicatively, 2 < cK < 6 for concrete of low porosity  whose cement content is above 350 kg/m3; 6 < cK < 9 for concrete of medium porosity; cK > 9 for highly porous concrete with cement content below 250 kg/m3, [The obtained results of the predicted 0 kg/m3, .2 ingress in the cement matrix after 56 days of testing. 2 has been changed into CaCO3. The carbonation front was evenly distributed in all tested specimens. However, a deeper carbonation front close to the limestone grain can be seen in The analysis of thin sections of tested concretes confirmed the values of the depth of the carbonation obtained from the phenolphthalein test. In the uncarbonated part of the specimen where the concrete was still highly alkaline, a purple colour was obtained. In the carbonated part where the alkalinity of the concrete was reduced, no coloration occurred. The analysis of test results and a comparison with published data reveal interesting insights. A beneficial effect of calcareous fly ash in blended cements on chloride permeability is observed, whereas the carbonation resistance was found to decrease with increasing content of calcareous fly ash. A presence of active mineral admixture used as a main constituent in blended cements may inhibit permeation of aggressive media , and thaThe use of blended cements containing calcareous fly ash decreased the resistance of concrete to carbonation at all test ages. However, when the concrete contained only 14.3% of HCFA in the cement, the carbonation depth reached the same value as for the reference concrete with Portland cement. A decreased carbonation resistance can be largely attributed to the lower calcium hydroxide content in the blended cements as suggested in .In et al. [2 diffusion, which explained the gradual carbonation front.The analysis of microstructure on thin sections revealed that the carbonation front is not sharp but gradual, opposite to the earlier studies and models which assume a steep carbonation front, . It was et al. , who shoThe significance of these findings in the context of nuclear power structures is related to the high importance of these structures, their failure having large social and environmental consequences. Published data on the long term performance of containment buildings revealed many cases that required repair . Overall2 and Cl− occurs mostly in the pores of concrete, highlighting the significance of the pore structure which could be engineered using active mineral additions in blended cement to enhance concrete durability. An investigation into the effects of blended cements with calcareous fly ash and two types of coarse aggregates on strength, chloride ion penetration and carbonation resistance of concrete resulted in the following conclusions.Concrete carbonation and chloride ingress into the cover layer are considered as the two principal factors responsible for the majority of durability issues of reinforced concrete structures designed for long-term performance. The transport of both CO1Due to pozzolanic and hydraulic activity of calcareous fly ash, the compressive strength of concrete containing blended binary cements was improved by 7% or 12% at the age of 28 days for granodiorite or limestone aggregate concrete, respectively. Increased clinker replacement levels resulted in a decrease in strength of 3%–19% or 25% for granodiorite or limestone aggregate concrete, respectively.2The carbonation resistance of concrete with blended cements containing calcareous fly ash increased linearly with an increase in the compressive strength of the concrete.3The carbonation resistance of concrete decreased with clinker replacement level, however, the depth of carbonation was low. Concrete containing Portland-calcareous fly ash cement  exhibited an equal carbonation resistance to a reference concrete containing CEM I.4The type of coarse aggregate did not affect the concrete resistance to carbonation except in the case of cement CEM II/B-M(V-W). Here, the carbonation depth of concrete containing limestone aggregate was higher by 17%–33% than for concrete containing granodiorite aggregate.5The concrete microstructure analysis performed on thin section confirmed the results obtained from phenoloftalein test and also revealed that the carbonation front was gradual, not sharp as previously assumed.6nssmD by 38%–41% after 90 days of curing, corresponding to an increased penetration resistance level from “unacceptable” to “acceptable”.The use of cements CEM V/A(S-W) and CEM II/B-M(S-W) in concrete mixes with granodiorite aggregate resulted in the reduction of the chloride migration coefficient 7nssmD = 7.2 × 10−12 m2/s, corresponding to “good” penetration resistance, was found in the case of concrete with CEM II/B-W.Chloride migration coefficient of concrete with limestone aggregate made with CEM II/A-W and CEM II/B-W cements decreased by 34%–64% in relation to CEM I reference concrete. The highest chloride penetration resistance, The use of new cements containing calcareous fly ash as one of the major components in concrete did not lead to any technological issues in mixing or compaction of concrete.


As implementation of the US Affordable Care Act (ACA) advances, many domestic health systems are considering major changes in how the healthcare workforce is organized. The purpose of this study is to explore the dynamic processes and interactions by which workforce planning and development (WFPD) is evolving in this new environment.Informed by the theory of loosely coupled systems (LCS), we use a case study design to examine how workforce changes are being managed in Kaiser Permanente and Montefiore Health System. We conducted site visits with in-depth interviews with 8 to 10 stakeholders in each organization.Both systems demonstrate a concern for the impact of change on their workforce and have made commitments to avoid outsourcing and layoffs. Central workforce planning mechanisms have been replaced with strategies to integrate various stakeholders and units in alignment with strategic growth plans. Features of this new approach include early and continuous engagement of labor in innovation; the development of intermediary sense-making structures to garner resources, facilitate plans, and build consensus; and a whole system perspective, rather than a focus on single professions. We also identify seven principles underlying the WFPD processes in these two cases that can aid in development of a new and more adaptive workforce strategy in healthcare.Since passage of the ACA, healthcare systems are becoming larger and more complex. Insights from these case studies suggest that while organizational history and structure determined different areas of emphasis, our results indicate that large-scale system transformations in healthcare can be managed in ways that enhance the skills and capacities of the workforce. Our findings merit attention, not just by healthcare administrators and union leaders, but by policymakers and scholars interested in making WFPD policies at a state and national level more responsive. As the implementation of the 2010 Affordable Care Act (ACA) advances in the United States, many healthcare organizations are taking bold measures to reorganize their delivery systems and finding that in order to do so, changes must be made to the healthcare workforce ; designiUnderstanding what workforce changes are occurring and how they are being managed is key not just for healthcare leaders but for policymakers as well. Traditional methods of projecting provider shortages and justifying the allocation of public funding to expand various professional pipelines are giving way to the notion that there are many models of care delivery and that they have vastly different staffing configurations. For example, several studies have demonstrated that including advanced practitioners in primary care medical homes allows practices to expand panel sizes , 8. ChoiThe policy question then becomes not just how will these changes alter the national demand for certain types of health workers at an aggregate level but how are organizations making choices about ways to reconfigure their workforce and, ultimately, what kinds of local, state, and federal policies are most supportive of workforce transformations that advance both workers’ well-being and the value of their services.We know from the literature reviewing the hospital restructuring of the 1990s that workforce change management faces many challenges. The critiques of this era were many, but chief among them, according to Walston and colleagues, were the following: goals for change were not clear, too many changes were implemented too quickly, there was a lack of communication with employees, a lack of engagement with physicians and unions, there was a poor understanding of the local site differences by management leading to a one-size-fits-all approach, and, lastly, that training needs were not anticipated  are good for us as an organization.” In addition, Montefiore’s centralized vision of socially oriented care links and integrates many locally driven innovations and care models to the overall system. “…Every facility [in the Montefiore Health System] has its own culture, but the core is… our vision and our values.” These values and vision are embedded in the formal and informal processes that drive care and change at Montefiore. “If they (a newly acquired facility) are following the process, the culture starts changing; there is no other way.”Weick  and Burkthe situation determines what type of adaptive WFPD is possible in the first place. This means that WFPD is not just a technical exercise; it must also appraise the political, economic, cultural, and social dynamics within specific contexts in which healthcare takes place [In both cases, we see that their historical and cultural context is key to understanding how they integrate WFPD activities into ongoing change processes. The emerging principle, then, is that es place . To be ees place .The second theme that emerged in both cases is the commitment to transparency with regard to the goals and criteria for making decisions about changes and to an early dialogue with stakeholders, in particular labor, around the best way to organize the change. In both systems, we see an institutional commitment to early collaboration with labor and other key partners throughout the change process.In KP, the national agreement and the investment in the LMP have resulted in a highly integrated system of corporate governance that involves labor in strategic decisions on every level of the company, from the UBT to national strategic planning efforts. The sharing of sensitive corporate information and performance data is essential to making these efforts work.The extent to which labor is involved in determining internal change in Montefiore is unclear, though HR leaders did talk about the importance of early dialogue with labor about planned changes: “…we contact them early so that they do not hear about things late.” According to an HR lead, this early consultation results in labor buy-in, which in turn provides employees with the assurances they need to engage in change.Greater emphasis on transparency and early dialogue between Montefiore and 1199SEIU, its largest union, was observed in external efforts to close gaps in the labor market and in their mutual engagement in the DSRIP planning process. The expansion of the one-time nurse bridge program to create a new curriculum to prepare nurses for care coordination roles is an example of how joint leadership resulted in improvements to the WFPD infrastructure in the region.The theory of LCS suggests that transparency and early dialogue are highly functional change mechanisms, because they open the process to many different interests and vantage points required for sense making . In addiintegrated with strategic and operational planning processes. Beekun and Glick [An emerging principle then is that WFPD is nd Glick  define ind Glick . With thThe third theme is changes often emanates from innovations to workflow that emerge from an analysis at the unit level and then take into account competing interests across the system. This is in contrast to change defined based on existing jobs and organizational structure or simply an analysis of who currently does what.For example, KP’s UBT engage in the process on an ongoing basis. In Southern California, efforts to massively revamp ambulatory care based on the principles of consumerism began at a central level with a complete rethink of consumers’ wants and then engaged stakeholders in a discussion about how and where work is carried out, as well as who does what.The innovation model in Montefiore also starts with an analysis of the optimum work design at the unit level, as opposed to the current workflows and job structures. The CMO competency map then uses the local analysis to build a whole-system approach to WFPD. It identifies the range of knowledge and skills that are required for coordination across the continuum of care, and it delineates what every occupation group needs to know and do to support the care model. This tool ensures that the required expertise is available across the entire system, while it also enables the customization of curriculum pathways for each role and individual in the CMO.There are several emerging principles here. The first related once again to integration, as discussed above. But in addition, we see principles of both a holistic approach and an approach that is adaptive to changing demand.holistic principle implies the consideration of the whole system of professions and occupations, as opposed to each profession having its own distinct role, training structure, and regulatory mechanisms. Dussault and Dubois posit that a traditional siloed approach in healthcare hinders the implementation of policy and complicates the change process, particularly when new, multidisciplinary models that require a high degree of interdependence among many different professions are required [The required .responsive to changing demand. Both systems have concluded that the traditional linear approach to WFPD is necessary but not sufficient. Their adaptive approaches begin with a focus on the demand for healthcare and try to account for the macro shifts and trends as well as the internal political dynamics affecting the health system and its workforce [A related principle is that adaptive WFPD must be orkforce . In the orkforce , 13. Neworkforce .The fourth theme is the new patterns of coupling, including both tightening and loosening of the alignment of each company’s component parts. These changes are consistent with the proposition of Bechun and Glick, who argue that institutional changes can set into motion new patterns of coupling within organizations as they respond to the changing environment. They also claim that the strategies used to foster new patterns of coupling will reflect the organizations’ traditional approach to implementing change.We have seen that, historically, KP grew as a loosely coupled network of providers (Permanente Group) and an insurer , across seven semi-autonomous regions. Recent efforts to streamline administrative systems through “One KP,” as well as HR’s work to create centralized skill standards and training, reflect an attempt to cut costs and to create a common corporate identity by tightening connections. In addition, the influx of new individual members is pushing KP to both loosen and realign their historic workflows and communication patterns by relocating care and consolidating roles to improve care and make it more accessible. Lastly, we see how technology continues to play an important role in meeting long-held objectives to tighten the connection between KP and its members, as well as, they hope, to improve the quality of care.Similarly, Montefiore’s historic strategy to promote value-based contracting led them to extend their care model by tightening their connections throughout a loosely coupled network of providers, and this approach continues to grow as they expand into new regions. Once connections are made, CMO takes the lead in tightening efforts by identifying the parts of the system where outcomes are weak and costs are high and then turns the focus to the redesign of work, followed by training, both initial and continuous. Now, with the expansion of the system into new regions, and the new relationships with external providers and community-based organizations that are being formalized through DSRIP, the CMO is poised to integrate its approach with external partners.integration, not just with regard to internal realignment but with external relationships as well. This is particularly striking in the case of Montefiore, where their new patterns of integration are aligning internal change with external partnerships.The emerging principle here is again Both systems work hard to continuously mature their approach to WFPD. Indeed, Burke anticipated that as LCS grew more commonplace in business and society, change agents would need deeper knowledge of the dynamics of LCS and more complex change strategies to enable both the tightening as well as the loosing of ties throughout the system. Change agents know how to tighten, according to Burke, but few can discern the need to loosen and then effectively intervene.Informants in both cases were quite articulate about their WFPD model and the need to improve and expand it beyond the traditional approach. Intermediary structures form the structural basis for the WFPD model in both cases. Intermediaries, according to Giloth, broker and integrate a variety of interests and resources to enact WFPD in local settings . As seenThe intermediary partnership in KP is made up of a loosely coupled network of staff housed in a variety of support units who “show up” at important corporate innovation meetings and establish a presence in the change process. In addition to showing up, informants talked about a variety of intermediary strategies, such as aggressive engagement, deep listening, and accommodation, that they utilize to help HR and the LM to “translate the workforce and labor piece” of the change. Thus, in KP, the intermediary strategies provide a valuable sense-making function that help the parties respond to change. One informant claimed that this intermediary, sense-making approach “…is core to how you transform workforce planning.”Intermediary partnerships also provide sense-making functions throughout Montefiore. The HR Business Partners also show up at business meetings and they link HR processes to change occurring in operational units. The CMO’s Education Council and frontline facilitators are listening mechanisms that align training with change occurring in the system. Lastly, in the context of DSRIP, Montefiore participates in workforce planning in the Bronx and the Hudson Valley PPS. In the Hudson Valley, they are engaging provider HR and operations staff in a preliminarily needs assessment to help make sense of future staffing needs and to identify gaps and resources. This was described as an analytical process to develop a strategy to close the gaps required to make each new role successful.process of consensus building that includes workers and are accommodative of the needs, interests, and preferences of participating groups. Again, WFPD is both a political and technical exercise [A major emerging principle regarding this theme is that decisions are being made through a exercise , and as exercise  among a exercise  change acontinuous and iterative. Dussault and Dubois suggest that the historic system of professional dominance in healthcare calls for an ongoing process (continuous) of adjustment (iterative design) that can attend to population needs as well as the changing expectations and roles of the healthcare workforce [In addition, we see that WFPD is a process that is orkforce . Furtherorkforce , 27. Achorkforce .generative, resulting in new resources and capacity for innovation. We see in both cases that WFPD requires institutional capacity and the investment of time and money in sense making and structuring activities [Finally, WFPD is tivities . Both caThe seven principles emerging from these case studies, when considered synergistically, help provide a framework for thinking about adaptive WFPD in specific contexts. Table This emerging framework is consistent with the theory of LCS and resonate strongly with the critique offered by Dussault and Dubois of human resource planning in the healthcare sector. We would suggest that others could adopt these propositions to think about WFPD in new and innovative waysThis comparative case study analysis suggests that the old way of doing WFPD by estimating the workforce needs within the confines of an institutional setting is giving way to new adaptive approaches. Institutional settings in the context of a post-ACA landscape are simply too complex and fast paced for the old approach to work. Both KP and Montefiore understand that the only way to do WFPD in periods of rapid transformation is to engage—to listen and interpret what is happening from a workforce perspective. This process requires developing an institutional capacity for sense making  across tWFPD is therefore no longer a centralized function at KP and Montefiore. Control mechanisms have been replaced with strategies to integrate various stakeholders and units across a broad continuum of WFPD activities and programs. The new approach to WFPD is aligned with strategic growth plans and is integrated with labor, employment relations, innovations teams, and local change initiatives. Both systems demonstrate a concern for the impact of change on their workforce and have made large political as well as financial commitments to avoid outsourcing and layoffs.We find that a series of new change principles defined by theorists as suitable for improving the functioning of LCS , 17 and The effective implementation of these principles in these two major health systems has given rise to a pattern of reciprocal interdependence and mutual adjustment among the diverse range of actors across the WFPD ecosystem. This new form of coordinating WFPD across the system is both enabled by and helps to foster a form of knowledge-based action and a pattern of thinking that is slow, deliberate, and explicit—and is more aligned with the complexity of health workforce changes in a post-ACA environment.These findings may be relevant to a range of other healthcare organizations. While the payment reforms that are spurring workforce transformations may be different for public systems, like the Veterans Health Administration in the United States, to the extent that they are embracing any major system changes, these WFPD principles would be applicable. In other words, the principles are about managing change in complex organizations, not about the specifics of the changes.The findings may also hold meaning for macro-level workforce policies at the state and federal governments. Technocratic WFPD at these levels is also likely to be insufficient during periods of large-scale system transformation. Traditional policy levers, such as scope of practice regulation, education and training curriculum and degrees, and professional codes, have not been responsive to the needs of LCS, because they are designed to ensure uniformity in roles and job structures across the broader healthcare system.If today, we are likely to see less uniformity in our distributed, free-market healthcare system as it continues to innovate and multiply new models of care, then WFPD at both the organizational and the public policy levels must also go beyond data analysis and engage in a political process of spanning traditional boundaries, listening to diverse interests, and building consensus. It requires new intermediary structures, and it must be generative of new resources and new talent. It also requires building the political and technical skills of WFPD professionals and empowering them to challenge old practices and ways of thinking about workforce issues and problems  and addr


PurposeThis study aims to establish the demographics and characteristics of patients with cervical spine injury (CSI) in an Irish cohort presenting to a regional emergency department.MethodsWe performed a retrospective analysis of the medical records of patients who underwent cervical spine computed tomography (CT) scans following trauma from January 2013 to July 2016. We looked at the mechanism of injury, mode of arrival to the emergency department, triage category, correlation between examination, and site of CSI and neurological status.ResultsOver the study period, 808 patients underwent CT scans of the cervical spine for potential CSI. The incidence of CSI in our cohort was 9.4% (n = 76). Approximately 70% (n = 53) were men. Falls (53%) and motor vehicle accidents (29%) were noted to be the more common mechanisms of injury in this cohort. The C2 region was the most common location for CSI. Only 7% (n = 5) of patients had documented neurology.ConclusionThis study demonstrates the epidemiology and characteristics of CSI presenting in an Irish cohort. The incidence of CSI was found to be 9.4% with a male preponderance and falls being the most common cause of trauma. Cervical spine injury (CSI) has been widely reported in patients with blunt trauma and represents an important subgroup presenting to the Emergency Department (ED). There is a variation in incidence and epidemiological data of patients presenting with CSI in different populations -7. The iThis was a retrospective study carried out in a regional tertiary university hospital in the West of Ireland with an annual attendance of over 65,000 presentations to the ED. This study period was from January 2013 to July 2016, inclusive. The patients who underwent cervical spine computed tomography (CT) scan following blunt trauma to the cervical spine were identified through the hospital radiology registry (PACS System). Variables retrieved included age, gender, triage category, Glasgow Coma Scale (GCS), mechanism and site of injury, mode of arrival, and clinical correlation with fracture site on CT. Neurological status and management outcomes were also documented.Over the study period, 808 patients underwent CT cervical spine for potential CSI. The incidence of CSI in our cohort was 9.4% (n = 76). Approximately 70% (n = 53) were men, and the mean age of patients presenting with CSI was 53.8 (standard deviation (SD), 23.2). Approximately 61% of patients were under 60 years of age but only 7.9% were under 20 years of age. Table  Most patients arrived at the ED by ambulance (76%). An assessment of the seasonal trend of injury presentations revealed that January, May, and August are the more common months for injury presentation Figure . Only 9% The C2 region was the most common level for the location of CSI Figure , closelyOur study will be the first to focus on patients presenting with CSI from the general population in the West of Ireland. The incidence of CSI in our cohort was 9.4%, which is within the range of 2% to 12% found in the published literature . Unlike Very few authors report falls as the most common mechanism of injury for CSI , with thUnderstanding the demographics of our patient population, their mechanism of injury, and expected findings can better help us prepare to manage this cohort when they present to the ED.This study demonstrates the epidemiology and characteristic of CSI presenting in an Irish cohort. The incidence of CSI was found to be 9.4% with a male preponderance and falls being the most common cause of trauma. This study is important as it would help with resource and personnel allocation to improve our services and optimize the management of patients presenting with CSI.


Antimicrobial resistance is an important problem that requires an urgent response from the scientific community . One of Early, appropriate empirical treatment is associated with better survival . FurtherThe use of techniques for the rapid etiologic diagnosis of germs and their resistance patterns seems to be the most promising strategy for achieving targeted, fast, appropriate initial treatment and for limiting unnecessary antibiotic use . VariousEnterobacteriaceae species) and must be performed on isolated strains. Controls were patients enrolled prior to the implementation of the technique. The authors found that cases had earlier antibiotic adaptation , which shortened the time to escalation in cases of inappropriate empirical treatment (50.5 (48–73) to 27 (24–28) h, p < 0.01) and increased antibiotic adequacy . Regarding the resistance detection, only one false-negative was observed. In previous reports, betaLACTA® showed a lower sensitivity for AmpC-overproducing Enterobacteriaceae detection than for extended-spectrum beta-lactamases [In a case-control study, Garnier and coworkers evaluated the usefulness of betaLACTA® in critically ill patients . BetaLACctamases .Among the main advantages of this device are its cost-effectiveness, the fact that the results can be assessed after few minutes, and the fact that no special equipment is required. Nevertheless, Garnier’s study has several limitations, in addition to the study design chosen. The selection of historic controls may have introduced a bias, given the changes in the local flora, in empiric antibiotic use protocols, and in clinicians’ behavior over the years with regard to escalating/de-escalating antibiotics.The performance of the device has been validated in various studies. One of the main strengths of the study by Garnier et al. was to assess not just the device accuracy but also its impact in clinical practice . InteresOther devices for rapid etiologic diagnosis of infection are also available . There aFuture research should validate this new diagnostic technique through prospective studies and randomized clinical trials. These studies should evaluate not just its accuracy, but also its net benefits and its impact in reducing the use of broad-spectrum antibiotics, the occurrence of adverse events, and the emergence of new resistances, followed by a cost-effective analysis.