TiO2 immobilization on the pervious concrete surface was done by different procedures containing slurry method (SM), cement mixed method (CMM) and different concrete sealer formulations. Irradiation of TiO2 was prepared by UV-A and UV-C lamps. Phenolic wastewater was selected as a pollutant and efficiency of the process was determined in various operation conditions including influent phenol concentration, pH, TiO2 concentration, immobilization method and UV lamp intensity.In this study, concrete application as a substrate for TiOThe removal efficiency of photocatalytic process in 4 h irradiation time and phenol concentration ranges of 25–500 mg/L was more than 80 %. Intermediates were identified by GC/Mass and spectrophotometric analysis.According to the results, photocatalytic reactions followed the pseudo-first-order kinetics and can effectively treate phenol under optimal conditions. Among AOPs, application of heterogeneous photo-catalysis by using semiconductors has been proved to be real interest as an efficient tool for degrading both aquatic and atmospheric organic contaminants [2) is an established photocatalyst utilized in the photo-oxidation process. When TiO2 is exposed to the appropriate wavelength of ultra-violet light (UV-A), electrons in the low-energy valence band will absorb the photon’s energy and move into the high-energy conduction band. The result of this electron excitation is a hole, or positive charge, in the valence band (h+) and an electron in the conduction band (e−) [2 particles becomes smaller especially below 100A° [The ability of Advanced Oxidation Processes (AOPaminants . Semiconaminants . Titaniuand (e−) . Reactio2 from the treated milk-like water suspension. Separation steps cause to complicate the treatment process and decrease the economical viability of the slurry reactor approach [2 catalysts on these substrates. Although these techniques and substrates had a suitable performance for treating different types of wastewater in laboratory scale experiments, but their application in wastewater treatment plants and pilot scale studies are questionable.Photocatalytic reactors for water and wastewater treatment can be classified to slurry and photocatalytic ones. In the slurry reactors, the catalyst particles are freely dispersed in the fluid phase (water) and consequently the photo-catalyst is fully integrated in the liquid mobile phase . Whereasapproach . Therefoapproach , fiber oapproach  fiberglaapproach , glass bapproach , quartz approach , silica approach  and staiapproach . Dip coaapproach , 13 are 2 were done for air pollutant removal and self-cleaning surfaces [2 photocatalyst process [2 substrate has unique characteristics such as porosity, natural abundance, absence of toxicity, and low price. This construction material is used in all of the water and wastewater treatment plants (WWTP) all over the world. Therefore, the photocatalytic process by TiO2 photocatalyst that immobilized on concrete surfaces can be used in large scale WWTP.Most applications of concrete modified by TiOsurfaces . Althoug process , 16, butPhenols and its compounds are widely found in paint, leather and textile, disinfectants, medicine, oil refinery and lubricant production wastewater industries in Iran –19. Phen2 powders (Degussa P-25) under UV irradiation [2 on perlit granules for photocatalytic degradation of phenol was done by Hosseini et al. (2009) [2 substrate for degradation of dyes and dye industry pollutants [Several investigations using different physical, chemical and biological systems and their combination for phenol elimination from wastewater have been reported –27. Bioladiation . The opt. (2009) . The Resllutants . Real wa2 nano powder immobilization to treat phenolic wastewater. For this reason, four methods were applied for immobilization of nano TiO2 on concrete. Kinetic of the reactions, long term use of the process and intermediates formed during the photo degradation were other objectives of this research.The main objective of this research was to study the feasibility of using concrete as substrate for TiO3. LECA application increased surface porosity of concrete and promoted the specific surface area as an important immobilization parameter. Concrete surface was fabricated in wooden moulds with an internal dimension of 500 × 250 × 50 mm. TiO2 Degussa P25, anatase/rutile ca. 70/30, with an average particle size of 20 nm and a BET surface area 55 ± 15 m2.g−1 was used as photocatalyst. UV radiation was provided by different powers of UV-A Philips medium pressure lamps. The spectral irradiance of UV-A lamp ranges from 300 to 400 nm. The primary wavelength distribution of the UV-A lamp was 365 nm and the light intensity was among 4.42-8.9 mW.cm−2. The incident UV-A light intensity was measured by a UV power meter (UVA-365- Lutron Taiwan). Also UV illumination was provided by UV-C lamps .Cement in the concrete was an ordinary Portland type V that is usually applied in WWTP construction in Iran. Selection of concrete mix proportion was done according to standard practice for selecting proportions of normal concrete (ACI 211.1 :1996) . Light e4OH, K2HPO4, KH2PO4, K3Fe(CN)6 and 4-aminoantiprine as phenol concentration reagents and other chemicals all offered by Merck Co., as an analytical reagent grade. Wastewater produced by adding deionized water and phenol in various concentrations (25–500 mg/L).Phenol (purity above 99 %) as a contaminant, NaOH, HCl for pH adjustment, NH2 nano powder on concrete surfaces was carried out by four different procedures. Adhesion properties of cement and concrete sealers were applied to fix photocatalyst on pervious concrete surfaces.Immobilization of TiO2 was prepared using 25 % (v/v) methanol in deionized water. Methanol would help with the attachment of TiO2 to the surface.20 g/L slurry TiOThe solution was stirred vigorously for 10 min at 20 °C.2 and to obtain more uniform slurry.The slurry was sonicated for 5 min to separate the flocculated TiOOne half of slurry sprayed on fresh concrete to use adhesive properties of cement.The coated surface was placed in oven at 100 °C for 2 h to remove the moisture content.The rest of the slurry sprayed on hardened concrete and annealed at 450 °C for 2 h to remove any organics from the surface.The support was let to dry and was washed with pure water to eliminate the excess of the catalyst.The details of this technique are given as follows:2 was mixed by cement grout (40 g cement + 20 mL water) and distributed on hardened concrete base by an ordinary brush. After 8 h the concrete surface was placed in oven at 100 °C for 2 h to be dried. The support was washed with pure water to eliminate the excess of the catalyst.In this method, 20 g/L TiO2 was examined. The details of this technique are as follows:100 mL of the selected concrete sealer mixed with 1000 mL of pure water and stirred vigorously for 10 min at 20 °C.Prepared emulsion was distributed on the hardened concrete surface with a trowel and let to dry for 20 min.2 poured on concrete surface for adhesion on sealer.After that time, 20 gr/L of TiOThe support was let to dry and was washed with pure water to eliminate the excess of the catalyst.In these procedures, the effect of epoxy concrete sealer (Nitofix- Fars Iran Company) and waterproof concrete sealer (Nitotile- Fars Iran Company) for adhesion of TiO2 particles. The phenol concentrations were measured by colorimetric 4-aminoantipyrine procedure using a Perkin Elmer-Lambda EZ 150 UV/vis spectrophotometer as described in standard methods (2005). The structure and morphology of prepared catalysts and concrete surface were determined using Philips XL30 scanning electron microscope (SEM) followed by AU-coated by sputtering method using a coater sputter . All other parameters were determined according to the standard methods (2005). The intermediates determined by GC/Mass (column: chrompack CP-Sil 8 CB 50 m × 250 μm × 0.12 μm). The gas vector used was helium and the detector was a FID. The program of temperature was: detector temperature = 240 °C, injector temperature = 230 °C, oven initial and final temperatures = 105 °C & 190 °C, oven rise 10 °C min−1, initial and final time = 2 & 15 min). All other parameters were determined according to the Standard Methods [The immobilized concrete surfaces were placed in the pilot scale photocatalytic reactor Fig. . A dosin Methods .Fig. 1Sc2 on concrete surfaces  were done to confirm the presence of TiO2 by cement as an adhesive agent caused the minimum level of active surface catalyst in CMM  in removal efficiency is shown in Fig. Effect of different initial concentrations  in slurry photo-reactor treated 60 % of 0.52 mM (~49 mg/L) phenol after 3 h and 400 W UV lamp. In other research, Hosseini et al. (2007) reached to 88.3 % phenol degradation after 4 h in initial concentration = 1 mM (~94 mg/L) and UV lamp intensity = 120 W [At first, in all experiments the removal efficiency was measured in pH = 7 without UV lamps for 60 min to determine the pollutants adsorption to concrete and phenol volatility. Removal efficiency in these conditions was less than 5 % and stripping of phenol by aeration was negligible because of its very low Henryconstant . Photoca = 120 W .+ and creation of negative charge on hydroxyl group) that was more reactive than phenol in a solution [ZPC of Degussa P-25 TiO2 used here is 6.5, and phenol is 9.89, respectively [2 surface increases as the pH decreases (TiOH2+); above pH 6.5 the negative charge at the surface of the TiO2 increases with increasing pH (TiO−). The optimum pH can be obtained between pHZPC of photocatalyst and contaminant. Effect of pH in the range of 4–12 on phenol removal efficiency in ESM was evaluated  when initial concentration was 100 mg/L and UV-A lamp intensity was equal to 5.33 mW.cm−2 and UV lamp distance to concrete surface = 10 cm in these experiments. Results showed ESM had the highest photocatalytic activities so that the removal efficiency of this method was more than 90 % after 4 h. The photocatalytic efficiency of the coating methods was in the following order: ESM > SM > WSM > CMM. The removal efficiency of CMM method after 4 h was 42 % that was the minimum efficiency between other immobilization techniques. The most important reason that proved by SEM-EDX analysis was reduction levels of active surface of nano particles that mixed with cement. While in other methods, TiO2 nano particles attached to a concrete top surface, in the CMM nano TiO2 particles mixed with cement as cohesive agent and a lot of percents of photoctalyst disappeared. Comparison between ESM and WSM showed that ESM had better performance due to hydrophobic properties of waterproof sealers that decreased connection between contaminants and immobilized pohotocatalyst.The photocatalytic activities for all combinations of coating methods are summarized in Fig. −2. This is reasonable because the stronger the irradiating UV, the more the UV penetrating. A few differences between phenol degradation since 8.9 and 8.1 UV intensity was confirmed that further increase in UV intensity couldn’t increase the amount of phenol destroyed.The effect of UV lamp intensity on the phenol photo degradation at constant initial concentration (100 ppm) and pH = 7 is presented in Fig. 2 photocatalyst showed proper spectral irradiance of UV-A lamp that degraded only 7 % of phenol when photocatalyst was deleted. On the other hand, UV-A lamps had appreciated feature in the photocatalytic process compare to UV-C lamps.Application of UV-C lamp promoted phenol removal efficiency more than 18 % compared to UV-A lamps at a constant irradiation time. Capability of UV-C lamp in degradation of 50 % of phenol without TiO2 particles detachment and catalyst surface fouling by formation of by-products during the degradation process. This limitation inhibited the application of immobilized procedure as a long term process for wastewater treatment. The influence of long term use in the degradation efficiency has been examined at a constant initial concentration (100 ppm), pH = 7 and UV lamp intensity of 5.33 mW.cm−2. Proper connection between TiO2 nano particles and concrete surface led to 2 and 3.5 % reduction in phenol removal efficiency for ESM and WSM, respectively. In SM that TiO2 poured on concrete surfaces and cement was used as a cohesive agent instead of concrete sealers, the reduction in removal efficiency after 45 times iterations was more than 21 %. Mixing cement by TiO2 caused 4 % removal efficiency reduction after 45 times in CMM. In other research, the elimination of some TiO2 from the pumice stone surface showed significant decrease of photocatalytic efficiency in long term use of process when SM was used [One of the most important parameters in photocatalytic reactors with immobilized photocatalyst is a reduction in removal efficiency because of TiOwas used .Langmuir-Hinshelwood kinetic has been used to charac-terize the destruction of many contaminants in different structure of catalyst . The fin0) is the organic concentration, (Kr) the reaction rate constant, (Ks) the apparent adsorption constant and (t) is the time of reaction. The term KsC0 is often negligible when the concentration is low, and the reaction rate can be expressed as pseudo-first-order model as shown in Eq. Where (r) is the rate of the photocatalytic degradation,  against (t) and slope of linear regression analysis is equal to the value of Kapp. The calculated result indicated that photocatalytic degradation of phenol at the reactions conditions follows a pseudo-first-order kinetics that compared with other researches [A plot of –ln and Kapp for the photo degradation of phenol at different immobilization method, pH values and initial concentration are shown in Table Regression coefficients  produced and after 60 min, intermediates convert to linear compounds such as oxalic acids and formic acids. Lastly, phenol is completely mineralized to CO2 and H2O. This can be explained given the fact that adsorbed phenol molecules on TiO2 are subject to variable interaction with hydroxyl radicals.The intermediates of photo degradation of 100 mg/L phenol at pH = 9 and intensity = 8.1 mW.cmChanges of the UV spectrum with respect to destruction of aromatic ring and phenol and variation of the absorbance at 268 nm in different irradiation time are shown in Fig. 2 on concrete surface.SEM determination has showed well uniformity of coating processes and EDX spectrum approved nano TiO2.The photocatalytic tests of phenol degradation showed a good photocatalytic activity for TiOThe ESM coating method was found to be the best technique, with the highest photocatalytic activity and adhesion. The removal efficiency of this method was more than 90 % after 4 h.Effect of pH showed that the removal efficiency of phenol increased as pH value increased from 4 to 9 while phenol was converted to phenoxide group.Photocatalytic efficiency in all immobilization methods improved about 50 % when UV lamp intensity increased 2 times.Process kinetics by Langmuir-Hinshelwood model was approved pseudo-first-order reaction for phenol photo degradation.2 detachment from concrete surfaces.Reduction of phenol removal efficiency was done as a reverse method for evaluation of nano TiOResults showed that application of concrete sealers had better performance in comparison with SM and CMM that cement was used as a cohesive agent. In WSM and ESM, reduction of removal efficiency was less than 2 and 3.5 % after 45 times iteration of process, respectively.2 photo-catalysts. Also concrete sealers showed good capability for attachment of TiO2 nano particles to concrete surfaces.Consequently, concrete due to its special characteristics and large consumption in WWTP as a construction material seems to be an ideal support for the immobilization of TiOIn this study, the performances of various coating methods alternatives on concrete surfaces for treating phenolic wastewater were compared. Based on the findings, the following conclusions can be drawn:


Type 1 autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD. Typically, lymphoplasmacellular inflammation, storiform fibrosis and obliterative phlebitis are found in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. Consequently, diagnostic criteria for IgG4-RD have been proposed recently. Treatment is largely based on clinical experience and retrospective case series. Glucocorticoids are the mainstay of therapy, although adjunctive immunosuppressive agents are used in relapsing patients. This review summarizes current knowledge on clinical manifestations, pathophysiology and treatment of IgG4-RD.Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder (ORPHA284264). Although patients have been described more than 100 years ago, the systemic nature of this disease has been recognized in the 21 Immunoglobulin G4- related disease (IgG4-RD) is a systemic fibro-inflammatory disorder of unknown origin. While single organ manifestations have been described already more than 100 years ago, a clear description and nomenclature of this disease have been achieved in the past 10 years. As IgG4-RD may affect virtually every organ, this disease is of interest not only for internal medicine physicians but also for other specialties such as ear nose & throat, dermatology, ophthalmology, and neurology.In January 2012, a 61 year- old female presented to a rheumatology unit with a long- standing history of recurrent inflammatory lesions of unknown origin since 1989, which had been previously diagnosed as pseudolymphoma and Sjögren’s syndrome (SS). The leading symptom was bilateral orbital masses, which eventually led to enucleation of the left eye. Further, suspicious enlarged lymph nodes in the head and neck region as well as recurrently enlarged salivary glands were evident. Moreover, paravertebral masses as well as thickening of ocular muscles and nerves were present.The patient underwent a series of organ biopsies over the years including resections of the orbital pseudotumor and left submandibular salivary gland, as well as biopsies of ocular muscles. All biopsies showed dense lymphoplasmacellular infiltrates of the respective organs. Due to the lack of evidence for monoclonal disease based on these biopsies and inconspicuous bone marrow investigations, the results were interpreted as “pseudolymphoma”. Nonetheless, the patient received treatments such as chlorambucil and radio-chemotherapy. All prednisone- containing treatment schemes were successful in decreasing mass sizes and organ swellings for a short period. However, the patient’s disease course was chronic relapsing during the first years. In the last 8 years before referral, however, the disease changed to a more chronic, stable course without major complications.When we saw the patient first in 2012, her medication included azathioprine 100 mg and prednisone 5 mg per day. She reported dry eyes and mouth, which had not changed during the last years. Otherwise, she was in good condition. Upon physical examination, mild swelling of the right submandibular gland was evident. On imaging, we found massive thickening of the ocular nerves  . HoweveMany organ manifestations of IgG4-RD including among others retroperitoneal fibrosis, sclerosing cholangitis, and sclerosing pancreatitis have since been described. Already decades ago, the systemic nature of the disease was recognized as evidenced by patients presenting with more than one organ involvement. For instance, Bartholomew et al. reported in 1963 on two patients with a combination of Riedel’s thyroiditis, retroperitoneal fibrosis and sclerosing cholangitis ].].7]].These findings have been replicated in different cohorts of patients with the above- described syndromes ]. Th]. Th9]].IgG4-RD can affect any organ or tissue. Thus, the clinical picture is highly heterogeneous. While some patients may present with a single site involved, others may have a few or many organs affected by IgG4-RD. These may arise synchronously or metachronously. The disease may manifest as a tumefactive lesion or a rather diffuse infiltrative process, further contributing to a diverse clinical picture. In addition, some organs show a distinct involvement, as for instance lymphadenopathy, periaortitis, or a secondary form of membranous glomerulonephritis (GN) [–13]].].13]].Laboratory findings in IgG4-RD are often inconspicuous. Inflammatory markers such as ESR and CRP may be highly elevated, but can be normal despite active disease in a substantial proportion of patients. Anti-nuclear antibodies, anti- SS-A as well as anti- SS-B antibodies are negative in the majority of patients, while low complement levels (C3 and C4) are not uncommon ]. P]. P15]].In some patients with active IgG4-RD IgG4 levels were found to be inappropriately low due to the prozone effect, a situation where too many antibodies prevent agglutination of antigenic particles in the test system. If disease activity is high, but IgG4 levels are low, sample dilution may lead to correction of the prozone effect and reveal – appropriately – much higher IgG4 levels in particular patients .While the location of disease manifestation may vary, the histological pattern is – with some exceptions – more or less uniform and shares particular features: (i) storiform fibrosis (resembling the spokes of a cartwheel), (ii) a dense lymphoplasmatic infiltrate with an increased number of IgG4+ plasma cells (at least > 10/high power field (HPF) – depending on the particular organ) and/or an increased IgG4/IgG ratio  and (iii) an obliterative phlebitis. Tissue eosinophilia is also very characteristic. The presence of neutrophils, granulomas, neutrophilic microabscesses, and necrotizing vasculitis strongly argues against IgG4-RD . In somThere are few studies reporting on the epidemiology of IgG4-RD, mainly derived from Asian studies. A cross-sectional study in 2009 estimated that approximately 8000 individuals in Japan were suffering from IgG4-RD, thus accounting for a prevalence of approx. 60 affected individuals per million inhabitants . SlightLittle is known about the initiation process of IgG4-RD or how and why these specific organ infiltrations occur. There is some evidence from Asian populations, that certain HLA alleles – particularly DRB1*0405 and DQB*0401 – increase the susceptibility to type 1 AIP . FurtheIt is suspected but unclear, whether IgG4-RD truly belongs to the group of autoimmune disorders. There is evidence of autoantibodies such as ANA, rheumatoid factor, and others in some patients . HoweveIn contrast to many autoimmune disorders, IgG4-RD seems to have a skewed T- cell response towards a TH2 phenotype. Increased tissue levels of TH2-cytokines such as Interleukin-4 (IL-4), −5 (IL-5) and −13 (IL-13) were found in IgG4-RD . FurtheWell-fitting to a TH2 immune response, IgG4-RD is characterized by both systemic and localized IgG4 production. It is currently unclear, whether these antibodies are acting as pathogenic antibodies or are just a bystander phenomenon. In healthy individuals, IgG4 is the least abundant IgG subclass molecule accounting for less than 5% of total IgG . In addInterestingly, low C3 and C4 complement levels can be observed in one third of IgG4-RD patients with renal involvement indicating immune complex formation . In typRecent insights into the pathophysiology of IgG4-RD suggest that one of the major drivers of the disease appear to be plasmablasts. Oligoclonal expanded plasmablasts with extensive somatic hypermutation were found to be increased in IgG4-RD patients with active disease. Of interest, depletion of B cells with rituximab leads to a reduction of these plasmablasts and correlates with disease remission . ComparType 1 AIP is the classical presentation of IgG4-RD, while type 2 AIP is not part of the IgG4 spectrum, has distinct histopathological features such as ductal neutrophilic abscesses and ductal injury and is not reviewed here in detail . Type 1Imaging techniques can provide clues to the diagnosis of AIP. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) may demonstrate pancreatic duct strictures and/or stricture of the common bile duct as well as irregular narrowing of intrahepatic ducts. Complete obliteration of the bile duct is unusual. Computed tomography (CT) and magnetic resonance (MR) imaging show focal or diffuse pancreatic enlargement, a peripancreatic capsule-like rim, and late phase contrast-enhancement, which is believed to correspond to peripheral inflammation and fibrosis ].].47]].While radiological and serological studies as well as clinical symptoms may help to establish the diagnosis, in less characteristic cases the final diagnosis needs to be based on histological tissue examination. In type 1 AIP a typical diffuse lymphoplasmacytic infiltrate and a storiform fibrosis are evident. IgG4-positive plasma cells are usually found >50 per high-power field (HPF). Obliterative phlebitis is common, but may be masked by the inflammatory infiltrate. In such cases, an elastic stain can be helpful. Tissue eosinophils are also frequently found. Of note, while there may be a periductal infiltrate, the ductal epithelium – in contrast to type 2 AIP - is preserved . DiagnoUnfortunately, AIP shares many similarities with pancreatic cancer, such as age, male predominance, painless jaundice or swelling of the pancreas . This mThe most characteristic clinical sign of IgG4- related cholangitis at presentation is obstructive jaundice. IgG4-related cholangitis typically affects large bile ducts, while small duct lesions are variable ]. I]. I53]].Histological features of IgG4-related cholangitis are similar to those found in other organs affected by IgG4-RD. Liver biopsies may be inconclusive for a final diagnosis of IgG4-related cholangitis. However, a high number of patients with AIP demonstrate pathological features on liver biopsies. The picture does not appear to be uniform in all patients and is composed of portal inflammation (with or without interface hepatitis), large bile-duct obstructive features, portal sclerosis, lobular hepatitis, and canalicular cholestasis. Multiple features can coexist in single patients . WhetheIf patients are diagnosed with type 1 AIP and have in addition characteristic manifestations on imaging in combination with elevated IgG4 levels, then a diagnosis of IgG4 related cholangitis is usually straightforward. However, in the absence of AIP a histological tissue examination will be required in most patients. Different strategies for tissue sampling are possible. Ampullary biopsies are rather easy to obtain. Sensitivity for IgG4 positive cells is 50%, but samples from this site are lacking information on storiform fibrosis. Bile duct biopsies, which are more challenging to perform, have the same sensitivity for IgG4 positive cells but can demonstrate the full spectrum of pathological features of IgG4-RD. Liver biopsies are invasive and have a sensitivity of only 20% for IgG4 positive cells. However, liver biopsy may be especially helpful in the consideration of differential diagnoses .Neoplastic disease is a main differential diagnosis of IgG4-RD in bile ducts, gallbladder, and liver. Cholangiocellular carcinoma has to be excluded and the differentiation of carcinomas to IgG4-RD can provide difficulties . IgG4 lSince 2010, Riedel’s thyroiditis is considered part of the IgG4-RD spectrum . In conSalivary and lacrimal glands are frequently affected in IgG4-RD. Chief complaints include a persistent asymmetric or symmetrical swelling of the involved glands and impaired secretion. Pain is uncommon . IgG4-rOne of the major mimics of Mikulicz disease is SS . In facOther diseases that need to be distinguished from IgG4-related sialadenitis and dacryoadenitis are lymphomas, sialolithiasis and carcinomas. The latter may be surrounded by an inflammatory infiltrate containing IgG4 positive plasma cells complicating the exact diagnosis .Orbital tumors of the ocular adnexa consist of a heterogeneous group. A large proportion of these tumors are lymphoproliferative disorders (LPDs). These LPDs represent malignant lymphomas and a diverse group of orbital inflammations, such as reactive lymphoid hyperplasia or infiltration . SeveraPathohistologically, characteristic signs of IgG4-RD can be found, but obliterative phlebitis seems to be rare . RatherRetroperitoneal fibrosis (RPF) is a rare disease characterized by the occurrence of fibrosis in the retroperitoneum. RPF usually affects adult middle-aged males and is strongly associated with smoking . ClinicOn CT imaging circumferential arterial wall thickening, which is caused by sclerosing inflammation in the adventitia, is characteristic. Plaque-like lesions can also be seen. Of note, perivascular lesions are usually prominent. Affected vessels demonstrate homogeneous enhancement at the late phase of contrast–enhanced CT. Some cases show dilated lumen of the affected vessels. Arteries penetrating the fibroinflammatory process surrounding the aorta are usually patent . HistopRPF is closely linked to inflammatory aortic aneurysm and thoracic aortitis and is therefore now being summarized as chronic periaortitis . RPF itIgG4-RD can affect the airways, pleura and mediastinum. Patients may present with cough, dyspnea, chest pain or frequently remain asymptomatic ]. I]. I89]].Imaging studies reflect the diverse nature of morphological manifestation of IgG4-related lung disease. A recent study categorized lung findings on imaging into four major subtypes: solid nodular type (nodule or mass); (multiple) round-shaped ground-glass opacity type; alveolar interstitial type ; and bronchovascular type (with thickening of bronchovascular bundles and interlobular septa) .Diagnosis of IgG4-RD in the lungs can be challenging. The lung tends to show a stereotypic morphologic response to a variety of different injuries. Thus, differential diagnostic considerations can be difficult. While fibrosis and obliterative vascular changes are common in solid areas, a characteristic storiform pattern may be lacking on tissue samples. While eosinophils are common as it is the case in other sites of IgG4-RD manifestations, neutrophils may also be seen ]. A]. A92]].Localized or systemic involvement of lymph nodes is common in IgG4-RD . DifferThe main manifestations of IgG4-RD in the kidney is tubulointerstitial nephritis and membranous GN ]. T]. T96]].Histopathology shows typical fibrosis and a lymphoplasmacytic infiltrate with a high number of IgG4 positive cells. IgG and/or C3 granular deposits on the tubular basement membrane are present in a significant number of patients. In addition, a variety of glomerular lesions, mainly different forms of glomerulonephritis, may be additionally present in such patients. All this has raised the suspicion that immune complexes are involved in the pathogenesis of IgG4-related tubulointerstitial nephritis . Of intSeveral structures of the nervous system were found to be involved in IgG4-RD. Peripheral nerves have been reported to be affected by IgG4-RD. Common sites of manifestations are the orbital and spinal nerves with predominant infiltration of the epineurium . Of interest, neurologic symptoms are seldom which seems to be related to the fact that nerve fascicles are usually intact and not damaged . In theIdiopathic cervical fibrosis, a rare sclerosing disease of the neck, seems to be part of the IgG4-RD spectrum . A unusOverall, there is no evidence for treatment options from randomized controlled trials. Clinical experience is that most IgG4-RD patients respond favorably to glucocorticoid (GC) treatment. The effect of GCs has been reported for several sites of IgG4-RD manifestations in different cohort studies. While it appears that spontaneous remissions do occur , the usWhether treatment in patients with IgG4-RD needs to be established depends on the localization and extent of disease manifestation. In some patients with minor involvement , immediate treatment may not be indicated and follow-up may be more appropriate. In other cases with organ dysfunction or pseudotumors  rapid introduction of therapy is necessary to avoid loss of organ function. Thus, treatment decision has to be individualized . Most cIn general, most experts would start with a dosage of 40 mg prednisolone or 0.6 mg/kg of body weight per day and taper the dose over several months, starting with a first dose reduction after 2–4 weeks –119]]. ]. 119]].]. ]. 119A promising treatment strategy in GC- dependent or refractory patients is rituximab (RTX) ,120],,]. RTX ha,]. H]. H22]].Currently, GCs are considered the first line therapy, but randomized trials to determine optimal dose and duration are warranted. In addition, data on the effect of other immunosuppressants are very limited. Further points that need to be addressed in the future are whether all organ manifestations respond similar to treatment and, finally, it needs to be investigated whether non-Asian populations do behave similar to Asian patients, for whom most data are published to date.Further, it remains unclear, how IgG4-RD patients should be followed. IgG4 seems to have some characteristics of a biomarker in patients with elevated IgG4 levels, but it is unclear whether IgG4 levels can be used to guide therapy for instance . FutureJZ received an unrestricted research grant for clinical research on IgG4-RD from Roche. JZ received honoraria for educational activities and advisory board participation from Roche.HP and JZ conceived and designed the manuscript. IP, AW, BO and JZ collected clinical and pathological data of the case vignette. All authors participated in the literature review process and drafted the final manuscript. All authors and the Vasculitis and Orphan Diseases Working Group of the Austrian Society of Rheumatology read the final manuscript and gave approval for the version to be published.


There is little data about adherence to surgical antibiotic prophylaxis guidelines in Brazil.To recognize the institutional initiatives to improve antibiotic prophylaxis practices in neurosurgery.Cross-sectional observational study, carried out with a population consisting of hospitals, medical records of neurosurgical patients, Infection Control Team (ICT), surgical team. The sample of hospitals and surgical team was used for convenience and the records for each hospital was calculated based on 40% of overall adherence.Among the nine assessed hospitals, five achieved quality certification in 2010. The mean weekly hours of ICT per hospital bed and per critical bed was 0.7 and 3.8. Eight hospitals disclosed SSI rates, seven stratified by surgical specialty, six created the antibiotic prophylaxis guidelines with the surgeons’ approval; in four the recommendations were disseminated. Of the 1,011 neurosurgeries 38 were excluded due to lack of records. Overall adherence was 10.0%. The administration route was appropriate in 100%, dose in 90.6%, indication in 90.0% and time of onset in 77.1%. There was a lower adherence regarding duration (26.1%) and a statistically significant association between hours of ICT/ICU bed (p=0.048), dissemination of surgical antibiotic prophylaxis use guidelines (p = 0.035), adherence monitoring (p = 0.024), disclosing of results (p = 0.015) and the period of the day when the surgery occurred (CI=1.7 to 6.6). Among the total of 43 anesthesiologists and surgeons interviewed more than 80% agreed with the institutional guidelines and more than 50% reported they always followed them.The number of ICT professionals/critical bed, dissemination of guidelines, monitoring and disclosing of results are associated with higher adherence regarding antibiotic prophylaxis use; period of surgery, dose (IC 1.72 - 6.65) and initial time (IC 1.12 - 3.01) and surgery type, initial time (IC 1.24 - 4.25) and duration (IC 1.09 - 2.59). The ICT had structure as required by law, but had shortcomings regarding the process of guideline implementation, monitoring and dissemination of results.None declared.


Heroin use and overdose deaths have increased significantly in the United States. Assessing trends in heroin use among demographic and particular substance-using groups can inform prevention efforts.FDA and CDC analyzed data from the National Survey on Drug Use and Health and National Vital Statistics System reported during 2002–2013. Trends in heroin use among demographic and substance using groups were compared for 2002–2004, 2005–2007, 2008–2010, and 2011–2013. A multivariable logistic regression model was used to identify characteristics associated with heroin abuse or dependence.Annual average rates of past-year heroin use increased from 1.6 per 1,000 persons aged ≥12 years in 2002–2004 to 2.6 per 1,000 in 2011–2013. Rates of heroin abuse or dependence were strongly positively correlated with rates of heroin-related overdose deaths over time. For the combined data years 2011–2013, the odds of past-year heroin abuse or dependence were highest among those with past-year cocaine or opioid pain reliever abuse or dependence.Heroin use has increased significantly across most demographic groups. The increase in heroin abuse or dependence parallels the increase in heroin-related overdose deaths. Heroin use is occurring in the context of broader poly-substance use.Further implementation of a comprehensive response that targets the wider range of demographic groups using heroin and addresses the key risk factors for heroin abuse and dependence is needed. Specific response needs include reducing inappropriate prescribing and use of opioids through early identification of persons demonstrating problematic use, stronger prescription drug monitoring programs, and other clinical measures; improving access to, and insurance coverage for, evidence-based substance abuse treatment, including medication-assisted treatment for opioid use disorders; and expanding overdose recognition and response training and access to naloxone to treat opioid pain reliever and heroin overdoses. During 2002–2013, heroin overdose death rates nearly quadrupled in the United States, from 0.7 deaths to 2.7 deaths per 100,000 population, with a near doubling of the rates from 2011–2013  and CDC examined demographic and substance use, abuse, and dependence trends among heroin users in the United States during 2002–2013.Substance use data are derived from the 2002–2013 NSDUH surveys. The NSDUH is conducted annually by the Substance Abuse and Mental Health Services Administration and provides national- and state-level estimates of the use of illicit drugs, including nonmedical use of certain prescription drugs, alcohol, and tobacco among the civilian, noninstitutionalized population aged ≥12 years  was based on diagnostic criteria contained in the  Edition .International Classification of Diseases, Tenth Revision (ICD-10).Mortality data from the 2002–2013 Multiple Cause of Death Files from the National Vital Statistics System were analyzed to identify heroin-related drug overdose deaths . Heroin-First, to assess trends in heroin use in the United States, rates of past-year heroin use per 1,000 persons aged ≥12 years were calculated overall and stratified by sex, age, race/ethnicity, place of residence, annual household income, insurance coverage, and substance use  for each study time interval. In addition, the percentage of past-year heroin users who also used at least one other drug in the past year were calculated.Second, to assess high-risk use of other substances among past-year heroin users, the percentages of past-year heroin users who met diagnostic criteria for past-year alcohol, marijuana, cocaine, or opioid pain reliever abuse or dependence were calculated. All rates are based on U.S Census Bureau population estimates. Two-sided t-tests were used to assess statistically significant differences between 2011–2013 rates and earlier survey year groups. To assess trends, bivariate logistic regression models were applied to test p-values of beta coefficients of the year variable.Third, to identify individual-level risk factors associated with the subset of past-year heroin users who met diagnostic criteria for heroin abuse or dependence, a multivariable logistic regression model incorporating sex, age group, race/ethnicity group, place of residence, annual household income categories, insurance coverage, and the presence or absence of past-year alcohol, marijuana, cocaine, opioid pain relievers, or other psychotherapeutic abuse or dependence was estimated using the 2011–2013 NSDUH data. Associations were reported as adjusted odds ratios with 95% confidence intervals.Finally, Pearson’s correlation coefficient (r) was used to assess correlation between the trend in rates of heroin abuse or dependence and heroin-related drug overdose deaths during 2002–2013.The weighted interview response rate for the NSDUH during the study period (2002–2013) ranged from 72% to 79% each year. The annual average rate of past-year heroin use in 2011–2013 was 2.6 per 1,000 persons aged ≥12 years . This raRates of past-year heroin use were higher among men than women for all time intervals; the rate in 2011–2013 for men was 3.6 per 1,000 compared with 1.6 per 1,000 for women; the gap in rates between men and women narrowed between 2002–2004 and 2011–2013. Both men and women experienced significantly higher heroin use rates during 2011–2013 compared with 2002–2004 and 2005–2007. Among age groups, persons aged 18–25 years experienced the largest increase (108.6%) between 2002–2004 and 2011–2013.The rate of past-year heroin use among non-Hispanic whites increased 114.3% from 1.4 per 1,000 in 2002–2004 to 3.0 per 1,000 in 2011–2013. Past-year heroin use increased across the three annual household income levels  between 2002–2004 and 2011–2013. Individuals with no health insurance as well as those with private or other insurance experienced statistically significant increases in heroin use rates between 2002–2004 and 2011–2013.During 2002–2013, past-year heroin use increased among persons reporting past-year use of other substances. The highest rate was consistently found among users of cocaine; during 2011–2013, this rate was 91.5 per 1,000. During the study period, the largest percentage increase, 138.2%, occurred among nonmedical users of opioid pain relievers. In this group, the past-year heroin use rate increased from 17.8 per 1,000 to 42.4 per 1,000, but was still considerably lower than the rate among cocaine users.Overall, 96% of past-year heroin users reported use of at least one other drug during the past year, and 61% reported using at least three different drugs. In addition, a significant percentage of heroin users met diagnostic criteria for past-year abuse of, or dependence on, other substances . The perThe rate of heroin-related drug overdose deaths was stable at approximately 0.7 per 100,000 during 2002–2006, and began to increase gradually through 2009, when the rate was 1.1 per 100,000. Beginning in 2011, the overdose death rate increased sharply, from 1.4 per 100,000 to 2.7 per 100,000 in 2013, a rate that represents a more than 286% increase since 2002 . There wThe multivariable logistic regression model, adjusted for demographic and specific substance abuse or dependence variables , indicatThere was a significant increase in the rate of past-year heroin use in the United States between 2002–2004 and 2011–2013. Rates remained highest among males, persons aged 18–25 years, persons with annual household incomes <$20,000, persons living in urban areas, and persons with no health insurance or with Medicaid. However, rates increased significantly across almost all study groups. The greatest increases in heroin use occurred in demographic groups that historically have had lower rates of heroin use: doubling among women and more than doubling among non-Hispanic whites. Of particular note is the near doubling in the rate of people with heroin abuse or dependence during the study period, with a 35.7% increase since 2008–2010 alone. This increase parallels the sharp increase in heroin-related overdose deaths reported since 2010.This study also indicates that the problem of heroin abuse or dependence is not occurring in isolation. Past-year alcohol, marijuana, cocaine, and opioid pain reliever abuse or dependence were each significant risk factors for heroin abuse or dependence. Research has identified poly-substance use as a risk factor for overdose death; most overdose deaths involve multiple drugs ,11. In 2The increased availability and lower price of heroin in the United States has been identified as a potential contributor to rising rates of heroin use . AccordiThis study is subject to several limitations. First, NSDUH data are self-reported, and their value depends on the truthfulness and accuracy of individual respondents; under- or over-reporting might occur. Second, because the survey is cross-sectional and different individuals were sampled each year, it is not possible to infer causality from the observed associations. Third, because NSDUH only captures noninstitutionalized civilians, it excludes active duty military personnel, homeless and incarcerated populations, and persons in residential substance abuse treatment programs. Therefore, the drug use estimates in this study might not be generalizable to the total U.S. population, particularly for estimates of uncommonly used drugs like heroin. Finally, the heroin mortality rate is underestimated in the Multiple Cause of Death Files, because the specific drug or drugs involved in the overdose is not specified in approximately 25% of death certificates where the cause of death is drug overdose .These findings indicate significant increases in heroin use across a growing number of demographic groups, including women, the privately insured, and persons with higher incomes. In fact, the gaps in heroin use rates between groups such as men and women, persons with low and higher incomes, and Medicaid and private insurance beneficiaries have narrowed during the past decade. These findings are consistent with recent research documenting significant demographic shifts among people entering heroin addiction treatment over the last 40 to 50 years (A comprehensive response that targets the wider range of demographic groups using heroin and addresses the key risk factors for heroin abuse and dependence is needed. Specifically, a focus on reducing opioid pain reliever abuse is needed given the strong association between opioid pain relievers and heroin abuse and dependence seen in this study, and prior research indicating that the rate of heroin initiation among people with a history of nonmedical use of opioid pain relievers was approximately 19 times greater than those with no history of nonmedical use . InterveKey PointsHeroin use in the United States increased 63% from 2002 through 2013. This increase occurred among a broad range of demographics, including men and women, most age groups, and all income levels.As heroin use, abuse, and dependence have increased, so have heroin-related overdose deaths. From 2002 through 2013, the rate of heroin-related overdose deaths nearly quadrupled.Persons often use heroin with other substances, including marijuana, cocaine, alcohol, and opioid pain relievers. This practice is especially dangerous.Groups with an increased risk for heroin abuse or dependence include men, persons aged 18–25 years, non-Hispanic whites, persons with annual household income less than $20,000, Medicaid recipients, and the uninsured.States play a key role in addressing heroin use, abuse, dependence, and overdose. States can implement strategies to reduce the abuse of opioid pain relievers, the strongest risk factor for heroin abuse or dependence. They can also improve access and insurance coverage for medication-assisted treatment for opioid use disorders and expand access and training for naloxone administration to reverse overdoses.http://www.cdc.gov/vitalsigns.Additional information is available at


A Statement of Concern was issued by Frontiers about the article “Questioning the HIV-AIDS hypothesis: 30 years of dissent” on 26 September 2014. The following statement summarizes the outcome of our investigation and replaces the Statement of Concern.Frontiers has received several complaints from public health professionals related to the article “Questioning the HIV-AIDS hypothesis: 30 years of dissent,” which questions the link between HIV and AIDS. Acknowledging the gravity of these concerns, and the implications that the weakening of the HIV-AIDS link has on public health in general, an internal investigation was conducted.Frontiers in Public Health and Frontiers in Immunology. Based on the conclusion of the investigation the article type of “Questioning the HIV-AIDS hypothesis: 30 years of dissent” has been changed to an Opinion article, which represents the viewpoint of an individual. In addition, a commentary on the article has been published “Commentary on ‘Questioning the HIV-AIDS hypothesis: 30 years of dissent’,” which discusses the concerns and analyzes the viewpoint within a scientific discourse on the topic.During the course of the investigation, Frontiers has sought expert input from the Specialty Chief Editors of the HIV and AIDS section of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Inflammation is a key etiologic component in atherogenesis. Previously we demonstrated that adeno-associated virus (AAV) 2/8 gene delivery of Netrin1 inhibited atherosclerosis in the low density lipoprotein receptor knockout mice on high-cholesterol diet (LDLR-KO/HCD). One important finding from this study was that FOXP3 was strongly up-regulated in these Netrin1-treated animals, as FOXP3 is an anti-inflammatory gene, being the master transcription factor of regulatory T cells. These results suggested that the FOXP3 gene might potentially be used, itself, as an agent to limit atherosclerosis. To test this hypothesis AAV2/8 (AAV)/hFOXP3 or AAV/Neo (control) gene therapy virus were tail vein injected into the LDLR-KO/HCD animal model. It was found that hFOXP3 gene delivery was associated with significantly lower HCD-induced atherogenesis, as measured by larger aortic lumen cross sectional area, thinner aortic wall thickness, and lower aortic systolic blood velocity compared with Neo gene-HCD-treated controls. Moreover these measurements taken from the hFOXP3/HCD-treated animals very closely matched those measurements taken from the normal diet (ND) control animals. These data strongly suggest that AAV/hFOXP3 delivery gave a robust anti-atherosclerosis therapeutic effect and further suggest that FOXP3 be examined more stringently as a therapeutic gene for clinical use. Inflammation is now known to be a key regulatory process that is common denominator among several risk factors for atherosclerosis, in addition to accompanying and associated altered arterial biology , 2. FurtWe recently published a study that demonstrated that AAV/Netrin1 systemic gene delivery was able to inhibit atherosclerosis in LDLR-KO mice on HCD . This waOf these two genes, FOXP3, in particular, the master transcription factor of regulatory T cells (Treg), is intriguing as a therapeutic gene as the Treg phenotype is tied to FOXP3 expression, and Treg affect both innate and adaptive immunity . It is tAll experimental procedures were performed in accordance with protocols approved by the Institutional Animal Care and Usage Committee of the Central Arkansas Veterans Healthcare System, Research and Development, at Little Rock. The project was funded by a Veterans Administration Merit Review grant to PLH.We directly addressed the hypothesis that hFOXP3 gene delivery can inhibit atherosclerosis by using AAV2/8 [AAV2 inverted terminal repeats (ITR) DNA combined with the AAV serotype 8 capsid] gene delivery. The human (h) FOXP3 cDNA was obtained from Open Biosystems and was ligated downstream from the cytomegalovirus immediate early promoter (CMVpr) within the gutted AAV vector dl3-97 to generate AAV/hFOXP3. The AAV/Neo vector has been described previously –14. AAV2Ldlrtm1Her/J) were purchased from Jackson Laboratories . Three groups of male mice, composed of ten animals each at 8 weeks old, were injected with AAV/Neo (positive control group), or AAV/hFOXP3 virus at a titer of 1 × 1010 e.g./ml via tail vein with 200 μL virus per mouse, two booster injections were followed at an interval of 5–6 days. High cholesterol diet (HCD) of 4% cholesterol and 10% cocoa butter diet  was provided from the first day of injection and maintained for the entire study period. Another group of mice fed with a ND was used as a negative control group. The normal background mouse chow was Harlan catalog #7012, and the HCD was #7012, 4% cholesterol/10% cocoa butter, custom formulated by Harlan. All experimental procedures conform to protocols approved by the Institutional Animal Care and Usage Committee of the Central Arkansas Veterans Health Care System at Little Rock.LDLR-KO mice  with a RMV 707B transducer having a center frequency of 30 MHz. Animal preparation was done as described earlier . In brieTotal plasma cholesterol of AAV/Neo and AAV/FOXP3 mice were measured by VetScan VS2  at the Veterans Animal Laboratory (VAMU).Whole dissected aortas were fixed in 10% buffered formalin, inspected under a dissecting microscope and any small pieces of adventitial fat that remained attached were removed very carefully without disturbing the aorta itself and the internal lipid accumulations/plaque. Unstained small animal aortas are normally translucent but show lipid deposition as white areas , 22. Aor2 exposure. Entire aortas, including the aortic arches, thoracic and abdominal aortas, were removed. The aorta was flushed with saline solution and fixed in 10% neutral buffered formalin (Sigma). After 24 h, the fixed tissue was used for paraffin embedding and sectioning for histological analysis. Finally representative sections were hematoxylin and eosin-stained.Twenty weeks after first injection of virus and on HCD, mice were killed by COP < 0.05.Parameters were analyzed with statistics software SPSS 16.0 by nonparametric ANOVA test. If differences were detected between means, Newman–Keuls test was used for multiple comparisons. Difference were considered as significant if We directly addressed the hypothesis that hFOXP3 gene delivery can inhibit atherosclerosis by using AAV2/8 [AAV2 inverted terminal repeats (ITR) DNA combined with the AAV serotype 8 capsid] gene delivery. The AAV2/8-hFOXP3 was delivered by tail vein injection and the animals placed on HCD . Another animal group received AAV2/8-Neo virus delivered by tail vein injection and also placed on HCD, which served as positive controls. Lastly, a group of animals received only a ND and served as negative controls. The animals were then analyzed by high resolution ultrasound and harvested at 20 weeks post-injection/post HCD initiation. Figure p < 0.05) in the hFOXP3/HCD-treated animals than the Neo/HCD-treated animals by HRUS. Moreover, the lumens of the aortas in the hFOXP3/HCD-treated animals versus the ND control animals (negative control) were statistically the same . This evidence of robust efficacy was surprising to us as Netrin1 gene delivery, while showing efficacy, did not give this higher level of efficacy. Moreover, further HRUS analysis, as shown in Figure p < 0.05) in the hFOXP3/HCD-treated animals than the Neo/HCD-treated, positive control animals. Additionally, the wall thickness of the aorta in the hFOXP3/HCD-treated animals and the ND control animals were statistically the same . Thus, this additional evidence of robust efficacy fully supports the lumen area analysis. Figure p < 0.05 than the Neo/HCD-treated animals, again consistent with a lower level of atherosclerosis. In this additional measurement the wall thickness of the aorta in the hFOXP3/HCD-treated animals and the ND control animals were statistically significant. However, it can also be easily observed that the systolic blood velocity of the hFOXP3/HCD-treated animals was much closer (lower) to the ND animals than to the Neo/HCD-treated animals. The correlation between low systolic blood velocity with thinner aortic wall thickness and larger aortic lumens we observed here matches the correlations we have seen in our other anti-atherosclerosis gene delivery studies in our studies of LDLR-KO mice on 4% cholesterol, 10% cocoa butter HCD [High resolution ultrasound (HRUS) was then used to analyze the aortas of at least eight animals per group. Figure tter HCD , 10–14. We further studied the effects of the transgene hFOXP3 transgene on the aorta challenged with HCD by visual inspection. It has already been documented that unstained small animal aortas show lipid deposition as white areas , 22. Figp < 0.05) was observed in regions associated with plaque compared to the opposing non-atherosclerotic region of the same micrograph.Finally, histologic sections were taken across the axis of the aortas to give representative cross sectional views. In Figure not statisticallydifferent from the ND control group. These data suggest that the FOXP3 gene gives a high level of efficacy against HCD-induced atherosclerosis in the well-established LDLR/KO-HCD animal model. None of our other therapeutic gene therapy in LDLR-KO/HCD mouse studies has given multiple aortic parameters which were statistically the same as the ND control group [Our earlier Netrin1 gene therapy study demonstrated that FOXP3 and CD25 were strongly overexpressed in aortas compared to controls , and thaol group , 10–14. ol group , 23–27.Very likely the efficacious ability of FOXP3 lies in its role as the master transcription factor for the Treg development and phenotype. It is known that the loss of FOXP3 expression (or mutation FOXP3) results in increases in chronic autoimmunity . The pheAs we age it is clear that inflammation increases and becomes a major threat to health –35. ThusOne possible mechanism for the AAV/hFOXP3-HCD animal group cholesterol levels being lower than the AAV/Neo-HCD group is the likelihood that Foxp3 is known to induce both transforming growth factor beta 1 (TGFβ1) and interleukin 10 (IL10). Both of these are known to be associated with lower cholesterol levels and both of TGFβ1 and IL10 are known to inhibit the development of atherosclerosis. Both inhibit macrophage trafficking into the arterial wall intima and thereby inhibit macrophage accumulation and foam cell formation. Additionally it has been reported by Klingenberg et al that Foxp3 expression is linked with lower cholesterol levels, as we see here . Thus, i


The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving  Lung cancer remains the most common cause of cancer-related death worldwide . Small-cPatients with limited-stage (LD) SCLC are candidates for a combination treatment of chemo- and radio-therapy and for consecutive prophylactic cranial irradiation (PCI) in case of tumor response. These patients achieve a response rate (RR) over 60%–70%, with a median overall survival (mOS) of 16–24 months and a two-year survival rate of 25% ,4,5. PatIn the last decades, little progress has been made in the treatment of SCLC and the prognosis of these patients remains poor; therefore, novel therapies are urgently required.The knowledge of new potential therapeutic targets might be able to enhance the efficacy of the standard treatments by concurrent administration or as salvage after failure of standard therapies.As happened for non-small-cell lung cancer (NSCLC), the detection of the genomic aberrations underlying SCLC invasiveness and progression is crucial for developing new therapeutic agents and improving patients’ outcome. The main genomic aberrations in SCLC are summarized in TP53 and Rb1 genes are frequent, reaching a very high prevalence (up to 90%); conversely, c-MYC amplification, activating mutations in EGFR, KRAS, PIK3CA genes, c-KIT overexpression and mutation/loss of PTEN are rare events [Inactivating mutations in e events ,9,10,11.et al. [PIK3CA was identified as one of the prevalent aberrant genes.Recently, Wakuda et al.  assessedPIK3CA mutations were detected in 36% and 6% of all cases, respectively [Other studies have been conducted using different high-throughput tumor genotyping platforms. In one study, 51 resected SCLC samples were analyzed and genetic alterations in PIK3CA pathway and ectively .TP53 and Rb1 genes were observed in almost all cases. Mutations in the PTEN gene, responsible for stimulating the activation of PI3K pathway, were identified in 10% of cases. No mutation in the PIK3CA gene was detected. Other gene alterations included: inactivating mutations in CREBBP and EP300 genes, MYC and FGFR1 genes amplifications. In particular, PTEN mutations and FGFR1 amplifications may represent potential druggable genome alterations. Other studies confirmed that, although rare events, FGFR1 gene alterations predict sensitivity to FGFR inhibition both in vitro and in xenograft models [In addition, two independent genomic analyses identified specific driver alterations in SCLC. In the first study , 99 SCLCt models ,16.TP53 and Rb1 genes were frequently mutated. Mutations involving other genes, not known previously in SCLC, were detected. Furthermore, SOX2 amplification/overexpression was observed in 27% and RLF–MYCL1 gene fusions in 9% of SCLC samples. These alterations may be considered as oncogenic-drivers and consequently as two possible druggable targets.In the second study , 80 humaIn vitro, SCLC cells were sensitive to PARP inhibitors both alone and in combination with chemotherapy; moreover, PARP1 levels correlated with PARP inhibitor sensitivity, supporting it as potential target in SCLCs.By using an integrative proteomic and transcriptomic analysis and after a comparison between 34 SCLC and 74 NSCLC cell lines, other researchers investigated proteomic profiling with the aim to identify dysregulated pathways in SCLC . In SCLCData from the literature show that also genomic aberrations in MET/HGF axis and its downstream modulators seem to be involved in SCLC invasiveness and progression. In contrast to the strong scientific evidence on NSCLC, few data are available on SCLC and MET to date. According to these concepts, in conjunction with insufficient treatment options in SCLC and its poor prognosis, we decided to discuss the role of the aberrant MET/HGF pathway in SCLC for the possible implications in clinical research and drug development.MET proto-oncogene is located on chromosome 7q21-31 and encodes the receptor tyrosine kinase MET. It was first identified in a case of human osteosarcoma tumor cells exposed to N-methyl-N0-nitroso-guanidine which led to a fusion protein between the translocated promoter region (TPR) on chromosome 1 and MET domain on chromosome 7 [The mosome 7 . Its priThe c-MET receptor is a disulfide-bound heterodimer expressed primarily in different epithelial cells and comprising an extracellular α-subunit and a transmembrane β-subunit. The extracellular portion includes: the Sema domain, responsible for its bond with the β-chain, PSI  domain and four Ig-like repeated domains (IPT), connecting the PSI domain to the transmembrane helix. The intracellular domain includes: a juxtamembrane (JM) sequence which downregulates the MET kinase activity through the phosphorylation of Ser975 and Tyr1003 residues; a catalytic region which positively modulates the kinase activity and, finally, a carboxy-terminal multifunctional docking site, responsible for the recruitment of many intracellular transducers and adaptors  Figure .HGF/SF is a protein belonging to the serine protease family and produced in cells of mesenchymal origin, such as fibroblasts and smooth muscle cells. It is secreted as a single chain, biologically inactive, and converted into its mature form by extracellular proteases, after a cleavage process. Its biologically active form consists of a disulfide-bond heterodimer containing an α-chain and a β-chain. The first contains an amino-terminal hairpin loop (HL) domain followed by four peculiar domains, known as kringle domains; the latter contains a serine proteases homology (SPH) domain that lacks proteolytic activity . HGF/SF Upon binding HGF/SF, MET receptor dimerizes resulting in the activation of tyrosine kinase domain through a process of trans-phosphorylation of the two tyrosine residues Y1234 and Y1235 and, in turn, of two docking tyrosines (Y1349 and Y1356). This process leads to the recruitment of several adaptor proteins (Gab1 and Grb2), which in turn activate different intracellular signaling pathways , responsible for driving proliferation, cell survival, morphogenesis, cell scattering, migration and invasiveness ,29,30,31In normal tissue, the interaction between c-MET receptor and HGF is crucial for embryonic development and organ regeneration.During embryogenesis a normal function of HGF/MET axis plays an important role in liver, placenta and muscle formation ,33,34, aIn the adults, the MET-driven signaling mechanisms are involved in liver, kidney and epidermis regeneration, after exposure to acute and chronic injuries ,39,40,41In several tumors, MET signaling pathway is aberrantly activated and represents one of the most important mechanisms of progression and invasiveness ,43. It iThe MET pathway can be aberrantly activated as a consequence of HGF or HGFR transcriptional upregulation, gene amplification and, rarely, as the final event of a MET gene mutation ,55,56. Oet al. [Approximately 20 years ago, Rygaard et al. , evaluatet al. . DemonstLater, another study demonstrated that the HGF/c-MET pathway is functional in SCLC. c-MET receptor expression was heterogeneous in various SCLC cell lines and highly phosphorylated when stimulated by its ligand; their interaction led to increased motility, cell migration and invasion, as well as higher production of reactive oxygen species (ROS). As a consequence of the aberrant c-MET/HGF signaling pathway, other adhesion proteins, such as paxillin, FAK, and PYK2, were active. By using an HSP90 inhibitor, all SCLC cell lines showed cell growth arrest and apoptosis, opening the way to a possible novel therapeutic approach .Another study demonstrated that, in response to HGF, several specific c-MET tyrosine residues were phosphorylated, including Tyr1313, the binding site for PI3K. LY294002, a PI3K inhibitor, led to a significant reduction in cell growth, viability of SCLC, cell motility and migration. Therefore, PI3K had to be considered one of the c-MET downstream signaling pathways .c-MET gene.As previously mentioned, particularly in NSCLCs and upper gastrointestinal cancers, tumor progression can be sustained through an aberrant activation of the c-MET/HGF pathway due to c-MET/HGF overexpression, copy number gain/gene amplification or c-MET mutations. Conversely, according to available data for SCLC, the alterations able to induce an aberrant activation of c-MET are limited only to rare somatic mutations in the MET coding sequence have been reported as somatic and germline variants in many solid tumors, particularly in hereditary and sporadic papillary renal cell cancer [Activating point mutations in the l cancer , but alsl cancer .et al. [c-MET gene, identified novel mutations in 3 out of 10 SCLC cell lines and in 4 out of 32 SCLC tumors. In cell lines, two different c-MET missense mutations (R988C and T1010I) in the juxtamembrane (JM) domain and one alternative transcript involving exon 10 were discovered for the first time. In SCLC tumors, two missense mutations were identified; one in the JM domain (T1010I) and the other in the Sema domain (E168D). In addition, 2 two-base-pair insertional mutations within the pre-JM intron 13 were detected. The presence of the JM domain mutations led to a constitutive protein tyrosine phosphorylation and resulted in altered morphology, adhesion and motility conferring an increased metastatic phenotype. Later, the same authors identified the E168D mutation in the Sema domain in one NSCLC tumor tissue (0.8%), the R988C mutation in the JM domain in one NSCLC cell line and both R988C and T1010I mutations in one tumor tissue (0.8%) [Ma et al. , sequence (0.8%) .In another study evaluating 44 SCLC tissue samples, none of the previous mutations was found, but two novel mutations were identified. There was a missense mutation in the JM domain (T995I) in a sample and a single amino-acid substitution in the Sema domain in two tumor tissues .et al. reported a mutation rate of 25% in cell lines and 6.5% in clinical specimens [Voortman pecimens . Found mpecimens .These results confirmed the low frequency of these mutations in SCLC , as wellThere are different strategies developed to inhibit aberrant c-MET/HGF signaling pathway, including antibodies directed against HGF, c-MET receptor or decoy-MET, and small molecule directed against MET receptor tyrosine kinase domain or against downstream signaling modulators.et al. [et al. [in vitro and in xenograft models, opening the way to a potential use of these technologies for the treatment of SCLC. Unfortunately, to date, no data from phase III trials are available on activity of MET inhibitors in SCLC.In SCLC, the proof of principle that MET could be an attractive therapeutic target was demonstrated by Ma et al. . By usin [et al. . In theiIn addition to its significance as predictor of poor outcome, in SCLC, the aberrant c-MET pathway plays a critical role as predictor of chemo-resistance.MET-mutant SCLC cell lines was predictive of poor outcome and the use of PHA-665752, a selective c-MET inhibitor, inhibited colony formation and invasiveness [Different studies showed that the presence of MET activation in siveness .in vitro by using MET inhibitors, such as crizotinib and PHA-665752 and translated in vivo in a significant decrease in tumor growth and local invasion. Furthermore, when crizotinib was added to etoposide, the highest inhibition rate both in vitro and in vivo was shown, suggesting that MET inhibition by crizotinib restored chemosensitivity [In two recent studies, the same authors showed a correlation between HGF exposure/levels and epithelial-mesenchymal transition (EMT); this phenomenon resulted in a mesenchymal phenotype and in a worse outcome ,67. ThisMET gene copy number and Top-I nuclear expression was detected, particularly in ED-SCLC tumors. Moreover, in SCLC H82 cells, a direct correlation between HGF stimulation and increased expression of phospho-MET and Top-I was demonstrated. This meant that Top-I activity was modulated by activation of the HGF/MET axis, suggesting a potential synergism of a dual block. Indeed, different cell lines were treated with SU11274  and SN-38 (the active metabolite of irinotecan and a specific Topoisomerase-I inhibitor). Su11274 and SN-38 were highly active alone and even more in combination, particularly in H69 cells harboring R988C MET mutation; conversely, H82 cells (wild-type MET) were less sensitive to c-MET and Top-I inhibitors.Recently, another research group published the results of a study, confirming that a combination treatment might be a reasonable choice to treat a SCLC patient subgroup . A signiet al. [More recently, according to previous data, Ozasa et al.  addresse2 IV days 1–3) plus cisplatin (75 mg/m2 day 1) or carboplatin (AUC 5 day 1) every three weeks up to 4–6 cycles followed by maintenance treatment with investigational drug. Primary end-point was overall survival (OS); secondary end-points were objective response rate (ORR), progression-free survival (PFS), pharmacokinetics and safety. Median OS in patients treated with rilotumumab plus chemotherapy (62) was 12.2 months and did not differ significantly than OS in the two other groups . There was also no difference between the three arms both in terms of PFS  and ORR . Two patients in the rilotumumab arm experienced a complete response. The treatment combinations were safe and tolerable without unexpected toxicities. Combined with chemotherapy, investigational drug exposure was comparable to that under monotherapy and did not affect the pharmacokinetics of chemotherapy. Survival analyses in biomarker and pharmacokinetic subgroups are ongoing.Data from phase 1/2 studies about chemotherapy in combination with AMG-102 (rilotumumab), a fully human IgG2 monoclonal antibody directed against HGF, have been presented. A Phase 1 dose-escalation study  of AMG-4SCLC remains one of the most aggressive tumors with a poor prognosis. The clinical outcome of these patients has reached its plateau with the standard treatment and new therapies are urgently required. In order to validate new effective drugs in SCLC, we first have to define the biological mechanisms underlying cancer promotion and progression, as was the case for NSCLC.Thanks to the introduction of genomic and proteomic platforms, we will be increasingly able to understand the different molecular profilings of SCLC and to identify specific druggable targets, such as PTEN, FGFR1, SOX-2, PI3K, PARP and others.To date, no target therapies are available in the treatment of SCLC. Paradoxically, several potential targets have been identified in SCLC and a plethora of promising biological agents are under investigation in clinical trials. Anti-angiogenic  drugs, mTOR , IGF1R (AMG479), HDAC , HSP90 (STA9090), Hedgehog (LY2940680), PARP (veliparib) inhibitors, anti-Bcl-2 compounds , immunomodulating agents (ipilimumab) either alone or in combination with chemotherapy are in development for SCLC in different setting.in vitro and in xenografts that the inhibition of MET signaling cascades by using selective MET inhibitors correlates with cell growth arrest and apoptosis. Furthermore, the combination strategy (MET inhibitors plus cytotoxic agents) results in an additive antitumor effect and also restores chemo-sensitivity in MET-mutated resistant cells. Unfortunately, these results have as of yet not been confirmed in clinical practice. In fact, many MET inhibitors are currently being tested in several trials, but none of them has been certified for clinical use and no conclusions on their efficacy can be given. This discrepancy between preclinical and clinical assessments has to be ascribed both to the investigational drugs (pharmacokinetics and pharmacodynamics), and tumors’ (molecular targets) and patients’ selection .MET/HGF axis seems to be one of the most functional signaling pathways involved also in SCLC tumorigenesis and progression. Unlike NSCLCs and other tumors, in SCLC, the aberrant MET pathway is related only to activating mutations involving specific domains of c-MET receptor gene. These mutations are responsible for the constitutive activation of the MET signaling pathway and its downstream modulators, leading to an aggressive phenotype. Several data have demonstrated both In conclusion, MET inhibitors may also be a promising arm in the battle against SCLC, but more questions remain unsolved. We have thus far been unable to accurately identify the tumors and patient subgroups that can benefit from MET inhibition, as well as the best treatment and combination strategies and the most appropriate setting. Finally, we need to detect new circulating biomarkers to predict a better outcome from MET inhibitors. Only in finding the answers to these questions will we be able to improve the treatment strategy of SCLC and, ultimately, the outcome of these patients.


Assessment of antibiotic prescribing is an important component of antimicrobial stewardship for the prevention of the misuse of antibiotics . The aimAntibiotics prescribed to patients admitted through the ED of CHB, over a three-week period in June - July 2014, were assessed for compliance with guidelines according to the documented indication for treatment. Data was obtained from patient charts and drug kardexes. Antibiotics prescribed by the ED and the subsequent antibiotics prescribed by the admitting team were recorded and evaluated for compliance with CHB antibiotic guidelines.119 patients admitted through the ED in the study period were evaluated; of these, 24 patients (20%) were prescribed an antibiotic and included in the audit. 73% of the prescriptions given by the ED were compliant with the current CHB Guidelines for the use of Antibacterials. 88% of the subsequent prescriptions given by the admitting medical team were compliant with guidelines and 77% of the subsequent prescriptions given by the admitting surgical team were complaint with guidelines. Only 20% of community acquired lower respiratory tract infection (CA-LRTI) cases had a CURB-65 score calculated in correlation with antibiotic prescription. All non-compliance was due to choice of antibiotic.The majority of patients prescribed antibiotics admitted to CHB through the ED were commenced on antibiotics compliant with CHB guidelines with appropriate documentation and dose. There is, however, improvement required to raise this level of compliance and the results from this audit will form the basis for further prescriber education.


Recently developed new transducers for ultrasonic transmission, which can be embedded right into concrete, are now used for non-destructive permanent monitoring of concrete. They can be installed during construction or thereafter. Large volumes of concrete can be monitored for changes of material properties by a limited number of transducers. The transducer design, the main properties as well as installation procedures are presented. It is shown that compressional waves with a central frequency of 62 kHz are mainly generated around the transducer’s axis. The transducer can be used as a transmitter or receiver. Application examples demonstrate that the transducers can be used to monitor concrete conditions parameters  as well as damages in an early state or the detection of acoustic events . Besides application in civil engineering our setups can also be used for model studies in geosciences. Concrete is a complex, multi-phase material. It is made of hydraulic cement, water and aggregates in lots of variations. The first two ingredients start to hydrate and crystallize when in contact with each other. This process is fast in the first hours and days, but can continue for months or years. The aggregates, gravel or crushed stone of various types and sizes (µm-cm range), are used as a filler to save cost and energy. Concrete contains pores, either filled with unbound water or air.Concrete is the material most produced by mankind. It is considered to be strong, resistive and durable. Some early concrete structures as the cupola of the Roman Pantheon are standing tall after almost 2000 years. However, under certain conditions  concrete constructions require attention. For example the apparently ever increasing traffic load  on bridges may lead to deterioration much earlier than expected at the time of design. Currently, inspections are still mainly based on visual methods, but sophisticated non-destructive methods are used more and more often. The use of bridge instrumentation increases rapidly . HoweverUltrasonic transducers with frequencies from 25 kHz to 400 kHz have been used for concrete since decades. They are used in the lab on samples (and sometimes on site) in transmission mode to measure elastic properties and to assess degradation. New point contact transducers have revolutionized the use of echo techniques for thickness measurements and structural imaging. Even the detection of voids in tendon ducts seems to be possible Stress ;,20;19,20Degradation (microcracking)  objects as aggregates, small cracks or reinforcement rebars. At the same time the amplitudes of the ultrasonic waves are affected by geometrical and intrinsical  attenuation. From literature it is known that the following factors  have an influence on ultrasonic velocities and the amplitudes:Traditional time of flight measurements are considering direct waves only . The area of influence is limited to a narrow band (“first Fresnel zone”) between transmitter and receiver  left.Lots of other waves, which arrive much later at the receiver, have undergone reflections and scattering, potentially even wave type conversion. It is quite often difficult to evaluate these arrivals separately. However, they contain useful information as they are covering larger areas of the concrete body  right anThe traditional way to interpret transmission data (“time of flight”) is described in the corresponding standards on ultrasonic pulse velocity measurements . Pic−5 [Recently methods have been introduced to ultrasound investigations in concrete, which are using the entire signal and not just the first arrival. Online monitoring systems can benefit from the use of correlation calculations (of a time series measured during/after load/damage against a reference one). Some more details and preliminary results have been published in . For qua−5 . The met−5 ,27,28,293 concrete block (“GK32”) has been cast in the BAM labs for various tests of the embedded ultrasonic transducers  and all consecutive measurement under various load conditions. Even small load changes of 5 kN can clearly be seen, even in the presence of noise. Tomographic coda wave evaluation of the entire embedded transducer data set showed that the area of significant influence of the load is limited to about 0.3 m away from the loading point .etc., all of which are caused by internal stress variations [The acoustic emission (AE) technique monitors acoustic waves produced by newly developing micro cracks, opening and closure of existing cracks, friction, riations . Based oriations . If a seLaboratory tests on the use of the embedded transducers for AE were conducted using a similar specimen as discussed in In a second set of experiments pencil breaks on the specimen’s surface (a commonly used test for AE systems according to ASTM E976) have been used. Again, the experiments have been repeated three times at points marked by circles in The experiment shows that the joint use of the embedded transducers in active and passive measurements is possible. The source needs to be within the sensor network to allow for an accurate localization. Future research will focus on the appropriate distance between the receivers for detecting and localizing acoustic emissions of different frequency and energy.This application example illustrates the use of the embedded transducers for model experiments in geophysical research. In geophysics, the validation of new approaches for measurement techniques or data evaluation is quite often limited to simulations as the real subsurface  can never fully be explored. So full scale experiments often lack of ground truth. Scaled model experiments might be of help.Time reversal is a technique to backproject elastic waves, which have been generated by events  inside a medium and registered by some sensors inside the medium as well or at the surface, numerically or physically back to their source point. Very few sensors are required for scattering media. In fact, the signals at the sensor, which have started as a spike at the source but then have been reflected, scattered, attenuated and dispersed on the way, can be focused back to the source point . Recently a method to improve the results using deconvolution was proposed . The tra3). These samples have been put into climate chambers or CDF test devices to evaluate the influence of temperature [The embedded transducers have been applied in two other fields of applications so far. In several experiments we have used them to instrument concrete lab samples  will follow.The ultrasonic transducers developed for embedment in concrete have shown to be valuable tools for various tasks in structural monitoring. They met our expectations in frequency (around 60 kHz), directivity  and range (at least three meters). The transducers proved to be very robust. We have developed deployment systems for existing and newly built structures. Early versions are now embedded and used in lab samples and real structures for a few years and are still fully operational.We have shown that the transducers are useful in a lot of applications. They can be used for active transmission experiments as well as for collecting passive acoustic emission data. They proved to be useful in lab samples, scale experiments and real world monitoring systems. Load changes can be detected and localized as well as environmental influences  and various degradation mechanisms. In connection with novel interpretation tools as coda wave interferometry we have very sensible methods for the detection of changes in concrete at hand.The embedment in concrete has various advantages: The coupling to the concrete is constant, transducers at lab samples have not to be removed before putting them into climate chambers, chemical baths or similar and installations are more vandal proof and less accident prone on real constructions.


Regions Hospital started a multidisciplinary antibiotic stewardship program (ASP) in 1998. The program effectively shut down from 2002–2004 as key personnel departed and was then restarted but without the dedicated pharmacist and infectious diseases physician. Purchasing data (in dollars or dollars/patient/day) unadjusted for inflation served as a surrogate marker of antibiotic consumption. These data were reviewed monthly, quarterly, and yearly along with antibiotic susceptibility patterns on a semi-annual basis. Segmented regression analysis was use to compare restricted antibiotic purchases for performance periods of 1998–2001 (construction), 2002–2004 (de-construction), and 2005–2011 (reconstruction). After 4 years (1998–2001) of operation, a number of key participants of the ASP departed. For the following three years (2002–2004) the intensity and focus of the program floundered. This trend was averted when the program was revitalized in early 2005. The construction, deconstruction, and reconstruction of our ASP provided a unique opportunity to statistically examine the financial impact of our ASP or lack thereof in the same institution. We demonstrate a significant economic impact during ASP deconstruction and reconstruction. Antibiotic stewardship is gaining universal acceptance as a valuable tool to limit bacterial antibiotic resistance, maximize clinical outcome with antibiotic therapy, minimize antibiotic induced adverse events, and to control cost. A recent policy statement by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) recommends 1) antibiotic stewardship programs (ASP) be mandated through regulatory mechanisms; 2) antibiotic stewardship be extended into the ambulatory healthcare setting; (3) there should be formal education regarding antibiotic resistance and stewardship; (4) antibiotic usage data be collected and shared for inpatients and outpatients, and (5) antibiotic stewardship research is needed [ antibiot antibiotRegions Hospital  is a 455 bed, level-one trauma center, with ~120,000 patient days of care per year. Among the hospital units are multiple intensive care units, including a burn unit. In 1998, Regions Hospital started an ASP with many of the key elements identified later in the IDSA ASP position paper published in 2007 [Hospitals that have committed to an ASP experience a significant reduction in antibiotic cost following implementation ,2,3,4,5.Monthly antibiotic purchasing for 1998 through 2010 were considered and analyzed in terms of total restricted and unrestricted antibiotics purchases, restricted antibiotics per patient/day, total antibiotics, total antibiotics per patient/day, and percent restricted to total antibiotics, with total purchase costs serving as a surrogate marker for utilization. Total patient days used census figures for adult inpatients including ICUs. Segmented regression analysis for interrupted time series  was usedData were missing or questionable for 4/156 monthly time periods. Thus we used the mean total restricted antibiotics for all other time periods to replace these four values of total restricted antibiotics. Other variables for restricted antibiotics per day and percent-restricted antibiotics were adjusted accordingly based on this modification.The antibiotic formulary was divided into two groups of agents, restricted and non-restricted; restricted classification was driven primarily by cost, dosing difficulty and risk of toxicity , and/or agent novelty . A patieA list of patients receiving restricted antibiotics was generated daily by the hospital’s information systems department, and the ID physician, ID pharmacist, pharmacy, and chair of the P&T committee received copies to identify for possible interventions. In most cases, the pharmacy personnel and ID consultation personnel worked in tandem; however, if the pharmacist encountered a patient not also being seen via an ID consultant, the pharmacist contacted the prescribing physician and discussed possible treatment options. Unresolved cases between the pharmacist and prescriber were then referred to the ID consultant for further review and action.In 1998, the only readily available and widely used metric to measure antibiotic consumption was antibiotic purchase data. As external comparisons of our performance were not possible, a decision was made to collect data over time and compare the internal performance of our ASP yearly. Over time, to maintain consistency in our internal comparisons, we have continued to use this metric. As a result, parameters of performance included total antibiotic purchases for the calendar year, total antibiotic cost per patient per day, restricted antibiotic cost per patient per day, percent of antibiotic dollars spent on restricted antibiotics, and the percent of antibiotic purchases as compared to total in patient drug purchases for the calendar year. The obvious drawback in using purchase data is that increases or decreases in annual antibiotic purchasing patterns are subject to the magnitude of inflation, better purchasing strategies, contract price changes, rebates, generic drug status, introduction of expensive new agents that are widely used, and now the purchasing and hording of antibiotics in short supply. However, this variability remained in play over the duration of the program. The clinical pharmacist and pharmacy director reviewed antibiotic use in the form of purchasing data monthly. These data were summarized and reviewed quarterly by the antibiotic subcommittee and passed on through the hospital committee structure. Annually and semiannually, the antibiotic subcommittee reviewed bacterial antibiotic susceptibility for Gram positive and Gram-negative pathogens as an alert for changing patterns of antibiotic susceptibility. The clinical microbiologist stratified these data by intensive care units and as comprehensive  data. Based on antibiotic subcommittee decisions, any changes of 5% of more in susceptibility from year to year were considered to be significant and warranted further action as necessary. Antibiotic susceptibility data were reviewed for the first six months of the year and at the end of the 12 months. The clinical microbiologist also alerted the team to any unusual organisms or unusual resistance patterns between the 6 and 12 month periods.A comprehensive yearly presentation of antibiotic purchase data and bacterial susceptibility data was prepared and shared with the infectious diseases physicians group, our hospital vice president, key physicians, the Pharmacy and Therapeutics Committee, the antibiotic subcommittee, and the pharmacy director. Minutes of the report are passed along to our Patient Care and Executive Committees.After initially establishing a baseline in 1998–2001, antibiotic costs  initially rose with the patient census 2002–2004 during ASP deconstruction and cost fell after reconstruction 2005–2010 despite continued increases in patient census . RestricBeginning in 2001, the antibiotic stewardship program experienced the loss of several key initial personnel on the ASP team, including the primary ID physician, the clinical microbiologist, and two clinical pharmacists who worked primarily with the stewardship program. With the departure of these individuals, the intensity and operation of the ASP floundered. Instead of a focused daily responsibility, these tasks were reassigned to the decentralized clinical pharmacists and made part of other daily clinical responsibilities. The program was revitalized in 2005 with a re-focusing of efforts on antimicrobial stewardship.p = 0.0021) and restricted antibiotic cost/patient/day (p = 0.0037) due to the deconstruction of the stewardship team . However, once reconstruction of the team occurred , a significant negative change  was observed .Using cost data for 2002, 2003 and 2004 and projecting future costs using the slope of that data into 2005 and beyond versus what actually happened after reconstruction clearly demonstrate the successful impact of restoring the program . Figure p = 0.0039) and total antibiotics per day (p = 0.01) was also observed related to the deconstruction of the team. However, when reconstruction of the team occurred, a significant decrease in cost (p < 0.0001 for both) was observed . A significant increase in cost for both overall total antibiotics (p = 0.0135) was observed related to deconstruction. Once the reconstruction occurred, a significant negative change (p = 0.0033) was observed (R2 = 0.58).Further, a significant positive change in percent restricted to total antibiotics (In 1998, we initiated our hospital wide effort at antibiotic stewardship. Elements of our initial program aligned well with the position adopted by the IDSA with regard to antibiotic stewardship goals and daily practice elements. On a monthly, quarterly, and yearly basis, we monitored overall antibiotic purchases , the perAnother expected lesson over the 14-year experience is that a program of antibiotic stewardship is likely to change over time. Pharmacy and medical personnel will change and the various tools that can be used to affect prescriber behavior may need to be rotated into and out of the stewardship program. Further, some elements, such as our trial of the antibiotic order form, did not work for us and failed to have the desired impact in our system. Stewardship programs over time are also likely to experience a fatigue factor especially in a teaching institution as prescribers rotate in and out throughout the year. Likely each institution will have to find the right stewardship niche that works for them and that may change somewhat from year to year. Lastly, while these programs are attractive, barriers often exist to procuring enlisting the specified personnel identified in the IDSA position paper and the provision of financial support for dedicated time on task .The IDSA primary goal for antibiotic stewardship is to optimize antibiotic clinical outcomes while minimizing unintentional consequences of antibiotic therapy . We haveMost ASPs can demonstrate an initial reduction in antibiotic costs. In this report we demonstrate the initial financial effect of our ASP, the increasing costs associated with the interruption of the program, and the return of financial stability when the program was restarted. These unique circumstances lent themselves to a segmented time sequence series analysis, which provided statistical evidence of the ASP effect on antibiotic costs.We demonstrate the need for the development and continued support of an ASP. Antibiotic costs were significantly influenced by the presence or absence of a functioning ASP during 14 years of operation/observation at Regions Hospital. The successes reported here should encourage hospitals and health-care providers to initiate and continue ASPs.