MET mutation or MET gene amplification. New therapeutics that selectively target c-Met or HGF, or that target c-Met and a wider spectrum of interacting tyrosine kinases, will be discussed.Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met , a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, angiogenesis, and motility. The c-Met pathway also stimulates tissue repair in normal cells. A body of past research shows that increased levels of HGF and/or overexpression of c-Met are associated with poor prognosis in several solid tumors, including lung cancer, as well as cancers of the head and neck, gastro-intestinal tract, breast, ovary and cervix. The HGF/c-Met signaling network is complex; both ligand-dependent and ligand-independent signaling occur. This article will provide an update on signaling through the HGF/c-Met axis, the mechanism of action of HGF/c-Met inhibitors, the lung cancer patient populations most likely to benefit, and possible mechanisms of resistance to these inhibitors. Although c-Met as a target in non-small cell lung cancer (NSCLC) showed promise based on preclinical data, clinical responses in NSCLC patients have been disappointing in the absence of  MET gene on chromosome 7 [MET gene produces a protein that is a tyrosine kinase receptor. The c-Met receptor, whose only known ligand is hepatocyte growth factor (HGF) [The c-Met oncogene was first isolated from a human osteosarcoma cell line, which contained a DNA rearrangement: the translocated promoter region (TPR) locus on chromosome 1 was fused to the or (HGF) , exists or (HGF) . In the or (HGF) . HGF in or (HGF) , and in or (HGF) .HGF, such as the c-Met receptor, is produced in an inactive state and then converted into its active form via proteolysis. The active state of HGF consists of four Kringle domains K1–K4), an amino (N) domain and a serine protease homology domain (SPH), whose interactions facilitate receptor dimerization , an amin,6. Binding of HGF to c-Met leads to autophosphorylation on the tyrosine residues Y1234 and Y1235 at the tyrosine kinase domain, activating further autophosphorylation of Y1349 and Y1356 residues near the COOH terminus. This activates the phosphotyrosine multifunctional docking site, which recruits intracellular adapters through Src and activates downstream signaling events . Another2 release occurring after COX2 induction can increase activity of matrix metalloproteinases that release EGFR ligands such as amphiregulin [It is also well-established that activation of other tyrosine kinases participate in maximizing HGF/c-Met effects. The epidermal growth factor receptor (EGFR) plays a paramount role in potentiating c-Met–mediated cell proliferation, cell invasion and cell survival . EGFR aciregulin . EGFR aniregulin ,14. Otheiregulin . RAS proiregulin . Hypoxiairegulin . A complGenerally, activation of c-Met by HGF is controlled through release of ligand by a paracrine process in which mesenchymal cells and cells of the innate immune system secrete HGF, followed by ligand activation on the cell surface and internalization of the activated receptor. In embryonic development, the HGF/c-Met system is active as organs are forming, but is largely silent in the adult, unless triggered during wound healing. In a variety of cancers however, the HGF/c-Met pathway is constitutively activated. The mechanism of activation include gene amplification, over-expression of the c-Met and/or HGF proteins, increased cross-signaling between c-Met and other tyrosine kinases, and MET gene mutation. Amplification of the MET gene has been found in a number of solid tumor types, including gastric cancer, where sensitivity to a c-Met tyrosine kinase inhibitor was high, and the c-Met pathway was important in maintaining cell survival . Cancer c-Met overexpression often occurs in the absence of gene amplification. In breast cancer, c-Met overexpression was an independent predictor of aggressive malignancy with poor patient survival . OverexpA rare mechanism that leads to c-Met activation is activating mutations. Both missense germ line mutations in the tyrosine kinase domain and rare sporadic mutations have been detected in less than 1% of renal carcinoma, melanoma, small-cell lung carcinoma and mesothelioma . OncogenMET amplification. In an in vivo model, c-Met inhibitors such as crizotinib and golvatinib arrested the cell cycle and led to decreased SCLC cell growth and metastasis. This indicates that some SCLC may be sensitive to inhibition of the c-Met pathway. MET amplification was also shown to promote resistance towards anti-cancer drugs in SCLC [MET gene amplification. Inhibition of c-Met caused anti-tumor effects on these chemoresistant SCLC cell lines both in vitro and in vivo. Thus HGF/c-MET-mediated signaling may be important in growth and progression of SCLC [Accumulating evidence shows that activation of the HGF/c-Met pathway in SCLC cells also leads to increased tumor growth and survival. Many small cell tumors have increased plasma levels of HGF and SCLC can also contain  in SCLC . In an o in SCLC . A recen of SCLC .The HGF/c-Met axis has been targeted in several ways for potential cancer treatment, including targeting receptor activation and ligand binding. Multiple agents  have completed or are currently in clinical trials. Active clinical trials targeting this pathway, including new investigational agents, are summarized in Synthetic small-molecule c-Met TKIs are low molecular weight molecules that compete for the adenosine triphosphate (ATP) binding site of the c-Met tyrosine kinase domain . This prVolitinib (Savolitinib) is a selective c-Met inhibitor that blocks c-Met activity in an ATP-dependent manner. It has been shown to have anti-tumor activity in gastric and papillary renal carcinoma ,40 in xe2 and was well tolerated [2 was observed in patients with MET amplification [SAR125844: This derivative of triazolopyridazine was first identified as a selective inhibitor of both wild type c-Met and c-Met with kinase domain mutations in gastric cancer cell lines. Xenograft studies with MET amplified gastric tumor cells showed significant tumor growth inhibition because of antiproliferative and proapoptotic effects of the drug and down regulation of PI3K/AKT and RAS/MAPK pathways . Pharmacfication .Tepotinib (EMD1214063) is a c-Met inhibitor with ≥1000 fold selectivity for c-Met as compared to other kinases. It inhibited both HGF-dependent and HGF-independent c-Met phosphorylation in vitro in lung and gastric cancer cell lines and showed tumor regression in xenografts model . TepotinCapmatinib (INCB28060) was identified as a very potent selective competitive inhibitor for c-Met, inhibiting activity at picomolar concentrations and displaying ≥10,000 selectivity for c-Met compared to other kinases. Effective anti-proliferative and anti-apoptotic properties of capmatinib were observed in c-Met driven mouse tumor models . In NSCLAn approach to improve responses to TKIs in patients lacking specific genetic alterations is to broaden the kinases being targeted. A number of TKIs are being tested clinically with ability to block multiple receptors . ForetinThe multi-kinase inhibitor glesatinib (MGCD265) targets c-Met, VEGFR1, VEGFR2, VEGFR3, TIE2 and RON . It is cSeveral types of biological antagonists have been developed that either neutralize HGF, c-Met, or the HGF-c-Met interaction. These agents are in various stages of development and can be used as a monotherapy or in combination with other targeted therapies. HGF-competitive analogs compete with the ligand for receptor binding on the cell surface. They do not lead to c-Met signaling and cannot induce c-Met dimerization, while HGF neutralizing antibodies bind to the fully processed HGF molecule, preventing interaction of HGF with the receptor. c-Met competitive variants competitively displace HGF and do not cause dimerization of the receptor. Decoys of c-Met have also been produced that bind to intact c-Met or HGF to disrupt dimerization of native c-Met receptor . The following biological antagonists have been, or are currently being, clinically evaluated:Onartuzumab (MetMAb): Onartuzumab is a monoclonal antibody against c-Met that obstructs the binding of the HGF α-chain to its c-Met ligand binding domain . After sEmibetuzumab LY2875358): Emibetuzumab is a bivalent antibody raised against c-Met that blocks HGF binding to c-Met, preventing signaling. Unlike onartuzumab, it leads to internalization and degradation of c-Met. In a study using mouse xenograft models, emibetuzumab blocked both HGF-dependent and -independent tumor growth . A phase: EmibetuLY3164530 is a bispecific monoclonal antibody that binds and degrades both c-Met and EGFR, which has shown strong ability to inhibit signaling from both receptors. In a xenograft model , LY31645JNJ-61186372: The anti-tumor activity of JNJ-61186372, a c-Met and EGFR bispecific antibody, was investigated in in vitro and in vivo studies involving NSCLC tumor models, and showed strong ability to reduce tumor growth . The safSAIT301: This is a humanized monoclonal antibody that targets the alpha chain of the extracellular domain of c-Met , preventMET gene [MET gene amplification and/or c-Met overexpression (ABT-700 (h224G11): The anti-c-Met monoclonal antibody ABT-700 has anti-tumor effects in lung cancer xenografts with amplification of MET gene . An ongopression . MET-positive patients with adenocarcinoma [MET amplification [Rilotumumab (AMG-102): Rilotumumab was the first HGF inhibitor to reach phase 3 clinical testing. It binds to the HGF β-chain, inhibiting HGF binding to c-Met . Rilotumarcinoma . Howeverfication . Rilotumfication . Rilotumfication , suggestFiclatuzumab (AV-299): Ficlatuzumab is a humanized anti-HGF neutralizing antibody. In a phase I trial, ficlatuzumab alone had a maximum tolerance dose of 20 mg/kg in patients with NSCLC. The toxicities observed were low grade . There wEGFR-mutant human NSCLC cells [TAK-701: This humanized monoclonal antibody against HGF was active in overcoming gefitinib resistance observed in LC cells . During LC cells . YYB-101LC cells ,74. Ther®) that functions as a neutralizing protein for both VEGF and HGF [ARGX-111 is a c-Met targeting human monoclonal that elicits antibody-dependent cellular cytotoxicity as part of its mechanism of action. A phase 1 study  showed a and HGF . It cont and HGF . The rat and HGF . MP0250  and HGF , and is DN30: This c-Met antibody under development for clinical use acts through several novel mechanisms to disrupt c-Met signaling, including causing degradation of the receptor. The mechanism of action of DN30 involves down-regulation of c-Met, in which receptor bound to DN30 at the cell surface is removed by proteolytic cleavage, resulting in shedding of the extracellular domain . The cleMultiple gene mutations and mechanisms are known to contribute to resistance to HGF/c-Met pathway blockade, such as HER, BRAF and KRAS pathways, or mutations in c-Met ,81. For MET gene are noted compensatory mechanisms that also are factors in acquired resistance in EGFR mutant NSCLC patients [The tumor microenvironment is engaged in resistance to molecular-targeted therapies. Stromal cells influence the action of cancer therapeutics, and stromal changes such as release of HGF can provide an alternate stimulus when other pathways are blocked. In a study using a RAF inhibitor, increased HGF secretion was identified as a prime mechanism for resistance . Althougpatients ,87. Alecpatients . Howeverpatients . This isMET, such as amplification or exon 14 deletion. Some patients with acquired EGFR TKI drug resistance that involves up-regulation of the c-Met pathway also have responded. Acquired resistance that eventually develops after initial response to c-Met pathway inhibitors often involves activation of parallel signaling pathways or induction of HGF secretion. Several new classes of HGF/c-Met inhibitors may show expanded activity in patients with MET genetic alterations, and might also prove effective in NSCLC with overexpressed c-Met in the absence of genetic abnormality. These include the multi-kinase inhibitors that block c-Met as well as a range of other kinases; the kinase inhibitors and monoclonal antibodies against c-Met that also cause degradation of the c-Met protein; and the bivalent antibodies that can block several pathways simultaneously. The newer c-Met TKIs with improved c-Met selectivity compared to earlier agents most likely will only be active as single agents in the presence of MET oncogene addiction. Combinations of kinase inhibitors that target both upstream and downstream in the signaling pathway, or reduce parallel kinase signaling from other receptors, could improve clinical benefit, but toxicity has been a problem with these targeted combinations in the past. Combining a c-Met TKI or antibody with an HGF neutralizing antibody may improve efficacy. Other approaches to expand efficacy of HGF/c-Met targeting include combining these agents with inhibitors of the viability or function of stromal cells such as tumor-associated fibroblasts, endothelial cells, or macrophages, or using immunotherapy in combination with HGF/c-Met agents. Such strategies might also increase activity of these drugs in a wider range of patients who lack MET genetic abnormalities. Although the c-Met pathway is frequently overactive in NSCLC, inhibiting either the c-Met receptor itself or its ligand HGF has not proven effective as single therapy in unselected NSCLC patients. Clinical response to these agents has to date been largely restricted to NSCLC patients with genetic alterations in


Sustained antibiotic resistance gene enrichment within the microbiota did not occur, as the enrichment effects disappears by week 4 of follow-up. DISCUSSION/SIGNIFICANCE OF IMPACT: The use of amoxicillin to treat uncomplicated SAM has therapeutic benefits visible by anthropometry and by content of the gut microbiota. The main concern with the use of prophylactic antibiotics for this purpose is the effect on antibiotic resistance gene enrichment in the children’s microbiota. This concern was not supported here. The benefit/cost ratio for the use of prophylactic antibiotics for individuals in this cohort is positive when weighing effects on anthropometry, microbiome, and antibiotic resistance. The results of this study impact the treatment of millions of children each year at nutritional therapy clinics around the world.OBJECTIVES/SPECIFIC AIMS: A course of oral broad-spectrum antibiotics frequently has a positive effect on morbidity and mortality in severe acute malnutrition (SAM), but the actual mechanism for this effect is unknown. This mechanism is especially important to find and quantify because of the possibility that using antibiotics prophylactically may accelerate the danger from antibiotic resistant infections. This study aims to answer (1) how antibiotic therapy improves the nutritional recovery and (2) how much it affects the prevalence of resistance genes in the microbiome. METHODS/STUDY POPULATION: Stool samples were collected from children with SAM between 6 and 60 weeks of age who received either one week of amoxicillin or placebo (n=164). The children were followed for 12 weeks with longitudinal sampling, and a subset were followed out to 2 years. All samples were frozen at −80°C and prepared for metagenome shotgun sequencing via the Illumina Nextera platform. RESULTS/ANTICIPATED RESULTS: Antibiotic treatment at the start of the nutritional program is associated with significant improvements in weight gain, mid-upper-arm circumference, and graduation from the treatment program. It is also associated with qualitative decreases in early-life fermenter Lactobacillus and known enteropathogen Campylobacter. Two years after the use of amoxicillin, the Shannon diversity index is significantly higher than that of malnourished children (effect size 0.507, 95% CI: 0.204–0.630,


Crystalline hydrophilic additives are increasingly used as efficient methods for reducing water permeability in concrete. Their effectiveness in hindering water penetration has been proven in different cementitious materials, although scarce information has been reported concerning their action mechanism. In the present work, the efficacy of a hydrophilic blended crystalline mix  as a water-reducing additive has been confirmed. Furthermore, an extended study about how the presence of the additive influences both the fresh state and the hardened state properties is presented. Finally, characterization techniques such as Mercury Intrusion Porosimetry (MIP), X-ray Powder Diffraction (XRD) and Back-Scattered Scanning Electron Microscopy (BSEM) with Energy Dispersive X-ray analysis (EDAX) have been used for deducing the mechanism of the additive. No significant deleterious influence on the concrete properties due to the addition of the additive has been detected. In fact, the additive seems to have provided a positive influence on the concrete given that a slight reduction in the w/c ratio for similar consistency has been detected, with the subsequent improvement of the compressive strength values. Its effectiveness as a water permeability reducing additive has shown encouraging results having reduced the water permeability by approximately 50% during testing. The action mechanism of the studied additive seems to be related to hydration reactions in the presence of water, producing new solid amorphous phases in the concrete bulk.  Resistance against water permeability is a key parameter related to the durability of concrete structures under hydrostatic service conditions. Different types of chemical admixtures, known as permeability-reducing admixtures (PRAs) , are comHydrophobic or water repellents admixtures and inert and/or chemically active fillers are proposed as PRANs suitable for damp proofing under non-hydrostatic conditions . CrystalIn general, crystalline chemicals are hydrophilic materials possessing the ability to react with cement in the presence of water, increasing the density of calcium silicate hydrates within the concrete and producing pore-blocking precipitates in the capillaries and microcracks . Also, sDifferent studies have reported the permeability improvement in concrete when incorporating crystalline admixtures ,9. PzderZheng et al. recently reported a study  focused In the present work, the water-penetration performance of a commercial crystalline admixture, Krystaline Add1, has been assessed. Krystaline Add1 is a blended dry powder admixture based on a proprietary mix of organic and inorganic materials able to create a hydrophilic technology that increases the density of calcium silicate. The microscopic modifications related to the water permeability improvements are discussed in this study.The chemical composition of the hydrophilic crystalline additive tested in this study is shown in 3 of Krystaline Add1 additive was used, while the other concrete mix was made without this additive. The w/c ratio was changed to obtain the same consistency in both concrete mixes. The efficacy of the crystalline additive was tested in two conventional concrete mixes. A CEM I 42.5R according to EN 197-1 was used. Two crushed siliceous gravels (12/20 mm and 4/12 mm) and one siliceous sand (0/4 mm) were used as aggregates. In one of the concrete mixes, 1 kg/mThe fresh state of the fabricated concrete mixes was assessed by measuring the consistency according to EN 13350-2 and the density according to EN 12350-6. Different concrete samples were fabricated in order to evaluate the modifications promoted by the Krystaline Add1 additive in the hardened state of the concretes. Three 100 x 200 mm cylindrical concrete specimens for each age and concrete type were produced, and their compressive strengths were measured at 7 and 28 days according to EN 12390-3 standards. During the 90 day curing process, all samples were submerged in water at 20 °C. Three samples of cylindrical concrete specimens each measuring 150 mm × 300 mm and for each type of concrete were taken for conducting permeability testing according to EN 12390-8. Prior to commencing the permeability testing, the concrete specimens were cured by submerging in water at 20 °C for 90 days. The samples were then put in an apparatus connected to a normal air compressor that ensures that 5 bars compressed air continuously. Each specimen was placed on the apparatus ensuring that the water pressure acts upon the upper face where the watertight seal between apparatus and the concrete specimen is located. Water pressure of 5 bars was then applied for 72 h. The specimens were subsequently removed from the apparatus and subjected to the Brazilian tensile strength test, according to EN 12390-6, in which the specimen was split in half perpendicular to the upper face on which the water pressure was applied. Methylene blue powder was then added to the surface of each sample face by using a brush thus clearly revealing the water penetration depth. The penetration depth was measured in ten different points along the penetration front of each sample size by using a digital caliper. The mean and the maximum water penetration depths were recorded for all concrete samples. 3 of each concrete sample was used to measure the total porosity and the pore size distribution by using a Mercury Intrusion Porosimeter . X-ray Diffraction patterns  were also recorded in powdered samples at room temperature at intervals of 5° < 2θ < 60°, with a step size of 2θ = 0.01973° and 0.5 s per step. Finally, back-scattering electron microscopy (BSEM) with Energy Dispersive X-ray microanalyses were used. The scanning electron microscope used was a Hitachi S-4800  equipped with an energy dispersive analyzer BRUKER 5030 . The samples were embedded into an epoxy resin, cut, polished and then coated with carbon. The size of the prismatic specimens used for the microstructural evaluations was not the perfect one considering the maximum aggregate size used in the concrete mixes. However, the authors wanted to use the exact same concrete batch in all the studies, and they wanted to obtain samples with a higher specific surface than that obtained with the standardized prisms for concrete samples with the same maximum aggregate size in order to increase the interaction between the water and the cement matrix.Additionally, 40 mm × 40 mm × 160 mm prismatic specimens were also cast to evaluate the microstructure of the differing concrete mixes for the purpose of explaining the mechanism used by the Krystaline Add1 additive. Three specimens of each concrete type were placed in a receptacle with a water level that covered up ¾ of the samples and cured for 90 days. Afterwards, some parts of the specimens were cut and analyzed using differing techniques. Samples were taken from the upper side of the specimen  and from the lower side (the submerged part of the sample). In all the cases, 1 cmFirst of all, the modifications promoted by the addition of Krystaline Add1, as it relates to the concrete characteristics, are shown with consideration to both the fresh and the hardened state. Secondly, the mechanism involved in the performance of this additive as it relates to the modifications promoted in the microstructure due to the interaction of the batched concretes with water is assessed.One of the primary significant aspects noted with the addition of the Krystaline Add1 additive when batching fresh concrete is the reduction of the w/c ratio for a similar slump considering the very low content of Krystaline Add1 used. The reference concrete (REF) slump was 8 cm while the Add1 concrete slump was 9 cm indicating an increase in flowability of the Add1 treated concrete over the REF concrete. However, the w/c of the REF concrete was 0.55 while the Add1 concrete was only 0.51, showing a reduction of water for an equal slump. This clearly demonstrates that even though a lower w/c ratio was used (7% less) in the Krystaline Add1 batch, its slump was slightly higher 12.5%). The obtained results indicate a significant filler action by the additive that increases the fluidity of the concrete mix. The increase in fluidity of fresh concrete due to the use of very small powdered particles is well known. For example, lime powder, basalt powder and marble powder are widely used to increase the fluidity of self-compacting concretes and flow-able concretes .5%. The ,14,15. O3 for REF concrete and 2.37 g/cm3 for Add1 concrete. Therefore, Krystaline Add1 additive does not generate any significant modification in this parameter.The density of the fresh concrete mixes was very similar in both cases: 2.35 g/cmWith respect to the water penetration tests, 3 samples that were partially in contact with water for 90 days. Firstly, the porosity microstructure of the concrete samples was assessed. Once the efficacy of using Krystaline Add1 additive to reduce the water penetration into the concrete matrix had been proven, the mechanisms involved were evaluated by using 40 × 40 × 160 mm3S [The porosity results obtained with this additive are different from those obtained with other powdered materials that also promote decreased water permeability such as limestone filler. The use of powdered materials with low particle sizes promotes the well-known filler effect. These powdered materials complete the fine portion of the granulometric curve of cement without a relevant increment on water demand, improving the cement packing and blocking the capillary pores. They also constitute nucleation sites of calcium hydroxide crystals and calcium silicate hydrate gels (C-S-H gels) at early hydration ages, accelerating the hydration of clinker particles, especially the C3S ,21,22,23Therefore, neither the porosity microstructure nor the crystalline component plays a significant role in the decrease of the water permeability detected in Add1 treated concrete. Thus, the possible formation of amorphous phases when adding Krystaline Add1 additive was evaluated by BSEM-EDAX. 2, Na2O and Al2O3, which agree with the chemical composition of the additive used. Therefore, they must be the anhydrous powdered particles of the Krystaline Add1 additive. The hydrated gel surrounding the particles has a different composition with respect to the hydrated gel further from the particles. While the latter has the typical composition of a C-S-H gel of a conventional Portland cement paste, the former has higher Na2O and Al2O3 (and even MgO) contents and lower CaO contents. The main difference detected between the cement matrix of the REF concrete and the Add1 concrete is the formation of the small phases shown in 2, Na2O and Al2O3, are detected in the REF concrete matrix. The EDAX microanalyses of For comparison reasons, According to these results, when water penetrates into the Add1 concrete matrix, the powdered particles from the additive react with the water forming calcium-silicate hydrate gels enriched in Na and Al. Furthermore, possible reactions of these new gels together with the C-S-H gels of the cement pastes cannot be rejected due to the continuing Na content decrease detected from the additive particle to the C-S-H gels. This reaction between both amorphous phases could be indicative of high compatibility of the new hydrates and the cement paste. Then, the formation of Na and Al (even Mg) enriched C-S-H gels must be the mechanism involved in the reduction of the water permeability stimulated by the addition of Krystaline Add1 additive. The formation of these calcium-silica hydrated gels with alkalis and Al in their composition has certain similarities to the hydration products formed from crystalline additives used in self-healing concretes, although with different morphology ,25,26. TFinally, with respect to the EDAX microanalysis made in the C-S-H gel of both concretes, a C/S ratio of 2.10 ± 0.33 is measured in the REF concrete while 1.94 ± 0.29 is measured in the Krystaline Add1 concrete. Considering the size of the microanalysis area, the obtained differences could not be relevant. However, a slight decrease in the C/S ratio in the C-S-H gels when adding Krystaline Add1 additive has not been dismissed, since the results shown in this study clearly identified a decrease of the C/S ratio in the C-S-H gels surrounding the powdered particles of the additive when it reacted with the incoming water. In any event, the differences detected are not very significant. Therefore, two types of chemical reactions could explain the mechanisms involved in the effectiveness of the additive evaluated. On one hand, the hydration of the un-hydrated additive particles when water penetrates into the concrete matrix takes part. This hydration of the additive particles generates the formation of amorphous calcium-silica hydrate gels-Na and Al enriched. On the other hand, these new amorphous hydrated gels could also react with the surrounding C-S-H gels previously formed during the cement hydration. This second type of chemical reactions is proposed due to a progressive Na content decrease being detected from the calcium-silica hydrate gels-Na and Al enriched to the C-S-H gels that are close to the formers, that is, the further away from the Na enriched gels, the lower the Na content of the C-S-H gels is and vice versa. In fact, if both types of calcium-silica gels did not react, the inclusion of Na in the C-S-H gels would not have this strong relationship with their distance from the Na enriched gels. Within this regard, the slight decrease of the C/S ratio detected in the C-S-H gels could be related to the introduction of Na into its composition, as previously reported elsewhere, considering C-S-H gels with low C/S ratio . A commercial additive used to reduce water permeability in concrete has been evaluated in the present paper. A complete characterization of the modifications promoted by this additive in the concrete performance has been evaluated and the mechanisms involved in its activity have been analyzed. The use of this additive in the concrete does not result in any loss of performance for concrete and even improves the mechanical properties by reducing the w/c ratio. The efficacy of the additive to reduce the water penetration into the concrete matrix has been also proven. The mechanisms involved in this reduction of the water penetration into the concrete matrix do not seem to be related neither to a filler action nor by the formation of crystalline hydration products, but instead two types of chemical reactions could explain its activity. On one hand, the hydration of the un-hydrated additive particles when water penetrates into the concrete produces amorphous calcium-silica hydrated gels-Na and Al enriched. On the other hand, these new amorphous gels could react with the surrounding C-S-H gels formed during the cement hydration, thus indicating the high compatibility of the new hydrates and the cement paste.


The prestressed near-surface mounted reinforcement (NSMR) using Fiber Reinforced Polymer (FRP) was developed to improve the load bearing capacity of ageing or degraded concrete structures. The NSMR using FRP was the subject of numerous studies of which a mere portion was dedicated to the long-term behavior under fatigue loading. Accordingly, the present study intends to examine the fatigue performance of the NSMR applying the anchoring system developed by Korea Institute of Construction and Building Technology (KICT). To that goal, fatigue test is performed on 6.4 m reinforced concrete beams fabricated with various concrete strengths and developed lengths of the Carbon Fiber Reinforced Polymer (CFRP) tendon. The test results reveal that the difference in the concrete strength and in the developed length of the CFRP tendon has insignificant effect on the strengthening performance. It is concluded that the accumulation of fatigue loading, the concrete strength and the developed length of the tendon will not affect significantly the strengthening performance given that sufficient strengthening is secured. Prestressed concrete (PSC) eases the control of the deflection and cracks in concrete structures by reducing the tensile stress through the introduction of a compressive force by means of tendons embedded in the tension zone of the structure. Ageing bridges may experience loss of their function and performance that should be recovered or improved by strengthening the structure. The strengthening of PSC girder bridge is achieved by enlarging the girder, external prestressing, carbon fiber bonding or steel plate bonding. The external bonding reinforcement (EBR) methods were applied to improve the performance by bonding the reinforcement on the tensile zone of the concrete member using an adhesive. This reinforcement took first the form of a plate made of steel that started to be replaced by Fiber Reinforced Polymer (FRP) since the mid of 1980s.The near-surface mounted reinforcement (NSMR) resembles the above mentioned external bonding reinforcement but embeds the FRP plate or bar in a groove cut with a definite depth in the concrete surface. De Lorenzis et al.  reportedIn view of the efficiency of FRP, both NSMR and EBR cannot exploit fully the maximum performance of FRP due to the premature occurrence of debonding at the reinforcement-concrete interface. As passive strengthening methods, their effect appears only under the application of additional live loads without clear improvement of the serviceability in term of cracking and deflection recovery. Accordingly, numerous researchers attempted the prestressed NSMR achieving the synergy of both NSMR and prestressing . For theIn particular, FRP is checked to apply in many sites because of strong points such as high strength, light weight, chemical resistance and need to secure reliability through real size test because of low applications, low construction cases, problems with design criteria ,5,6,7,8.Despite of the numerous studies related to NSMR using FRP, a very few of them studied the long-term behavior under fatigue loading . The repAccordingly, the present study intends to examine the fatigue behavior of the prestressed NSMR applying the anchoring device developed by KICT. The cumulated effect of the fatigue load on the strengthening performance is examined by means of a series of fatigue tests performed on 6.4 m reinforced concrete beams fabricated with various concrete strengths and developed lengths of the Carbon Fiber Reinforced Polymer (CFRP) tendon. The fatigue tests were conducted in two stages. The first stage applied 2 million loading cycles and the second stage applied static loading until failure of the specimens to measure the residual strength after the accumulation of fatigue.This study intends to examine the fatigue performance of the prestressed NSMR. To that goal, the specimens are designated as shown in As shown in The structural tests were executed in two stages. The first stage applied 2 million loading cycles and the second stage applied static loading until failure of the specimens to measure the residual strength after the accumulation of fatigue.y and 0.7fy, where fy is the steel yield stress. Accordingly, the present study adopted fatigue load ranging between 60 kN and 100 kN. In addition, the loading rate was set to 2.0 to 3.0 Hz. The fatigue test conducted using a dynamic actuator with capacity of 1000 kN to apply 2 million loading cycles. Static load of 100 kN was applied after 1, 1000, 5000, 10,000, 100,000, 1 million and 2 million cycles to measure the deflection, strain and cracks and examine the eventual progress of damage according to the accumulation of fatigue.The size of the fatigue load was determined with reference to the stress of the tensile member using the calculation method suggested by ACI, AASHTO and CSA ,17,18,19Static loading was performed by 4-point loading on all the specimens using static actuators  with capacity of 2000 kN to measure the deflection and strain according to the gradual increase of the load until failure. As shown in −6 and 6500 × 10−6 during the tensioning work.The tendon used in the fabrication of NSM specimens is a CFRP rod with diameter of 10 mm and its mechanical characteristics are arranged in The residual strength can be measured using the static loading results listed in The ductility of the specimens with respect to the concrete strength is shown in This study examined the strengthening performance of the prestressed NSMR according to the accumulation of fatigue loading. To that goal, fatigue test was performed on 6.4 m reinforced concrete beams fabricated with various concrete strengths and developed lengths of the CFRP tendon. The fatigue tests were conducted in two stages. The first stage applied 2 million loading cycles and the second stage applied static loading until failure of the specimens to measure the residual strength after the accumulation of fatigue. The following conclusions can be derived.The observation of the fatigue behavior with respect to the concrete strength revealed that the deflection exhibited the largest increase rate below 1000 cycles, increased gradually until 100,000 cycles and stabilized until 2 million cycles. The strain measured at the center of the CFRP tendon showed also similar tendency according to the accumulation of fatigue cycles. Moreover, the same tendency was also observed for the fatigue behavior according to the developed length of the tendon.The analysis of the strain developed during tensioning and the strain caused by the accumulation of fatigue revealed that all the specimens presented similar behavior and strain at the rupture of the tendon. In addition, the tendon could reach its tensile performance before rupture under the loading applied after the compressive failure of concrete. This indicated that the accumulation of the fatigue load had poor effect on the loss of the performance like the tension force of the CFRP tendon.The results of the static loading test with respect to the concrete strength showed that the accumulation of the fatigue load did not provoke damage nor performance loss of the prestressed NSMR specimens. Moreover, the test results of the specimens with concrete strengths of 30 MPa and 40 MPa appeared to be practically identical to those of a previous experiment without fatigue load accumulation. This indicated that the strengthening performance of the prestressed NSMR is insensitive to the accumulation of fatigue loading and the concrete strength given that sufficient strengthening is secured.The insignificance of the change in the performance provided by the specimens with developed lengths of 67%, 80% and 93% of the CFRP tendon demonstrated that the developed length of the tendon has practically no effect on the strengthening performance given that appropriate tensioning has been secured. However, an appropriate and sufficient developed length should be secured to prevent the anchor be installed outside the effective depth d in which case shear failure would occur due to the increase of inclined cracks.The analysis of the ductility with respect to the concrete strength and the developed length of the tendon provided results complying with those of previous research. All the specimens exhibited nearly the same ductility according to the concrete strength and the ductility appeared to increase with longer developed length of the tendon. Accordingly, adopting longer developed length of the tendon was recommended for securing stable ductile behavior.


Antibiotics are among the most commonly misused of all drugs, which results in antibiotic resistance and waste of resources and it has not been studied in Ethiopia. Therefore, this study was carried out to assess antibiotic use–related problems and their costs among patients hospitalized at the surgical ward of Jimma University Medical Center.Hospital-based prospective observational study was used to assess the prevalence, cost, and determinants of antibiotic use–related problems; multiple stepwise backward logistic regression analysis was done for a P value of < 0.25 to look for predictors of antibiotic use-related problems. Written informed consent was obtained and confidentiality was secured.Among 300 participants, antibiotic use–related problems (ABURPs) were found in 69.3% of the study participants. The direct total cost attributed to these problems was approximated to a minimum of 2230.15 US$. Independent predictors for antibiotic use–related problems were: indication for antibiotic use like: use of antibiotic for prophylaxis; p < 0.0001, antibiotic use for both therapeutic & prophylaxis; p < 0.0001, CDC wound class I and II; p = 0.016 and; p = 0.002 respectively, overall poly-pharmacy and greater than 2 antibiotic exposure during hospital stay; p = 0.019and p = 0.006 respectively and hospital stay for ≥21 days; p = 0.007.The prevalence of antibiotic use-related problems was high and resulted in extra cost. Antibiotic use for prophylaxis, prophylaxis, and treatment, poly-pharmacy, greater than 2 antibiotic exposures during the hospital stay, CDC wound class I and II, and duration of hospital stay of ≥ 21 days was found to be independent predictors of antibiotic use–related problems. Surgery is an essential component of health care . Antimic“catastrophic” or “big risk of terrorism”; to human beings, is a very real possibility for the 21st century than antibiotic use for therapeutic purpose alone. Surgical discipline or disorder related to Cardiothoracic was about 96% time less likely to incur ABURPs  than upper and lower GIT. Patients with CDC wound class I and II were about 15 times more likely to have ABURPs  and  respectively, than patients with no wound. Overall poly-pharmacy relative to patients with no poly-pharmacy and greater than 2 antibiotic exposure relative to less than 2 antibiotic exposure during hospital stay were about 3 times more likely to have ABURPs  and about 5 times more likely to have ABURPs  respectively. Referral was about 98% times less likely to incur ABURPs  than patients whose clinical outcome was improved. Similarly, compared with those who stayed for less or equal to 20 days, patients that stayed for ≥ 21 days were about 4 times more likely to have ABURPs  .It was found that overall ABURPs were 69.3% among study participants. Similar to this study, in a different area of the world antibiotic use related problems were reported with different prevalence; in Ethiopian University Hospitalsit ranges from 75.7% to 80.6%, 29;and7The most frequent type of overall antibiotic use-related problem identified was dose too low, (32.9%) followed by dose too high (20%) in JUMC surgery ward, compared to study done in JUMC medical ward  needs adDose too high (20.7%) in this study was slightly higher than that of JUMC medical ward (15.1%) Hospitalized patients initially on intravenous antibiotics can be safely switched to an oral equivalent, within the third day of admission once clinical stability is established and for a disease that can be treated by the oral antibiotic. BecauseIn this study, the total cost attributed to direct ABURPs among 132 patients in the 3-month period was approximated to a mean (SD) 16.9 US$(18.26) and at least 2230.15 US$. The true extra cost related to ABURPs might be greater than what was mentioned above, because of the study was interventional and the cost of an instrument like IV set, laboratory and treatment costs for morbidity secondary to antibiotic use related problems were not included. Other studies reportwere almost similar to our study finding. But, still extra cost added to patients was higher than that of Iran; this miIn this study, multivariate logistic regression analysis showed that indication for antibiotic use for SAP was 7 times, p < 0.0001 and dual indication (therapeutic & SAP) was 8 times,p< 0.0001 more likely to incur ABURPs, respectively. As other study indicated, the reason for this was related to the absence of well-defined guideline and poor knowledge of SAP protocols . On the The prevalence of ABURPs was high; especially in SAP use compared to therapeutic, which deserve rapid action to preserve those antibiotics in the market and to reduce the occurrence of surgical site infection (SSI). The most prevalent type of ABURPs was dose too low followed by dose to high. The consequences of irrational antibiotic use resulted in high extra cost. An indication of antibiotic use for prophylaxis, a dual indication (prophylaxis and treatment), poly-pharmacy, greater than 2 antibiotic exposures during a hospital stay, CDC wound class I and II, and duration of hospital stay for ≥ 21 days was found to be independent predictors for antibiotic use-related problems in the study area. To reduce the problem, government and stakeholders should prepare and implement the strategy that was found efficient and effective by research, in order to reduce inappropriate use of antibiotics and extra cost.S1 FileAttached as a separate file with title name of “supporting data/ data collection tool”.(DOCX)Click here for additional data file.S1 Dataset(SAV)Click here for additional data file.


The pervasive, often inappropriate, use of antibiotics in healthcare settings has been identified as a major public health threat due to the resultant widespread emergence of antibiotic resistant bacteria. In nursing homes (NH), as many as two-thirds of residents receive antibiotics each year and up to 75% of these are estimated to be inappropriate. The objective of this study was to characterize antibiotic therapy for NH residents and compare appropriateness based on setting of prescription initiation.This was a retrospective, cross-sectional multi-center study that occurred in five NHs in southern Wisconsin between January 2013 and September 2014. All NH residents with an antibiotic prescribing events for suspected lower respiratory tract infections (LRTI), skin and soft tissue infections (SSTI), and urinary tract infections (UTI), initiated in-facility, from an emergency department (ED), or an outpatient clinic were included in this sample. We assessed appropriateness of antibiotic prescribing using the Loeb criteria based on documentation available in the NH medical record or transfer documents. We compared appropriateness by setting and infection type using the Chi-square test and estimated associations of demographic and clinical variables with inappropriate antibiotic prescribing using logistic regression.P = .023. Regardless of infection type, patients who had an antibiotic initiated in an outpatient clinic had 2.98  times increased odds of inappropriate use.Among 735 antibiotic starts, 640 (87.1%) were initiated in the NH as opposed to 61 (8.3%) in the outpatient clinic and 34 (4.6%) in the ED. Inappropriate antibiotic prescribing for urinary tract infections differed significantly by setting: NHs (55.9%), ED (73.3%), and outpatient clinic (80.8%), Antibiotics initiated out-of-facility for NH residents constitute a small but not trivial percent of all prescriptions and inappropriate use was high in these settings. Further research is needed to characterize antibiotic prescribing patterns for patients managed in these settings as this likely represents an important, yet under recognized, area of consideration in attempts to improve antibiotic stewardship in NHs. The pervasive, often inappropriate, use of antibiotics in healthcare settings has been identified as a major public health threat due to the resultant widespread emergence of antibiotic resistant bacteria . In nursAlthough commensurate attention has been given to improving antibiotic stewardship within NHs –10, littWe conducted a detailed medical record extraction involving all NH residents at five southern Wisconsin facilities who had an antibiotic prescribing event from January 2013 through September 2014. Antibiotic events were identified from NH facility pharmacy records. Outpatient clinic and ED health records were reviewed when available. The location of the antibiotic start was determined by review of orders (which includes prescriptions sent from outpatient clinics or the ED), transfer documents, and documentation in the NH records. These NH facilities are required to document an assessment of any resident change-in-condition, regardless of whether they are transferred to another care setting. The change-in-condition documentation in ideal circumstances includes a detailed record of the signs and symptoms of the resident. The decision to seek care for a NH resident at an outpatient clinic or the ED could result from a wide variety of scenarios that range from patient or family member request to an acute change in condition that the NH cannot manage to routine follow up after a procedure. Most commonly this decision results from a shared decision making process that occurs between the NH staff, the resident, the resident’s family and the resident’s primary care provider.All facilities were skilled nursing facilities located in Wisconsin, a state in the Midwest United States. Four of the facilities were located in Dane County which is the second largest County in Wisconsin with a total population of just over half a million residents and has 19 NHs . One of A trained research specialist entered health record abstraction data directly into an electronic, standardized report form in a REDCap™ database. In order to ensure consistency, the principle investigator abstracted the first 20 records and no discrepancies were observed. The local Health Sciences Minimal Risk Institutional Review Board approved all study activities.. There were 1442 antibiotics initiated in the sample. As our focus was on comparing antibiotic starts in a NH facility with antibiotic starts in an outpatient clinic or the ED, we excluded prescriptions initiated at the time of discharge from an inpatient hospital unit as noted in the NH pharmacy order records. In order to focus on the most commonly encountered bacterial infections, we only included antibiotic starts associated with a diagnosis of LRTI, SSTI, or UTI. We also excluded prophylactic antibiotic prescriptions as they are not associated with change of condition documentation and the selected appropriateness criteria is specific for acute infections.Figure Data extracted included setting of prescription initiation , indication for antibiotic , patient demographics , vital signs on day of prescription, symptoms, and antibiotic prescribed. Antibiotic appropriateness  was determined according the Loeb consensus criteria which proposes a minimum set of clinical criteria  that should be present before initiating empiric antibiotics for suspected, acute bacterial infections in NH residents .For the purposes of this analysis, the 15% of patients who met 2 of 4 systemic inflammatory response syndrome (SIRS)  criteriaDifferences in the frequency distributions of baseline covariates by setting were compared via Chi-square test for categorical variables and a one-way analysis of variance (ANOVA) for continuous variables. Covariates considered for all statistical approaches included age, gender, setting of antibiotic initiation and infection type. Frequency of antibiotic use by class was calculated and then ranked from most prescribed to least prescribed by setting and within each of the three infection types. The frequency of inappropriate antibiotic use by infection type and setting was also calculated.Stata Statistical Software: Release 14 .A multivariable logistic regression was then performed to determine if any of the covariates were associated with inappropriate antibiotic use. The analytic strategy for selecting the final model was to investigate each predictor to the outcome through a univariate analysis process. After gaining inferences from the univariate analysis, interactions among the predictors were checked before proceeding to fit a full model. As the presence of sepsis criteria automatically resulted in antibiotic prescribing being characterized as appropriate, it was removed from the model due to collinearity. Since the interaction terms were not significant, our main effect model was used as our final model. All analyses are interpreted as odds ratios. Data analysis was preformed using p = .006). The majority of antibiotic prescriptions were initiated within the NH (85.2%). Overall, urinary tract infection (UTI) was the most commonly treated type of infection (49.7%). Lower respiratory tract infections comprised a significantly higher proportion of cases managed in the NH (p = .013) while SSTI comprised a higher proportion of cases managed in the ED and outpatient clinic settings (p < .001). We could not calculate SIRS or qSOFA scores for 2.5% (n = 18) of all subjects due to missing vital sign documentation.Table P = .048. Inappropriate antibiotic prescribing for UTIs varied significantly by setting: NH (55.9%), ED (73.3%), and outpatient clinics (80.8%), P = .023. Inappropriate antibiotic prescribing for skin and soft tissue infections also varied significantly by setting: NH (21.5%), ED (25.0%), and clinics (53.6%), P = .002.Inappropriate antibiotic use by infection type and setting is displayed in Table A detailed representation of antibiotic class prescribing frequency by setting and infection type is available in Table In our multivariate analysis Table , odds ofThrough this cross sectional study of antibiotic prescribing events for NH residents, we have identified important differences in prescribing patterns between those initiated in-facility and other outpatient settings  for this vulnerable population. Consistent with previously published data, overall we observed nearly 50% inappropriate antibiotic initiation for NH residents using the Loeb consensus criteria , 14. AltWhen examining inappropriate prescribing in our regression model, prescriptions in the outpatient clinic setting were observed to have nearly 3 times the odds of being inappropriate. There were no increased odds with prescriptions initiated in the ED setting, which is consistent with results from several recently published reports –21. AlthAnother potential factor in the observed setting variability is disagreement between medical specialties when it comes to diagnosing infections in older adults. Caterino et al. observed that nearly 20% of ED patients admitted with suspected infection were not diagnosed as such by the inpatient physicians . AdditioIn addition to setting, infection type was also significantly associated with increased odds of inappropriate prescribing. UTIs increased the odds of inappropriate prescribing by nearly 4.5 times, which is consistent with prior literature highlighting the clinical uncertainty which surrounds the diagnosis of UTI in elders –27. The Similar to UTI, LRTIs increased the odds of inappropriate prescribing by nearly 3.5 times in our regression model. This again reflects the diagnostic challenges specific to LRTIs in the older adult population. Previous literature suggests that nearly 75% of elders with pneumonia will not have fever and less than half report cough, with increased risk of atypical presentations among NH residents specifically –40. AlthRelative to UTIs and LRTIs, SSTIs had the lowest overall rate of inappropriate antibiotic prescribing and were therefore selected as the reference condition in the regression model. This is likely because the Loeb criteria for initiating of antibiotics for SSTIs focus more on signs of infection which are readily identified by conducting a basic physical exam as opposed to patient reported symptoms . DespiteIn comparing the classes of antibiotics between settings Table , we obseThis study has several important limitations that we would like to mention. First, this study was conducted using data from 5 NHs in one US state which limits generalizability. Local practice patterns vary which highlights the need for additional investigation into antibiotic prescribing appropriateness for NH residents by setting. The small number of antibiotic starts occurring in the ED and outpatient clinic setting as compared to the NHs is also a limitation. The small sample size may have reduced our ability to detect true differences in appropriateness when present. Another limitation of this study is that our reported inappropriateness rates are likely underestimates because we did not assess the appropriateness of antibiotic selection or duration. In contrast, although we reviewed all clinical records available at the NH, documentation of care provided at outside settings (ED or outpatient clinic) was not always available. Without reviewing these records directly, it is unknown if additional symptom documentation or diagnostic testing would have satisfied the criteria for antibiotic initiation. However, our approach accurately reflects appropriateness assessed from the NH perspective based on all records available to providers in that setting. The bidirectional transfer of information for NH residents treated in the ED has already been highlighted as an important area of focus to improve the quality of care in this population , 44. AltIn conclusion, our report represents the first comparative analysis of antibiotic use for NH residents based on setting of prescription initiation. Antibiotics initiated in the ED and outpatient clinics constitute a small but not trivial percent of all NH prescriptions and inappropriate use was high across all settings. Inappropriate antibiotic prescribing overall and by condition varied significantly by setting. Overall, outpatient clinics had significantly higher odds of inappropriate antibiotic prescribing, as compared to NHs and the ED. Antibiotic prescribing for NH residents that is initiated outside of the facility is an important area for additional investigation and must be considered in quality improvement efforts targeting antibiotic stewardship in NHs.


In this work, aramid fibers (AF) are modified in scCO2 by glycidyl-polyhedral oliomeric silsesquioxane (POSS) with 2-ethyl-4-methylimidazole (2E4MZ) on the basis of cleaning with acetone. The surface morphology and chemical structure of the modified AF were measured and characterized by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), Scanning electron microscope (SEM), Thermogravimetric (TG), and Atomic force microscope (AFM). The interfacial shear strength (IFSS) was measured by a micro-bond pull-out test, then the modified AF/EP composites were prepared and the interlaminar shear strength (ILSS) was characterized. Research has shown that some of the glycidyl-POSS molecular chains permeated into the surface of the fiber and grafted onto the surface of the AF after modification, and the other glycidyl-POSS self-assembled on the surface of the fiber. XPS indicated the introduction of C–O and –COO–, which confirmed the existence of chemical reactions between AF and glycidyl-POSS. AFM and SEM images revealed that 2E4MZ, not only promoted the grafting reaction of glycidyl-POSS, but also intensified the self-assembly of glycidyl-POSS, both of which increased the roughness of the fiber. A monofilament tensile test and micro-bond pull-out test showed that there was a negative effect on the tensile strength after scCO2 processing. The tensile strength of modified AF, with glycidyl-POSS, increased the highest strength of 25.7 cN dtex−1, which was 8% higher than that of pristine AF. The improvement of ILS roughness and the polar chemical groups produced in grafting reaction. These results indicated that AF, treated in scCO2, with glycidyl-POSS, which is a suitable way of fiber modification, can significantly improve the surface adhesion of AF reinforced composites.The outstanding diffusivity and permeability of supercritical carbon dioxide (scCO Aramid fiber (AF), also called aromatic polyamide fiber, is a new type of high performance industrial fiber with high modulus, high strength, low density, high temperature resistance, low elongation at a break and low lag loss. However, AF has disadvantages, such as surface smoothness, high crystallinity, and low chemical activity, which result in weak interfacial adhesion between the fiber and matrix materials ,2,3. The2) not only has great solubility and permeability, but also has a relatively high diffusion coefficient, which caused the polymers and fibers to bulge [2 processing by an interfacial reaction between glycidyl-POSS and the polar groups on AF surface has not yet been reported. Traditional surface coating treatment makes it difficult for surface treatment agent to penetrate the surface of aramid fiber. Moreover, stress concentration is easily caused by the uneven grafting point in the process of chemical grafting, which reduces the tensile strength of single fibers [Glycidyl-polyhedral oliomeric silsesquioxane (POSS) is one such hybrid material that possesses both organic and inorganic properties. The chemical structure of these organic groups of glycidyl-POSS can interact with amino and carboxyl . For nonto bulge ,12. The e fibers . Therefo2 and study the effects on mechanical properties of epoxy resin reinforced by AF.Various studies have been carried out in characterizing POSS reinforced materials. These have included studying the formation of nanoscale structures ,11, the The polymer system, used in this work, consists of glycidyl-POSS  and 2-ethyl-4-methylimidazole . Aramid fiber  was produced by South Alkex Company, Seoul, Korea. Epoxy resin (EP), E44, ShangHai Resin Factory Co., LTD .Cleaning process of aramid fiber: Aramid fibers  used in this study was produced by South Alkex Company with 0–0.3% surface sizing agent, as stated by manufacturer. The sizing agent on the surface of AF is used to make the fibers antistatic to help with processing and handling. In order to eliminate the effect of sizing agent on grafting reaction, all samples were washed with acetone and rinsed with ethanol and dried in vacuum before surface treatment. Preparation of samples: The AF was uniformly mixed with 5 wt % glycidyl-POSS , left to dry in an oven at 150 °C for 1 h. A large number of fibers may stick together during the processing. The fiber bundles were overturned and scattered before the heat treatment process to prevent fibers forming bundles. The schematic drawing of glycidyl-POSS-AF is shown in +, Waltham, MA, USA). The microstructure of the samples was studied by using field emission scanning electron microscopy . Atomic force microscopy  was used to examine the fiber surface in more detail.The surface chemical modification of the modified AF was studied using FT-IR , which provided the information about various chemical bonds. TGA was performed on the Thermogravimetric Analyzer  in nitrogen at a ramp rate of 10 °C/min. The samples were analyzed in the range of 80–800 °C. XRD analyses were performed by using a diffractometer with the type of X Pert PRO from Panalytical, Netherlands. Test conditions are following: Cu-Ka radiation, tube voltage with 40 KV, tube current with 40 mA. Scan range from 10 to 40, scan rate with 2/min. In addition, the XPS tests were conducted by X-ray photoelectron spectroscopy  and embedding length (L) of the fibers were measured by Inverted Metallographic Microscope . The test was conducted at room temperature, and the maximum load causing debonding was measured. For each group, 20 samples were tested and averaged. Assuming the IFSS is approximately constant along the entire interface, then the average IFSS can be calculated from the following Equation (1):d is the maximum load of interfacial failure, D is the fiber diameter, and L is the embedded length.In order to investigate how processing affects the interfacial shear strength, specimens were made using AF and a certain amounts of epoxy resin E44 (5 wt % 2E4MZ as a curing agent). The micro-bond pull-out test was carried out on a Single Filament Testing device XQ-1  . After sm (N) is the maximum load during the test, b (mm) is the measured specimen width, and h (mm) is the measured specimen thickness.To investigate how the treatment affects the interlaminar shear strength (ILSS), the ILSS of AF reinforced epoxy composites before and after modification was tested according to ASTM D2344 by using a universal tensile machine . The samples were made using AF (10 wt % ± 0.2) and a certain amount of epoxy resin E44 (4 wt % 2E4MZ as a curing agent). The specimens were prepared by moulding, and the pressure and temperature are 10 MPa, and 100 °C, respectively, the pressure holding time is 1 h. For each group, average value was determined from five different samples. The ILSS were calculated by Equation (2):−1 , 1636 cm−1 , 1540 cm−1 (curved vibration of –N–H), 1307 cm−1 (bending vibration of –N–H) [−1 was broader and moved to a lower wave-number, which made it clear that the hydrogen bond between the surface molecular chains was weaker after cleaning and coating during scCO2 processing. These indicated that scCO2 can destroy the surface structure of AF to some extent [−1, which derive from –CH– and–CH2– indicated a good dispersion of glycidyl-POSS on the AF surface. In addition, the Si–O–Si stretching peak may be masked by AF peaks between 1095 cm−1 and 1118 cm−1, which exhibited that glycidyl-POSS was well-consumed in the surface of AF after scCO2 processing. 2, the amino and carboxyl groups on the surface of aramid fiber were released. Carboxyl and amino groups attacked the oxygen and carbon atoms of epoxy groups respectively, so that glycidyl-POSS were opened and grafted (of –N–H) ,18,19. Te extent ,12. The  grafted . Firstly grafted .2, can be observed by analyzing the XPS spectra. The wide scan and C1s core-level spectra of AF before, and after, modification represented in 2 processing . 10.7 wt % residues were the glycidyl-POSS which grafted or coated on the surface of the fibers.In detail, the pyrolysis characteristic near 150 °C can be attributed to the evaporation of absorbed water and remained glycidyl-POSS (or 2E4MZ). There was almost no weight change within 100–450 °C for AF0 and AF1. According to the analysis of the mass residual rate, the mass residual rate of AF1 is 8.4% lower than in AF0, which may be the residual organic solvent in the processing. By comparing AF1 and AF2, we can draw a clear conclusion that, whether the attachment is a graft product or self-polymerization product, only a little of glycidyl-POSS can attach onto the fiber surface after scCO2 processing, even part of the surface structure of the fiber was obviously broken. For comparison, the SEM images of AF2 and AF3, which were without scCO2 processing, are also listed in 2 processing The surface morphologies of the specimens were observed by SEM, just as shown in 2 processing clearly. The details of the roughness of different samples were examined and shown in 22 with glycidyl-POSS a and Rq increased to 136.54 and 112.41 nm respectively. In particular, 2E4MZ as a curing accelerator can effectively promote glycidyl-POSS self-assembly and graft on fiber surface.The microscopic morphology on the fibers surface was examined with AFM. These images revealed the changes in surface structure of the specimens due to scCO2 processing, which was directly related to the looser surface structure. The decrease in the tensile strength of the fiber after high temperature treatment is related to the change of its surface structure [2 molecules which diffused into the surface of the fiber would improve the movement capacity of the fiber segments in some extent, and the segments would be adjusted, rearranged and even recrystallized. These molecular chains generated stress concentration under the action of stress, thus resulting in the decline of fiber filament strength [2 (AF2), which can reduce the damage of scCO2 to the fiber. As a curing accelerator, 2E4MZ promoted the ring-opening reaction and the grafting (or self-assembly) of glycidyl-POSS on the fiber surface, which was favorable for the improvement of fiber mechanical properties (AF3). Compared with AF0, the tensile strength of AF3 increased 8% to 25.7 cN·dtex−1.It can be seen in tructure ,22. The strength ,12. Nano2 processing, the epoxy resin (epoxy micro-droplet) can easily penetrate the surface molecular chain of the fiber, the abundant carboxylic acids and amine functional groups could provide many reactive anchoring sites for the cross-linking of the epoxy resin, thus increasing adhesion performance. Moreover, a large number of glycidyl-POSS grafted (or self-assembly) on the surface of the fiber, improved the level of roughness after using 2E4MZ, and was critical for the adhesion. Although the value of IFSS in our research was not better than that of the processing of macromolecules grafting on the aramid fiber (increased by 34%) [To evaluate the influence of the grafted AF on the interlaminar shear strength (ILSS), the composites which were made of epoxy and AF treated with different type of processing were tested by inserting a grafted fiber layer in the AF/epoxy composites. The results of the micro-bond pull-out test and the measurement of the ILSS were both shown in  by 34%) ,3, the I by 34%) , which s2, the roughness of AF1 increased and the surface structure was destroyed. The fiber was torn under an external force impact To further evaluate the ILSS of fiber/epoxy composites, the impact fractured surfaces were examined under SEM. The fracture of AF0 is perfectly flat, as well as the fiber surface, and there was no adhesive epoxy resin on the fiber surface. Due to the action of scCO2 processing can destroy the surface structure of the fiber to a certain extent, which is beneficial to the permeation and grafting of glycidyl-POSS. This method can effectively improve the roughness and polarity of AF. XPS showed the introduction of C–O and –COO–, which confirmed the existence of chemical reactions between groups. 2E4MZ not only promoted the grafting reaction of glycidyl-POSS but also intensified the self-assembly, both of which increased the roughness of the fiber. The ILSS of the modified AF/EP composites increased 25.33% to reach at 84.26 MPa. These results indicated that AF treated in scCO2 with glycidyl-POSS and 2E4MZ, which is a suitable way of fiber modification, can significantly improve the surface cohesiveness of AF reinforced composites.In this study, a new and simple solution dipping method, using glycidyl-POSS as a modifier to modify AF, and the AF/EP micro-bond pull-out test, were evaluated. The results showed that scCO


Preterm birth (PTB) is one of the greatest challenges in obstetric and children’s healthcare. PTB remains the most important cause of perinatal morbidity and mortality worldwide. We studied the number of publications concerning PTB over the last two decades using advanced bibliometric visualization methodology. We put the number of publications in perspective of growing awareness of PTB as a major health problem.We analyzed publications over time and performed bibliometric analysis of publications on PTB in the Web of Science from 1997 to 2016. The subjects of publications were visualized using a term map showing the relevant terms occurring in titles and abstracts.Obstetrics & Gynecology is the leading research field (with 10.4% on the subject PTB in 2016) followed closely by Pediatrics (7.6% on the subject PTB in 2016), within the field Public, Environmental & Occupational Health minimal increase was observed (only 1% was published on the subject PTB in 2016). The publications on PTB have increased at higher rates than the overall increase of publications. In recent years we found more publications on PTB describing epidemiology and clinical characteristics/outcomes whereas in earlier years publications focused more on translational, basic research.We identified 47,811 publications. The annual number of publications on PTB increased significantly by 443% in 2016 (n = 5027) compared to 1997 (n = 1135). A significant increase in research concerning PTB was observed over the last two decades. This increase of publications is in line with the growing global awareness of the need to reduce PTB by clinical research.The online version of this article (10.1007/s10995-019-02772-x) contains supplementary material, which is available to authorized users. What is already known on this subject? Preterm birth is the most important cause of perinatal morbidity and mortality worldwide. The attention for the general problem of preterm birth increased over the last decades. Yet, the incidence of preterm birth has hardly changed.What this study adds? Medical research is the foundation needed to build and improve health care. A significant increase in research concerning preterm birth was observed over the last two decades. The number of preterm birth publications has increased at a much higher rate than the overall number of publications. This is in line with the growing global awareness of the need to reduce preterm birth by clinical research.Preterm birth (birth before 37 weeks of gestation) is one of the most comprehensive obstetric and pediatric challenges in medical practice today. Preterm birth is the most important cause of perinatal morbidity and mortality  bibliographic database. We selected all publications in the WoS database in the period 1997–2016 that include ‘preterm birth’, ‘preterm labo(u)r’, ‘preterm delivery’ or ‘prematurity’ in their title, abstract or keywords. The WoS database classifies all publications into a document type, such as ‘article’, ‘review’, ‘meeting abstract’, ‘letter’, or ‘editorial material’. In order to select only the most significant publications we excluded all publications but ‘article’ or ‘review’. Hence, we selected 47,811 publications to include in our analysis. We collected the title, abstract, and publication year for each publication.Lancet and the British Medical Journal, are assigned to a special field called General & Internal Medicine. In this way for each publication the field to which the publication belongs in the WoS database was determined.The WoS database assigns one or more fields to each publication; this field is based on the publishing journal. In case a publication belongs to more than one field, the publication counts fractionally in each of the fields to which they belong. For instance, a publication belonging to two fields is counted as half a publication in each of the two fields. Publications in general medical journals, such as the To evaluate the validity of the selected publications, three random samples of 100 publications  were analyzed by reading (LV) their titles and abstracts. 92% of the first sample, 99% of the second and 88% of the third sample turned out to concern preterm birth.www.vosviewer.com), a tool for constructing and visualizing bibliometric networks  to green (score of 2009) to yellow (score of 2013 or higher). Therefore, if a term is colored blue, the term occurs mainly in older publications. On the other hand, if a term is colored yellow, the term occurs mainly in more recent publications.Each circle represents a term. Sometimes no label is shown for a term, more labels become visible by using the VOSviewer software to zoom in into a specific area in a term map.The size of each term is directly proportional to the number of publications in which the term occurs.The distance between two terms reflects their relatedness, as measured by their co-occurrence frequency.The horizontal and vertical axes have no special meaning in a term map, rotation does not affect its interpretation.The color of a term indicates either the cluster to which the term has been assigned or the age score of the term.This study is not based upon clinical study or patient data.The interpretation of the term maps has been described in earlier publications  of all 7047 publications concerned preterm birth, this portion rose to 10.4% (1445) of all 13,899 publications in 2016. All other fields show a more or less equal increase. In the field of Pediatrics 5.0% (440) of all 8828 publications concerned preterm birth in 1997 and this portion rose to 7.6% (1399) of all 18,332 publications in 2016. The field of Public, Environmental & Occupational Health showed an increase from 0.6% (61) of all 10,042 publications on the subject of preterm birth in 1997 to 1.0% (332) of all 33,399 publications by 2016. The portion of preterm birth publications in field of Reproductive Biology rose from 1.5% (55) of all 3576 publications in 1997 to 4.6% (215) of all 4662 publications in 2016. And finally, in the field of Medicine General & Internal an increase from 0.3% (52) of 18,230 publications in 1997 to 0.9% (375) of 44,028 publications in 2016 concerned preterm birth. The share of preterm birth publications has more than doubled in nearly all fields, Reproductive Biology has relatively the biggest share increase.The field of The number of publications on preterm birth has increased, far more than the overall number of publications. The overall increase is most noticeable from 2003 onwards.Figure Yellow cluster represents cause and prevention of preterm birth with terms such as: ‘concentration’, ‘preterm labour’, ‘preterm premature rupture’, ‘bacterial vaginosis’ and ‘cervical length’.Red cluster represents obstetric conditions leading to preterm birth, with terms such as: ‘preeclampsia’, ‘twin’, ‘pregnancy outcome’ and ‘sga’.Purple cluster represents clinical long term outcome, with terms such as: ‘neurodevelopmental outcome’, ‘preterm child’, ‘behavior’, ‘brain’ and ‘injury’.Green cluster represents pediatric, neonatal outcome, with terms such as: ‘bpd’, ‘nec’ and ‘chronic lung disease’Orange cluster represents ophthalmology, with terms such as: ‘rop’, ‘eye’ ‘retinopathy’, ‘stage’ and ‘laser treatment’Blue cluster represents basic, translational research, including animal studies, with terms such as ‘inflammation’, ‘protein’, ‘placenta’, ‘cell’ and ‘expression’The clusters represent the following research areas:Figure Showing that in recent years emphasis was on epidemiology and clinical characteristics and outcomes. In previous years publications focused more on basic and translational research.Obstetrics & Gynecology and Pediatrics. The share of preterm birth publications has more than doubled in nearly all fields; Reproductive Biology shows relatively the biggest share increase. In all research fields the number of preterm birth publications has increased at a much higher rate than the overall number of publications. Over time we observed a shift in attention from basic and translational research to epidemiology and publications focusing on clinical characteristics and outcomes in the most recent years.Over the last two decades a strong increase of the number of preterm birth publications was observed, especially since 2003. The two most dominant research areas are An important strength of our study is its advanced bibliometric methodology. We evaluated publications not only at the level of the pre-defined fields in the WoS database, but we also used advanced bibliometric visualizations to study the structure and development of the preterm birth literature  neonatal care. In developing countries, where women have limited access to prenatal and delivery care, the number of neonatal deaths and deaths related to preterm birth remain high. The differences between the developed and developing worlds were similarly described regarding the 5th millennium Goal; reduction of maternal mortality  research is important to help identify new approaches in treatment and technologies in order to reduce preterm birth and reach the Sustainable Development Goals by 2030. However, the significant increase in the number of scientific publications concerning preterm birth has had little to no effect on the incidence of preterm birth. Our data showed a shift from basic research to epidemiology and clinical research. We observed a recent interest in key terms such as preeclampsia and perinatal outcomes with a potential to improve preterm birth rates and outcomes, especially when placed in the context of the In this perspective the research challenges for the developed and developing world are not equal. The developed world should lead the way with innovations in research focused on etiology, prevention and treatment. Whereas the developing world might benefit more from pragmatic research focused on addressing public health issues and implementing proven interventions.Obstetrics & Gynecology is the leading research field followed closely by Pediatrics.Preterm birth is the leading cause for mortality for children under 5 years. Despite the significant increase in scientific publications on the subject, the incidence of preterm birth remains unchanged. We observed an increase of 443% in the number of preterm birth publications, this is in line with the increasing global awareness of the need to reduce preterm birth. In all research fields the number of preterm birth publications has increased at a much higher rate than the overall number of publications. Supplementary material 1 (TXT 153 kb)Below is the link to the electronic supplementary material.


Patients infected with the Human Immunodeficiency Virus (HIV) are susceptible to many diseases. In these patients, the occurrence of one disease alters the chance of contracting another. Under such circumstances, methods for competing risks are required. Recently, competing risks analyses in the scope of flexible parametric models have risen to address this requirement. These lesser-known analyses have considerable advantages over conventional methods.FPM1 and SDHFPM2) with the Fine & Gray model. To make a complete inference, we performed cause-specific hazard flexible parametric models for each event separately as well.Using data from Multi Centre AIDS Cohort Study (MACS), this paper reviews and applies methods of competing risks flexible parametric models to analyze the risk of the first disease (AIDS or non-AIDS) among HIV-infected patients. We compared two alternative subdistribution hazard flexible parametric models (SDHFPM1 and SDHFPM2 provided consistent results regarding the magnitude of coefficients and risk estimations compared with estimations obtained from the Fine & Gray model, However, competing risks flexible parametric models provided more efficient and smoother estimations for the baseline risks of the first disease. We found that age at HIV diagnosis indirectly affected the risk of AIDS as the first event by increasing the number of patients who experience a non-AIDS disease prior to AIDS among > 40 years. Other significant covariates had direct effects on the risks of AIDS and non-AIDS.Both SDHFPM1 models each event separately and requires calculating censoring weights which is time-consuming. In contrast, SDHFPM2 models all events simultaneously and is more appropriate for large datasets, however, when the focus is on one particular event SDHFPM1 is more preferable.The choice of an appropriate model depends on the research goals and computational challenges. The SDH There are a variety of possible subsequent outcomes other than Acquired Immunodeficiency Syndrome (AIDS) among HIV-infected patients –3. When To evaluate the effects of covariates in a competing risks analysis, model-based approaches on two important measures —the cause-specific hazard and subdistribution hazard— are more common. The difference between these two measures is in their risk sets. In the cause-specific hazard, patients who experienced a competing event will be excluded from the risk set for the event of interest and considered as censored. Modeling on cause-specific hazards provides causal effects of covariates on the hazard of the event of interest in a counterfactual world, where there are no competing events and patients can only fail from the event of interest , 14, 16.There are alternative approaches in modeling of competing risks based on the decomposition of the CIF  known as mixture and vertical models. Mixture models factorize the CIF as the product of the marginal distribution of event type and the conditional distribution of failure time given the type of the event. A multinomial regression model is used to assess the effects of covariates on the type of event and parametric or semi-parametric hazard regression models are used to evaluate their effects on the conditional failure times –24. In cOne important issue with Cox or Fine & Gray models is that the baseline hazard or subdistribution hazard functions remain unspecified and are not estimated parametrically , 9, 20. AIDS, non-AIDS, and death prior to AIDS or non-AIDS diseases— in an HIV-infected male population and evaluated the covariates that are associated with the risks of these outcomes. Furthermore, we implemented a cause-specific hazard flexible parametric model to investigate the direct  and indirect  effects of covariates on the risk of the competing events. In the next section, we present a description of the Multicenter AIDS Cohort Study (MACS). In the third section, the association of the cumulative incidence function with the hazard and subhazard functions is explained. In the fourth section, the Competing risks flexible parametric models (CRFPMs) for multiple types of events are reviewed. In the fifth section, the CRFPMs are applied to the MACS dataset and predictions for the risks are obtained. The last two sections contain results and conclusions.The primary aim of this paper is to apply two alternative subdistribution hazard flexible parametric models to the HIV-infected men population and compare these models with the Fine & Gray model as a standard model in competing risks analysis. We have identified the competing risks as the first event —Multi Centre AIDS Cohort Study (MACS) is a 30–year prospective study of HIV infection among homosexual or bisexual men (HBM) who were 18 years or older with no prior AIDS-defining illness. MACS began in 1984 at four US sites; Chicago, Illinois; Baltimore, Maryland; Pittsburgh, Pennsylvania; and Los Angeles, California. It has multiple patient recruitments. The first recruitment, which consists of 4954 HIV-infected and uninfected HBM was conducted in 1984–1985. In 1987–1990, recruitment was reopened and 668 HBM were enrolled. During 2001–2003 another 1350 HBM were enrolled. Another MACS expansion commenced at the beginning of 2010 and 371 HBM were recruited until April 2014. HIV-related symptoms, demographic characteristics, blood specimens, and behavioral history at each 6-month follow-up visit were collected. Among 7232 HBM, seroconverter patients were selected and patients with a non-AIDS disease before seroconversion were excluded from the study. This analysis includes 674 seroconverter or prevalent patients with a known visit of seroconversion.Study outcomes were determined as the time duration from seroconversion to the occurrence of the first event. The midpoint of the last negative and the first positive visits was used as the time of seroconversion. The primary event was the occurrence of AIDS without evidence of a non-AIDS disease before. The secondary event was time to a non-AIDS disease prior to AIDS. Non-AIDSs included the following diseases: kidney, liver, cardiovascular, cerebrovascular diseases; lung infection, bacteremia, septicemia; malignancies, neurologic; cancers —all cancers excluding Kaposi sarcoma, lymphoma, and invasive cervical cancer. Since the occurrence of death precludes observing AIDS or non-AIDS diseases, we considered unrelated death as the third outcome. These types of deaths may occur for reasons unrelated to AIDS or non-AIDS diseases . Other patients who were lost to follow-up or did not experience any failure event at the end of the study  were censored. Such variables as MACS recruitment calendar years, age at seroconversion time, laboratory results including the number of positive CD4 cell counts, CD8 cell counts, white blood cells, red blood cells and platelets at baseline were considered based on the expert knowledge and previous studies on HIV/AIDS , 33, 34.th (k = 1 … K) cause by time t while being at risk of failing from other competing events [Cause-specific CIF is a measure of absolute risk and defined as the probability of failure from kg events . So, we Fk(t) is the CIF function, T is the survival time i.e. the minimum of the true survival time and censoring time, u ≤ t. S is the overall survival function and is defined as.In the above equation, ` S). An increase in the hazard of competing events will lower the risk occurrence of the event of interest as the first event by decreasing the overall survival function. In other words, in a competing risks framework, a covariate can increase the risk of the event of interest directly via increasing the hazard of the event or indirectly by decreasing the hazards of competing events. So, a discrepancy between the hazard and risk of the event of interest may be observed. The magnitude of this discrepancy depends on the severity of competing risks. The stronger the competing risk, the greater the discrepancy [Equation  implies crepancy , 12, 14.In contrast, the cause-specific subdistribution hazard is defined asAlthough this definition of the risk set is not practically meaningful because the patient does not actually remain in the risk set to experience the event of interest as the first event; however, this can lead to the following direct relationship between subdistribution hazard functions and corresponding cause-specific CIFs:So, modeling on cause-specific subdistribution hazard will show the associations between covariates on the cause-specific CIF. The subdistribution hazard-based models use the information that the occurrence of competing events gives about the event of interest. That is, the event of interest never occurs as the first event if a competing event has already occurred. So, whenever a competing event occurs the chance of occurrence of the event of interest as the first event will be reduced. However, to investigate whether an association is direct or indirect the effect of the covariate on all cause-specific hazards should be assessed.FPM performs a flexible parametric model for each type of event separately considering competing events as censoring. It regresses the cause-specific log cumulative hazard function on a Natural Cubic Splines (NCSs) function of the log of time that isThe CSHHcs(t|X) is the cause-specific cumulative hazard function for event k with matrix Xk of covariates at time t, Hk0 (t) is the cause-specific baseline cumulative hazard function, βk is a vector of covariates coefficients and NCSk{lnt; γk, dk0} is a natural cubic spline function of ln(t) with d0 knots and parameters γ for event k. The number and position of knots in the spline function determine the complexity of the baseline cumulative hazard function. However, sensitivity analysis showed that they have little effect on the model fitting and there is no need for optimal selection to have a good fit [Where good fit . Model [good fit  has the good fit .FPMs, Hinchliffe and Lambert introduced a unified CSHFPM on stacked data based on the Lunn-McNeil approach [FPM is fitted for all competing events simultaneously and parameters related to each competing event are jointly estimated [FPMs, covariate estimations of this model would be equivalent to those obtained from separate models [Instead of separate CSHapproach , 39. In stimated . Differee models , 41.FPM, the effects of covariates directly model on the cause-specific log cumulative subdistribution hazard functions using NCSs as follows:In the SDHFPM using standard software of FPMs [Lambert et al. proposed a parametric version of the Fine & Gray model . Patient of FPMs . To achi of FPMs . Lambert of FPMs , 41.FPM1 and the latter as SDHFPM2.As an alternative method, Mozumder et al. introduced a unified likelihood function to obtain a direct estimate of all cause-specific CIFs simultaneously using FPMs . This moWe performed a Complete Case Analysis (CCA), 629 of 674 patients, and assumed the data were Missed Completely at Random (MCAR). However, Multiple Imputations (MI) using the multivariate normal regression method with 10 imputed data sets for missing data were performed to explore the sensitivity of the inferences to departures from MCAR assumptions.transcan function in R, which transforms covariates while imputing missing values of them [FPM1, for patients experiencing a competing event the time was split every .1-year. The time dependent censoring weights were estimated through fitting an FPM on the initial set of covariates, with three degrees of freedom. The CSHFPMs were conducted for each event separately.The possibility of a reduction in the number of initial set of covariates, generated based on the expert (background) knowledge, was explored. We used  of them . The tra of them . HoweverAll significant effects were detected using the Likelihood Ratio (LR) tests at a 5% level. The findings are summarized with hazard and subdistribution hazard ratios and 95% Confidence Intervals (CI). Statistical analyses were performed in STATA  and R (Version 3.5.2) .transcan function showed that none of the covariates selected by the expert (background) knowledge had strong correlations with the others  for AIDS, nonAIDS, and death respectively, had minimum values. For all CRFPMs, Interactions between the age with ln(t) on non-AIDS diseases was statistically significant . More complicated time dependent effects of age had been assessed. However, ln (t) had the lowest AIC and BIC among them. Table FPM1, SDHFPM2, and Fine & Gray model, which show the effects of covariates on the subdistribution hazards or equivalently on the risk of the first observed event. There was a high agreement between estimated subhazard ratios obtained from Fine & Gray and two SDHFPMs. The results of performing CSHFPM also show the effects of covariates on the hazard of each event separately . In addition, the hazard of non-AIDS diseases among patients of period 2 was 2.45 times that of period 1 . By increasing the hazard of non-AIDS diseases in period 2, fewer patients remained at risk to experience AIDS prior to non-AIDS diseases compared to period 1. Consequently, the risk of observing AIDS as the first event was lower in period 2 compared to period 1 . In a similar way, the risk of observing a non-AIDS disease prior to AIDS increased in period 2 compared to period 1 . Therefore, there were direct and indirect associations between the MACS recruitments and the risk of AIDS and non-AIDS. MACS recruitments were not associated with the hazard and risk of unrelated death.The results showed that the hazard of AIDS occurrence in period 2 declined to about 96% compared to period 1 . However, the risk of AIDS prior to a non-AIDS disease in the ≥ 40 age group decreased by 31% compared to 40 . This discrepancy between the hazard and risk of AIDS indicated an indirect effect of age on the risk of AIDS that came from the higher hazard rate of non-AIDS diseases and unrelated death among the older age group. The effects of age groups on both the hazard and risk of non-AIDS diseases, controlling other covariates, were time dependent and the average effect of the ≥ 40 group on the hazard of non-AIDS diseases was about 3.7 times that of < 40 group . As a result, fewer patients in the ≥ 40 age group remained exposed to experience AIDS prior to non-AIDS diseases. These findings also indicated that age at diagnosis had direct effects on the risks of non-AIDS and unrelated death.Age at HIV diagnosis was not associated with the hazard of AIDS . The risk of AIDS for patients with CD4 cells < 350 reached statistical significance comparing to patients with ≥ 500 . Levels of CD4 had no significant association with the hazards and risks of non-AIDS diseases. Hence, the effect of CD4 levels on the risk of AIDS was quite direct. Levels of CD4 had no significant associations with hazards and risks of non-AIDS diseases and unrelated death. Hence, the effect of CD4 levels on the risk of AIDS was quite direct.Hazard of AIDS increased about 83% for CD4 levels < 350 compared to CD4 levels≥ 500 . Figs. FPM1 and 2 were close to their corresponding values in the Fine & Gray model. The SDHFPM1 and 2 could accurately capture nonlinear trends of the risk of AIDS in different patterns of covariates and provide parametric estimations of them. For all patterns, the risk estimations of AIDS were dramatically higher than non-AIDS and risks of death were close to zero.We compared risk estimations of competing events for different patterns of covariates in a 15-year time interval using all subdistribution hazard-based models  for deaths prior to AIDS or non-AIDS disease, which may lead to sparse data biases and overfitting problem . HoweverThis paper presents an application of flexible parametric models on multiple event types when each event alters the probability of occurrence of the other events. The choice of an appropriate model depends on the goals of the research and computational challenges. A review of these models and their required packages are summarized in Table Additional file 1: Table S1. Results of Transforming and Imputing Variables.Additional file 2: Table S2. Results from the Fine & Gray Analysis of 10 Multiply Imputed Datasets.