Medical imaging applies different techniques to acquire human images for clinical purposes, including diagnosis, monitoring, and treatment guidance. As a multidisciplinary field, medical imaging requires the improvements in both science and engineering to implement and maintain its noninvasive feature. Computational and mathematical methods are involved with imaging theories, models, reconstruction algorithms, image processing, quantitative imaging techniques, acceleration techniques, and multimodal imaging in medical imaging. The main purpose of this issue is bridging the gap between mathematical methods and their applications in medical imaging. This special issue covers most of the common medical imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and various image processing methods, such as segmentation, enhancement, and registration.This special issue has 23 papers which were reviewed by at least two reviewers. Six papers are involved with CT technique. One of the papers proves that the X-ray projection of the 3D mother wavelet is a 2D mother wavelet under certain conditions, which may be applied to 3D CT image processing. For accurate low-dose CT imaging, a practical method is presented by combining measurement-based scatter correction and compressed sensing-based iterative reconstruction in one paper. Another paper describes a CT imaging system with adjacent double X-ray sources. In one of the papers an imaging model is introduced to determine the best energy bin of the energy-discriminative photon counting detector for maximum material discrimination. Another paper presents an ASD-POCS-based optimization dual energy reconstruction algorithm with additional piecewise polynomial function constraint from the fully sampled low-energy data and undersampled high-energy data. In one paper, a so-called distributed alternating direction total variation minimization algorithm (Dis-ADTVM) is presented for few-view CT reconstruction. For multiecho T2-star weighted MRI image analysis, one paper presents an automatic mapping extraction algorithm to improve morphological evaluations in human brain. As a typical and important application, there are 13 papers involved with various medical image processing methods including segmentation, registration, enhancement, denoising, detection, and target location. In seven papers, 7 image segmentation methods are presented, respectively, by using different image features and mathematical methods, such as the symmetry technique, snake, multiscale technique, level-set, region growing, fuzzy C-means, graph cut, and random field. Two papers present two registration methods by using a Harris & SIFT features detection method and a coherent continuous formulation of multiple constraints, respectively. One paper introduces a mammographic image enhancement method by using multiscale transform and mathematical morphology. In another paper, a fast nonlocal means denoising method is proposed for 3D ultrasound speckle reduction based on the programmable graphic-processor-unit (GPU) hardware. One paper presents a nonnegative mixed-norm convex optimization method for mitotic cell detection in phase contrast microscopy. Another paper shows the evaluation results of the location of the mandibular canal and the thickness of the occlusal cortical bone at dental implant sites from the dental CBCT images. In addition there are 3 interesting papers on other mathematical applications in medical imaging. One of the papers shows the analysis and clinical evaluation of a single hemodialysis on phosphate removal of the internal fistula patients. Machine learning has been successfully applied in medical image processing even in image reconstruction. One paper provides an overview of recent support vector machine-based methods developed and applied in psychiatric neuroimaging. Another paper proposes a framework based on Quick Response (QR) coded watermark for patient authentication and controlled access to medical records in cloud-based teleradiology.We hope that this special issue may represent the state of the art and would attract wide attention of the researchers in medical imaging field.Liang LiLiang LiTianye NiuTianye NiuSeungryong ChoSeungryong ChoZhentian WangZhentian Wang


P < 0.001). Subgroup analysis by country and hs-CRP detection methods suggested a negative relationship between atorvastatin treatment and hs-CRP levels among Chinese AF patients  and by using ELISA method , but not among Turkish population and using INA method . Egger's test showed no publication bias (P = 0.450). hs-CRP was clearly lowered in AF patients treated with atorvastatin, which may be helpful in the choice of statin agents for AF treatment. However, longer follow-ups are necessary to assess the clinical value of lowering hs-CRP in the clinical setting of AF treatment outcomes.We investigated whether serum hs-CRP levels predict the efficacy of atrial fibrillation (AF) treated with atorvastatin. Bibliographic databases were exhaustively searched for studies relevant to the research topic. Newcastle-Ottawa Scale (NOS) criteria, combined with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS), were applied for study quality assessment. Our meta-analysis identified seven cohort studies (2006~2013), providing information on the change in serum hs-CRP levels in AF patients receiving atorvastatin therapy. After atorvastatin treatment, hs-CRP level in AF patients decreased significantly (SMD = 1.02, 95% CI: 0.58–1.47,  Atrial fibrillation (AF) refers to extremely rapid and disorganized cardiac rhythm which may result in elevated afterload, increased filling pressures, and left atrial enlargement , 2. The Atorvastatin belongs to a class of drugs known as the statins, routinely prescribed to reduce blood cholesterol and to prevent adverse events related to cardiovascular diseases . StatinsBibliographic databases, , and China National Knowledge Infrastructure (CNKI)), were exhaustively searched to identify published studies that assessed the change in hs-CRP levels in adult AF subjects who were administrated with atorvastatin. The search included studies available from the inception to June 2014. We used medical subject heading (MeSH) and keywords for atorvastatin and AF as follows: “atorvastatin” or “liptonorm” or “lipitor” and “Atrial Fibrillation” or “atrial fibrillations” or “fibrillation, atrial” or “familial atrial fibrillation” or “auricular fibrillation.” The search was limited to human studies and without restrictions to the language of the paper. In addition to the above electronic search, relevant articles were checked manually to identify additional potential papers.This meta-analysis focused on observational studies where monitoring of hs-CRP was used to predict AF patients treated with atorvastatin. To be included in our meta-analysis, published studies fulfilled the following selection criteria: (1) patients with AF and the opportunistic screening for AF by pulse palpation, followed by recording of an electrocardiogram (ECG) to verify diagnosis ; (2) humIn order to reduce the bias and enhance the confidence, two investigators separately extracted information from the selected studies based on the selection criteria and arrived at a consensus on all the items through discussion and reexamination. The following relevant data was extracted from the final selected studies for analysis: surname of first author, time of publication, source of publication, study type, study design, ethnicity and country of subjects, sample size, gender and age information, and detection method for hs-CRP levels in the human subjects. All authors approved the selected studies.To determine whether the study in question was of high quality, two investigators independently scored the studies based on the Newcastle-Ottawa Scale (NOS) criteria . The NOS Z test, to determine the effect size for each study. The ORs were calculated utilizing the STATA software, version 12.0  by two separate investigators. In order to supply quantitative data from all of the selected studies and to minimize the variance of the summary SMDs and 95% CI, we performed the current statistical analysis by utilizing a random-effects model (DerSimonian and Laird method) or a fixed-effects model (Mantel-Haenszel method). The random-effect model was applied when heterogeneity existed among the studies, while fixed-effects model was applied when there was no statistical heterogeneity. The heterogeneity across the enrolled studies was evaluated by Cochran's Q-statistic , and the degree of interstudy heterogeneity was measured by I2 test   failed to report this information. The screening steps and study selection procedure are shown in n = 256). The remaining 55 studies were reviewed and an additional 45 studies were excluded since they were not case-control or cohort designed studies, not relevant to atorvastatin or not relevant to AF and hs-CRP levels. After the remaining 10 papers were fully reviewed, 7 papers were finally selected for our meta-analysis, and the other 3 articles were excluded for lack of data integrity. The quality scores of the studies were higher than 7 , as shown in Our present meta-analysis identified a total of 7 cohort studies, published between 2006 and 2013, that provided information on the changes in hs-CRP level in AF patients before and after administration of atorvastatin , 25–27. P < 0.001). Subgroup analysis based on country and detection methods showed that atorvastatin treatment reduced serum hs-CRP levels in AF patients in the Chinese populations , and by using the ELISA detection method of hs-CRP level , but not among Turkish populations  and using the INA method for detection of serum hs-CRP  (As shown in = 0.062) .t = −0.82, P = 0.450).Sensitivity analysis to evaluate the stability of the results was performed by removal of each study one by one. The corresponding pooled ORs in overall comparison and stratified analyses were not significantly altered, indicating a stable and credible outcome . As showα, and MMPs [β-catenin to inhibit proliferation and induce apoptosis in pancreatic cancer cells [In order to investigate the relationship between atorvastatin treatment and the serum hs-CRP levels in AF patients, an extensive meta-analysis was undertaken, and our main result shows that a significant reduction in serum level of hs-CRP was achieved after atorvastatin treatment in AF patients. Statins inhibit HMG-CoA reductase and are used in dyslipidemia patients to reduce blood cholesterol levels and prevent cardiovascular diseases . Statinsand MMPs . Furtherand MMPs . Atorvasand MMPs . Atorvaser cells . Atorvaser cells . Additioer cells . It has er cells . After ter cells . The lower cells . Atorvaser cells . As a reer cells . Consister cells . Based oer cells .To further analyze the influence of other related factors such as country and serum hs-CRP detection methods on the relationship between atorvastatin treatment and lower hs-CRP serum level, a subgroup analysis was performed. From the result of country-stratified analysis, we observed that the relationship was not affected in Chinese population but was not statistically significant in Turkish population. One possible explanation could be different life styles and genetic backgrounds of individuals from different countries. Based on the detection method for hs-CRP, the ELISA method did not affect the observed relationship between atorvastatin therapy and hs-CRP serum level. However, the INA method showed no statistically significant relationship and might be explained by technical differences between the different detection methods. In summary, our results of the effect of atorvastatin treatment in lowering hs-CRP serum levels in AF patients are in agreement with other studies, suggesting atorvastatin therapy is effective in AF patients.There are several limitations in our study. First, we did not take into consideration the viral load or treatment efficacy of atorvastatin over time, and the long-term follow-up of patients was not completed. Second, our study was single-center, cross-sectional retrospective study, with relatively small number of articles and a smaller number of patients. This may have resulted in article and patient selection bias. Another restriction may be that we only evaluated the role of hs-CRP in AF patients treated with atorvastatin, while comparison with other anti-inflammatory indexes such as IL cytokines are lacking. Lastly, since only paroxysmal AF was analyzed, patients with persistent AF or postoperative AF may have responded differently to atorvastatin but were not investigated.In conclusion, our meta-analysis investigated the hs-CRP levels in AF patients treated with atorvastatin. We observed that hs-CRP levels decreased significantly in AF patients who used atorvastatin during the study period. Nevertheless, this study did not follow up patients over time, so the predictive values of hs-CRP levels may be limited. Therefore, further investigation is necessary.


The hypothesis that raising high-density lipoprotein cholesterol (HDL-C) levels could improve the risk for cardiovascular disease (CVD) is facing challenges. There is multitudinous clear clinical evidence that the latest failures of HDL-C-raising drugs show no clear association with risks for CVD. At the genetic level, recent research indicates that steady-state HDL-C concentrations may provide limited information regarding the potential antiatherogenic functions of HDL. It is evident that the newer strategies may replace therapeutic approaches to simply raise plasma HDL-C levels. There is an urgent need to identify an efficient biomarker that accurately predicts the increased risk of atherosclerosis (AS) in patients and that may be used for exploring newer therapeutic targets. Studies from recent decades show that the composition, structure and function of circulating HDL are closely associated with high cardiovascular risk. A vast amount of data demonstrates that the most important mechanism through which HDL antagonizes AS involves the reverse cholesterol transport (RCT) process. Clinical trials of drugs that specifically target HDL have so far proven disappointing, so it is necessary to carry out review on the HDL therapeutics. Hyperlipidemia, a risk factor for atherosclerosis (AS), is a serious consequence for people who have experienced coronary heart disease, stroke, and artery stenosis disease. AS, which is the leading cause of cardiovascular disease (CVD), is responsible for 50% of all mortality in many developed countries . A persiThis paper is aimed at looking for a better HDL biomarker to predict AS precisely and explaining how HDL functions in detail, then providing an overview of novel therapies that target HDL to enhance HDL’s ability to reduce residual cardiovascular risk in the population. Finally, we carry out an assessment of a natural drug that has been linked to HDL, which represents a unique field in the treatment of AS that warrants exploration.AS can be considered to be a form of chronic inflammation, beginning with increased endothelial permeability of monocytes under the influence of adhesion molecules . It promBecause trends relating high plasma levels of HDL-C and decreased incidence of CVD endpoints were observed in prospective epidemiological studies conducted in several countries many years ago, HDL-C levels have served as a significant predictor for relieving AS in the clinic. There have been several attempts to increase HDL-C levels using pharmacological intervention ,17. HDL-2, and HDL3, HDL3 best predicts CAAD risk, and the remaining phenotypes do not add significant predictive power -cholesterol-labeled J774 macrophages with either increased or reduced ABCG1 expression and primary macrophages lacking ABCG1 expression, followed by measurement of the macrophage-derived [3H]-cholesterol levels in plasma and feces  cholesterol in feces was increased, which promoted macrophage-to-feces RCT, and its ability to protect against LDL oxidation was enhanced [LCAT, a lipoprotein-associated enzyme, is a key player in the RCT pathway. LCAT has two different catalytic activities that account for its ability to esterify cholesterol. One is phospholipase A2 activity, and the other is its transesterification activity. It requires apoA-I and, to a lesser degree, other apolipoproteins, which most likely activate LCAT by modifying the presentation of its substrates, namely, phospholipids and cholesterol, on the surface of lipoproteins . After Fs to HDL . This efs to HDL ,81. EL hs to HDL . Althougs to HDL . The coms to HDL ,85,86,87enhanced .––/ mice [CETP is a hydrophobic glycoprotein that is synthesized in several tissues but mainly in the liver. It facilitates the exchange of cholesteryl esters and triglycerides between HDL and apoB-containing particles  and represents a major branching point for RCT ,8. This –/– mice ,95, and –/– mice ,97.After efflux, cholesterol in HDLs may be esterified by the enzymatic activity of LCAT whereupon HDLs can deliver the excess cholesterol from peripheral cells back to the liver in in distinct ways: HDL cholesteryl esters, but not the protein component of HDLs, are selectively taken up into the liver via SR-BI. Ultimately, cholesterol is excreted from the liver into the bile, either directly as free cholesterol or after conversion into bile acids, and eliminated from the body via the feces. In humans, HDL-C can be metabolized by the liver via another pathway: CETP exchanges of HDL CE for triglycerides in apoB-containing lipoproteins, followed by hepatic uptake mediated by LDL-r. An LDL-r deficiency in mice substantially decreases selective HDL CE uptake by liver and adrenals. Thus, LDL-r expression has a substantial impact on HDL metabolism in mice .Via the classic RCT pathway, excessive cholesterol collected from peripheral tissues, which is delivered back to the liver, is followed by biliary secretion and elimination via the feces. In addition to the traditional RCT-mediated biliary pathway, in the last few years, direct trans-intestinal excretion of plasma-derived cholesterol (TICE) was shown to contribute substantially to fecal neutral sterol (FNS) excretion in mice, describing the transport of cholesterol from blood to the intestinal lumen directly via enterocytes. The TICE pathway was called a nonhepatobiliary-related route, which has been shown to have a high degree of correlation with the main contributors Niemann-Pick disease, type C1/2 (NPC1/2), ABCG5/G8, LDL-r, and LXR ,100,101.in vitro.LDL is one of the main causes of AS. Oxidation of LDL yields a more pro-atherogenic particle, and numerous studies have found that HDLs are capable of impeding oxidative changes in LDL. HDL exhibits potent antioxidant activity, which may arise from synergy in the inactivation of oxidized LDL lipids by enzymatic and nonenzymatic mechanisms, in part reflecting distinct intrinsic physicochemical properties . The antTraditionally, the endothelium has been considered to be an inert component of the vessel wall. Injury to the endothelium results in deleterious alterations of endothelial physiology, also referred to as endothelial dysfunction, which represents a key early step in the development of an atherosclerotic lesion and is implicated in the malignant development that follows. It has become evident that HDL from healthy subjects can exert direct potential atheroprotective effects on endothelial cells and can positively affect several endothelial functions in the regulation of vascular tone, inflammation  and endoHDL and apoA I are believed to protect against the development of AS, in part, which is closely related to their anti-inflammatory function. The anti-inflammatory properties of HDL encompass suppression of macrophage inflammatory cytokine production and inhibition of the expression of endothelial cell adhesion molecules that promote the entry of monocytes and neutrophils into arteries. HDLs potently block murine experimental endotoxinemia, indicating that HDLs bind lipopolysaccharides (LPS), which leads to lower systemic proinflammatory cytokine levels and improved survival rates . Up-regu––/ mice [in vivo [One approach to increase the serum levels of HDL is to infuse reconstituted HDL (rHDL) or recombinant HDL particles into the circulation rather than by increasing HDL indirectly by modulating HDL metabolism. CSL-111 is a reconstituted HDL-particle comprising both human apoA-1 and soybean phosphatidylcholine. CSL-112 is being evaluated in phase II trials to improve the weakness of CSL-111. There is a benefit of CSL-111/CSL-112 infusions to increase HDL-C levels and up-regulation of cellular cholesterol efflux in patients with acute coronary syndrome (ACS). Some trials have demonstrated that infusions of recombinant HDL-containing apoA-I Milano and CER-001 significantly reduce or stabilize mean plaque atheroma volume and still exert greater anti-inflammatory effects in LDL-r–/– mice ,115,116.–/– mice . Pegylat[in vivo .Another novel approach to HDL therapeutics is to raise the levels of HDL particles by intravenous infusion with the use of autologous delipidated HDL. Preclinical evaluation of selective delipidated HDL in a nonhuman primate model of dyslipidemia achieved a significant 6.9% reduction in aortic atheroma volume, as assessed by intravenous ultrasound (IVUS) . In a sml-4F (the 4F peptide synthesized from l-amino acids) and d-4F . Compared with high plasma l-4F levels not improving HDL anti-inflammatory function, a single dose of d-4F was found to have a significant effect on the inflammatory index of HDL with modest oral bioavailability [ApoA-I mimetics, which are short synthetic peptides, mimic the amphipathic a-helix of apoA-I. Because the first apoA-I mimetic consisted of 18 amino acids, additional improved peptides were generated by increasing the number of phenylalanine residues on the hydrophobic face  of the polypeptide. Two different types of apoA-I mimetic peptide 4F were used in clinical trials, including lability . ABCA1-ilability . Furtherlability .LXR and miR-33  have been demonstrated to regulate macrophages ABCA1 and ABCG1. The activation of the former can upregulate the expression of two genes, which promote macrophage cholesterol efflux and augment intestinal HDL generation, while the opposite is true of the latter. In the animal experiments, LXR agonists exhibit a significant decrease of atherosclerotic plaque formation and exert anti-inflammatory characteristics . The negLCAT plays a major role in this part of RCT, and mediates the esterification of free cholesterol located at the surface of lipoprotein particles. Several drug development approaches have recently been initiated for modulating LCAT activity. Recombinant human LCAT (rhLCAT) efficiently promotes the process of RCT, which induces a marked increase in HDL-C levels and the maturation of small preb-HDL into α-migrating particles in LCAT-deficient plasma . CurrentAnacetrapib. The Determining Efficacy and Tolerability of Anacetrapib has shown a 138% increase in HDL-C, a 40% reduction in LDL-C, and a 36% decrease in Lp(a) of patients with CAD. This results from the ability of anacetrapib to inhibit both heterotypic and homotypic CE transfer. A large phase III study, Randomized EValuationof the Effects of Anacetrapib Through Lipid-modification (REVEAL), will be completed in January 2017 [ary 2017 .Evacetrapib. Evacetrapib has a similar structure and mechanism of action as torcetrapib but, based on IC50 values, appears to be a more potent CETP inhibitor than torcetrapib or anacetrapib [cetrapib . It is tcetrapib . The AssBAY 60-5521/TA-8995. BAY 60-5521 and TA-8995 are two potential inhibitors of CETP. The clinical results suggest that these two agents are safe and well tolerated, with effective inhibition of CETP activity and increased high HDL-C [gh HDL-C ,135.CETP ASO. Antisense oligonucleotide inhibitor of CETP (CETP ASO) is associated with reductions in CETP mRNA and also shows an enhanced effect on macrophage RCT. It is reported that the CETP ASO does not act through binding and inactivating CETP associated with the HDL particle. Instead, it specifically targets and degrades CETP mRNA. In hyperlipidemic, CETP transgenic, LDL-r––/ mice, CETP ASO provided comparable reductions in HDL cholesterol, decreases in CETP activity with an enhanced effect on macrophage RCT, and results in less accumulation of aortic cholesterol [lesterol . CETP ASin vivo.SR-BI, the HDL receptor, is expressed on hepatocytes and facilitates selective absorption of cholesterol ester from HDL. The discovery and development of traditional drugs that can modulate SR-BI expression and/or activity are being investigated through high-throughput screening of chemical compound libraries. Endogenous or exogenous agents  and the detailed high-resolution molecular structure of SR-BI protein, the regulators of SR-BI activity, should provide new insights for the progress of non-genetic therapies to modulate HDL metabolism As an alternative to traditional drugs, gene therapeutics are being extensively explored. In general, miRNA-125a and miRNA-455 can bind to specific sites in the 3′ UTR of SR-BI mRNA and act as endogenous attenuators of SR-BI protein expression . It is cetc. Specifically, natural products provide a great contribution to the development of new agents for the treatment of hyperlipidemic diseases. Compared with chemical drugs or other synthetically created products, natural products could more closely mimic physiological processes and may be more effective in treatment of cardiovascular diseases. There are many natural drugs for the treatment of AS associated with HDL, such as polysaccharide, sesamin, anthocyanins, 24(S)-Saringosterol and many others. Chitosan and its related products, which are polysaccharides, are used to enhance natural products and may represent promising strategies in the near future.Nature is an irrefutable source of inspiration for the modern man in many aspects. The observation and understanding of nature have allowed the development of new materials, new sources of energies, new drugs, et al., based on six randomized placebo-controlled clinical trials in hypercholesterolemic patients has showed that chitosan only induced a decrease in total cholesterol level but without any significant changes in LDL-cholesterol, HDL-cholesterol or triglyceride concentrations [Chitosan (CTS), the only positive alkaline polysaccharide extracted from shrimp or crab shells and exhibiting biocompatibility and a nontoxic nature, has the potential for hypolipidemic and weight loss activities. In 1980, the first article demonstrating that proper supplementation of chitosan to the diet seemed to be effective in lowering plasma cholesterol in rats was published . And thetrations . Since ttrations ,142,143,trations ,145.in vivo and stimulates hepatic LDL-r expression, inducing the LDL cholesterol lowering. Furthermore, chitosan oligosaccharides have anti-inflammatory functions similar to that of HDL, which downregulates the expression of E-selectin, ICAM-1 and IL-8 induced by LPS in endothelial cells through blockade of p38 MAPK and PI3K/Akt signaling pathways [Chitosan oligosaccharides (COS) are depolymerized products of chitosan by either chemical or enzymatic hydrolysis. COS is a polymer of glucosamine with a number of bioactive properties. Recent studies have suggested that COS inhibits adipogenesis and promotes RCT through altered expression of a number of key regulators of lipid metabolism, including leptin , SR-BI apathways ,148.in vitro and in vivo that may protect arteries from chemical or biological hazards or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One possible reason may be the complexity of HDL particles, resulting in the physiological heterogeneity that contributes to the antiatherogenic functions of HDL. Moreover, for more than 50 years, HDL-C has been known as an independent clinical biomarker of cardiovascular risk. However, the failures of drugs to increase HDL-C drive scientists to search for new biomarkers to replace it, such as HDL functions, HDL size, and HDL-P. Among these, HDL functions will be a reliable diagnostic biomarker for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk. The functionality of HDLs has two important roles. First, it promotes reverse cholesterol transport; second, it modulates inflammation and oxidation. HDL-based interventions in promoting the RCT process may be more promising. Meanwhile, some natural products with functions similar to that of HDL also play unique roles in the RCT process and will enter a new era in treatment of CVD in the near future (HDL particles have various effects r future .


Sepsis sequelae include critical illness polyneuropathy, myopathy, wasting, neurocognitive deficits, post-traumatic stress disorder, depression and chronic pain. Little is known howlong-term sequelae following hospital discharge are treated. The aim of our study is to determine the effect of a primary care-based, long-term program on health-related quality of life in sepsis survivors.In a two-armed randomized multicenter interventional study, patients after sepsis (n = 290) will be assessed at 6, 12 and 24 months. Patients are eligible if severe sepsis or septic shock (ICD-10), at least two criteria of systemic inflammatory response syndrome (SIRS), at least one organ dysfunction and sufficient cognitive capacity are present. The intervention comprises 1) discharge management, 2) training of general practitioners and patients in evidence-based care for sepsis sequelae and 3) telephone monitoring of patients. At six months, we expect an improved primary outcome  and improved secondary outcomes such as costs, mortality, clinical-, psycho-social- and process-of-care measures in the intervention group compared to the control group.This study evaluates a primary care-based, long-term program for patients after severe sepsis. Study results may add evidence for improved sepsis care management. General practitioners may contribute efficiently to sepsis aftercare.DRKS00000741, CCT-NAPN-20875 (25 February 2011).U1111-1119-6345.  Sepsis is a worldwide major health concern with increasing incidence . About 8Thus, the majority of sepsis survivors suffer from a considerable deficit in physical and psycho-social functions , showingAt least, sepsis sequelae are considered to be generic for symptoms after critical illness in general , which iRehabilitation after critical illness states that ‘evidence is often missing and only incorporates aftercare for up to three months’ [et al. observed functional improvement of amputations associated with sepsis by an intensive rehabilitation program [et al. presented an increase of physical function in 126 critical illness patients who were provided a self-help manual for six months [et al., with 21 critical care patients, showed a non-significant reduction of post-traumatic symptoms using an in-house, multifaceted telemedicine program [To improve care for long-term conditions, coordination of the fragmented process by structured interventions is effective . The Bri months’ . Based o months’ . Of thes program . Jones ex months . A Briti program . In cont program . A nurse program .After ICU care and hospital-based rehabilitation, most sepsis survivors receive aftercare from their primary care physician, as with most chronically ill patients. This setting is characterized by a long-lasting doctor-patient relationship, with all health services being coordinated . PrimaryThis study will evaluate the effects of a primary care-based intervention to improve aftercare for sepsis survivors.This study will evaluate whether health-related quality of life (SF-36) and further clinical, psycho-social, process-of-care outcomes and costs of sepsis survivors will be improved by a primary care-based, sepsis-specific aftercare program.After six months, the intervention group will show an improved primary outcome (SF-36) compared to patients with usual care in the control group.The study is a multicenter, prospective, two-armed randomized controlled trial. Since the intervention could compromise educational elements for primary care physicians and patients, we are not able to perform a blinded intervention. GPs are allocated only to one patient - either to the control or intervention group.et al. [et al. [A wide range of effect sizes is found in comparable studies. Jackson et al.  reported [et al.  reportedWith a statistical power of 90% and a significance level of 0.05, we need n = 172 patients at T2 for two-sided tests. Assuming a 40% drop-out rate  and 30% Patients will be recruited from 20 ICUs in nine study centers across Germany  is collected by the study nurse, including clinical and socio-demographic characteristics. At the same time, the liaison physician contacts the responsible general practitioner (GP) by telephone to ask for study participation.Given the GP’s written consent, patients are randomized in the intervention versus control group with n = 145 patients per group. Randomization sequence is computer-generated and provided in a sealed opaque envelope.Patients are eligible on the presence of severe sepsis or septic shock, as defined by the definitions of the German Sepsis Society . Two sysFurthermore, patients must be 18 years or older and capable of sufficient German language skills.Patients are excluded from study participation due to insufficient German language skills, deafness, blindness or speech impairment. Furthermore, patients suffering from severe cognitive impairment are not eligible for study participation (determined by a telephone interview of cognitive status (TICS-M) ≤27 points) .The intervention contains three main components:1. Discharge management with structured information between inpatient and outpatient care in accordance with the transitional care model , which w2. Training of GPs and patients in sepsis sequelae and evidence-based treatment options . A speci3. Monthly telephone monitoring of patients through specifically designed telephone interviews is provided for 12 months regarding sepsis sequelae symptoms. Systematic monitoring improves the physician-patient interaction and supplies relevant information on patient clinical status to the GP, according to the chronic care model ,33.The ietcetera.After discharge from the ICU, intervention patients receive specific discharge forms from the case manager. All treating physicians  are requested to record sepsis-related clinical and social information about the patients and his or her needs. This supports the GP to manage ambulant treatment and special therapeutic needs of the patient like home care, physiotherapy, specific adjuvants Both, patients and GPs are trained in evidence-based diagnostics and therapy of the most prevalent sepsis sequelae. The liaison physician trains the GP face-to-face using audiovisual education material to impart knowledge about etiology, symptoms, diagnostic instruments and therapy options of sepsis sequelae.Patients in the intervention group are educated as well in a face-to-face situation by the case manager to get better information about:1. the study course,2. the monitoring program,3. origin and therapy of sepsis,4. possible sepsis sequelae,5. physical and psychological impacts of intensive therapy and6. coping strategies and self-efficacy.Patients and GPs receive a written manual, including both training content and monitoring instruments. Manuals are used to support training sessions. The patient manual is based on the Discern-criteria . PatientThe liaison physician provides this information to the GP with the help of a stratification of urgency (traffic light scheme). The GP is contacted immediately by phone if a new clinical condition arises and gets information about diagnostic and therapeutic possibilities, whereas the liaison physician is available for supervision and requests. In addition, the patient is asked to visit his/her GP if health problems occur.Patients in the control group are treated as usual by their GPs or ambulant specialists without any additional information or monitoring. There aren’t any outpatient sepsis follow-up clinics in Germany.Due to the lack of sepsis aftercare guidelines in Germany, there is no treatment standard available. Usual care is assessed in control group patients. Qualitative interviews of GPs and patients provide additional information.Data are collected from patients in questionnaires by trained study staff, initially face to face, and from T2 onwards, by phone call. In addition, GPs and ICU staff are asked to provide clinical information after patients have given their informed and written consent. Data are documented as written case report forms and stored in a protected cabinet.T-1, retrospectively) until 1, 6, 12 and 24 months after discharge from the ICU (T1-4).Measurements take place from 3 months before hospitalization , a multidimensional construction of physical, mental, social and behavior-related components of well-being and operational capability, validated also for German primary care .Secondary outcomes focus on the most relevant sepsis sequelae, including the assessment of physical activity, level of pain, and cognitive deficits or neuropathic symptoms by established questionnaires, all of which are patient-reported outcomes.Furthermore, for GP compliance review, treatment and cost-effectiveness analysis, patient rehospitalizations, medication, care needs, mortality, physical therapy and instrumental diagnostic procedures are documented by the primary care provider. GPs are asked to provide details of their practice characteristics.For clinical analysis, diagnoses and ICU procedures are extracted from the ICU documentation system.For detailed variable/outcome parameter descriptions see Table To gain insight into processes, barriers and mechanisms of the intervention, qualitative interviews with patients and GPs are performed on a subsample. In this context, the roles of patients’ relatives are also to be evaluated.Randomization process will be proofed using binary logistic regression. The dependent variable logarithmic odds ratio of patient is in the intervention versus control group. As predictors, we use potential confounders . Primary outcome will be analyzed based on a two-sided t-test. Secondary endpoints will be analyzed depending on scale level, using descriptive or hypothesis generating test procedures. For evaluation of average treatment effects, we will analyze the outcome variables with a generalized analysis of covariance (g-ANCOVA) and control for potential confounders. Based on these results, we are able to adjust means, which are comparable with outcome means of a perfect randomized and balanced design ,50.Furthermore, mortality is taken into account. Using survival analysis models, we are able to examine the relationship between mortality and treatment. In this way, we also try to identify mortality risk factors.Finally, we plan cost-effectiveness analyses. Therefore, we sum up the costs of micro interventions and compare the averages of treatment and control group using g-ANCOVA (see above).Showing 6- month mortality of more than 30% , severe The study is planned and conducted in accordance with medical professional codex and the Helsinki Declaration of 1996 as well as the Federal Data Protection Act (BDSG).Patients participate in the study voluntarily and give written informed consent. Patients are informed that they can cancel their participation at any time without disclosing reasons for their cancellation and without negative consequences for their future medical care. The study protocol was approved by the institutional review board of the University of Jena, 26 January 2011 (No.3001/111).The patient names and other confidential information are secured by the medical confidentiality rules and are treated according to Federal Data Protection Act (BDSG).All study-related data and documents are stored on a protected central server at Jena University Hospital. Only members of the study team have access to the study files.Intermediate and final reports are stored in the office of the Institute of General Practice and Family Medicine at the Jena University Hospital.Contacting control patients via phone calls for data collection may create a small intervention (Hawthorne) effect in the control group. Therefore, the intervention effect is likely to be underestimated. This might be acceptable because we would not overuse any effect of the trial.In addition, contamination by information flow between the intervention and control group cannot be excluded. However, this risk seems to be minimized by the allocation of one GP to one patient of either intervention or control group. Most GPs in Germany practice alone.To our knowledge, SMOOTH is the first study evaluating the effects of a primary care-based intervention for patients after a critical illness, that is sepsis . Using eThe first patient was included on 28 February 2011. Patient recruitment is ongoing but not completed.CSCC: Center of Sepsis Control and Care; g-ANCOVA: generalized analysis of covariance; GCPS: graded chronic pain scale; GP: general practitioner; GSS: German Sepsis Society; I/ADL: instrumental activities of daily life; ICD-10: international statistical classification of diseases and related health problems; ICU: intensive care unit); KFM: short form for medication use; MDI: major depression inventory; MUST: malnutrition universal screening tool; NSS: neuropathic symptom score; ODSS: modified overall disability sum score; PACIC: patient assessment of care for chronic conditions; PHQ-9: patient health questionnaire; PTSD: post-traumatic stress disorder; PTSS-10: post-traumatic stress syndrome 10-questions inventory; RIS: Regensburg insomnia scale; SF-36: short form 36 health survey; SIRS: systemic inflammatory response syndrome; SMOOTH: Sepsis Survivors Monitoring and Coordination in Outpatient Health care; STIFT: Thuringian Foundation for Technology, Innovation and Research; TICS-M: modified telephone interview for cognitive status; XSMFA-D: short musculoskeletal function.The authors declare that they have no competing interests.FM, JG, KS, JM and PT participated in the study design, study conduct/data collection and in writing the final manuscript; KBF, KSc, NS and SW participated in the study design and study conduct/data collection. AF, ChE, DD, FMB and MW participated in study design and the critical revision of the manuscript. ABK, StK and UJ participated in the study conduct and data collection. All authors approved the final version of the manuscript.Scientific advisory council and SMOOTH study centres.Click here for fileSIRS/Sepsis Criteria.Click here for fileMonitoring instruments.Click here for fileOutcome instruments.Click here for file


Post-translational modifications (PTMs) constitute a major aspect of protein biology, particularly signaling events. Conversely, several different pathophysiological PTMs are hallmarks of oxidative imbalance or inflammatory states and are strongly associated with pathogenesis of autoimmune diseases or cancers. Accordingly, it is of interest to assess both the biological and structural effects of modification. For the latter, computer-based modeling offers an attractive option. We thus identified the need for easily applicable modeling options for PTMs.We developed PyTMs, a plugin implemented with the commonly used visualization software PyMOL. PyTMs enables users to introduce a set of common PTMs into protein/peptide models and can be used to address research questions related to PTMs. Ten types of modification are currently supported, including acetylation, carbamylation, citrullination, cysteine oxidation, malondialdehyde adducts, methionine oxidation, methylation, nitration, proline hydroxylation and phosphorylation. Furthermore, advanced settings integrate the pre-selection of surface-exposed atoms, define stereochemical alternatives and allow for basic structure optimization of the newly modified residues.PyTMs is a useful, user-friendly modelling plugin for PyMOL. Advantages of PyTMs include standardized generation of PTMs, rapid time-to-result and facilitated user control. Although modeling cannot substitute for conventional structure determination it constitutes a convenient tool that allows uncomplicated exploration of potential implications prior to experimental investments and basic explanation of experimental data. PyTMs is freely available as part of the PyMOL script repository project on GitHub and will further evolve.The online version of this article (doi:10.1186/s12859-014-0370-6) contains supplementary material, which is available to authorized users. Post-translational modifications (PTMs) are chemical alterations that occur after protein synthesis ,2. PhysiConversely, pathophysiological PTMs are associated with episodes of oxidative imbalance, and there is a constant cellular endeavor to prevent and repair their occurrence. Unlike physiological PTMs, pathophysiological PTMs typically occur in proximity to the origin of the modifying agent in an uncontrolled fashion. The formation of such pathophysiological PTM on their target proteins may impinge on cellular homeostasis and immune recognition -8. SmokiAs implicated above, the effect that a PTM exerts on its carrier protein is highly individual and context-dependent ,4,12,13.There are accumulating examples of specific PTMs being recognized by scavenger receptors, complement components and antibodies due to alterations in structure and charge ,15-17. OThe antigenicity of complement-bound antigen has been demonstrated to increase by several orders of magnitude, as evidenced by co-ligation of the B cell receptor and CD19 bridged by complement component C3dg . This agIn fact, most autoimmune diseases have an implied involvement of PTMs, and associated altered peptide ligands (APLs) have been identified -5,24,25.In Rheumatoid Arthritis there is a strong association of specific MHC alleles and their ability to present citrullinated APLs, i.e. epitopes that have undergone enzymatic deimination of arginine residues to citrulline. The molecular basis of this association has only recently been characterized at a structural level . There aIn conclusion, PTMs constitute a complex layer in protein biology and immune recognition. The diversity and context-dependence of PTM-mediated effects calls for individual assessment at a structural level. Furthermore, we identify an unmet need for easily applicable modeling tools in respect to PTMs.in silico provides a rapid alternative. The online resource PhosphoSitePlus (http://www.phosphosite.org/)  and a nitrated escape variant [PDB: 3ROL] [in silico and sterically refined the structure. First we tested alternative ortho-positions for the nitration (rotamer of 3-Nitrotyrosine). We thereafter chose alternative backbone-dependent rotamers for GLU152 in the MHC side chain and TYR116 in the beta-sheet of the MHC heavy chain peptide-binding cleft. These two adaptations were expected to accommodate the nitro group without significant steric clashes. Finally, we aligned the resulting models with the experimentally resolved structure containing the nitrated epitope. The alignment demonstrated that the model created using PyTMs corresponded well to the previously determined crystal structure [Crystal structures of the immunodominant lymphocytic choriomeningitis virus (LCMV)–derived epitope gp34 in complex with a murine Major Histocompatibility Complex  encodes a potassium channel infamous for off-target drug side-effects that result in cardiac arrhythmias. Structurally hERG1 resembles other members of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels [The human channels . The porchannels . The intchannels  and/or Cchannels  residueschannels ,46.Our extended model in Figure Based on this model the critical role of CYS723 in the susceptibility of hERG1 to oxidation derives from its open accessibility and positioning at the dimer interface. The equivalent explanation is valid for MET844. For the remaining Methionine sulfoxides the inhibition is expected to be less direct and may involve rearrangement of the associated C-linker helices. Hence, several Methionine residues may require oxidation to confer the same degree of inhibition as oxidation of CYS723 or MET 844 alone.in silico using PyTMs is that the target atom is still available. For instance, it is possible to co-modify an N-terminal Tyrosine by phosphorylation, nitration and N-terminal acetylation  in a model of BSA and introduced Malondialdehyde-acetaldehyde (MAA) adducts. We implemented a basic vdW strain optimization for this PTM category as many adducts are comparatively bulky and tend to sterically clash with adjacent residues. Applying optimization rotates the modified Lysine to a more favorable rotamer, but requires some calculation time. We implemented that this optimization can be animated in PyMOL  derived from lipid peroxidation, will primarily target the most accessible residues while buried residues are likely spared. Using PyTMs we selected only surface-exposed epsilon-amines  and Major Histocompatibility Complexes (MHCs), modeling can be useful to explain or predict whether an APL can be presentable by a respective MHC allele and/or how the introduced PTM and APL may be oriented.b MHCs in complex with the lymphocytic choriomeningitis virus (LCMV)-derived immunodominant epitope gp34, without or with nitration [Herein we made use of a pair of crystal structures of murine H-2Kitration . The nititration . Using tAs described in Figure b. The acetylated peptide is too long to fit the confinements of the MHC class I groove, and the anchoring pocket cannot properly accommodate the oxidized methionine. In summary, modeling of MHC-associated APLs is possible and yields predictive results within a reasonable frame of confidence. Larger global conformational changes, however, cannot be accounted for using this approach.Furthermore, in Additional file We conclude that modeling of APLs can be a useful approach prior to experimental investments. Furthermore, it can also be applicable to predict whether a PTM is likely to be in contact with the MHC and/or a corresponding T-cell receptor.To summarize, we have presented several examples of how modeling using PyMOL and PyTMs can be applied to straightforwardly address various research questions related to PTMs. In either predictive or explanatory settings, modeling constitutes a rapid approach to investigate structural implications. The advantages of using a plugin to introduce PTMs include standardized generation of PTMs, rapid time-to-result and facilitated user control. In addition, modeling is an option to maximize cost-efficiency.in silico modeling alongside conventional structure determination.We identified two current limitations of the plugin, namely the incompatibility of non-standard residues with tested charge force field applications and a limited ability to assess changes in global conformation. Many PTMs are associated with drastic alterations in the charge pattern, rather than steric blocking, citrullination being a prime example. In concordance with this, conformational changes are probably a major mechanism through which certain PTMs mediate their effects. As both aspects are limited in PyTMS, this may restrict the interpretability of resulting models, unless well supported by experimental observations. Resolving these shortcomings presents a future challenge. Bearing this in mind, we support the reasonable application of In conclusion, PyTMs is a free, user-friendly and very convenient plugin for PyMOL and can be applied to straightforwardly address research questions connected to PTMs. We hope to address the discussed challenges over time and further extend the applicability with additional PTMs.Project name(s): PyTMs, PyMOL script repository.Project homepage:http://www.pymolwiki.org/index.php/Pytms.https://github.com/Pymol-Scripts/Pymol-script-repo.Operating systems: Platform independent.Programming language: Python (https://www.python.org/).Other requirements: PyMOL (http://www.pymol.org/).License: GNU General Public License, version 2 (GPL-2.0).


Anoxybacillus thermarum AF/04T was isolated from the Euganean hot springs in Abano Terme, Italy. The present work reports a high-quality draft genome sequence of strain AF/04T. This work also provides useful insights into glycoside hydrolases, glycoside transferases, and sugar transporters that may be involved in cellular carbohydrate metabolism. Anoxybacillus spp. are Gram-positive alkalothermophilic bacteria that thrive in a variety of habitats  was isolated from thermal mud at the Euganean hot springs in Abano Terme, Italy , according to the manufacturer’s protocol. The paired-end library was prepared using the standard protocol of the Nextera DNA sample preparation kit . Sequencing was performed using the Illumina MiSeq sequencing platform with 300-bp paired-end reads. The adapter sequences, low-quality regions, and reads were filtered out using Trimmomatic  and glycoside transferase (GT) enzymes that are possibly involved in cellular carbohydrate metabolism. The GHs  and GTs  may be required for cellular starch and sucrose metabolism. Some of the aforementioned GHs  may also be involved in cellular galactose metabolism. Genes encoding several putative sugar transporters, such as ATP-binding cassette (ABC) and phosphotransferase system (PTS) transporters, were also found in the genome, suggesting that these transporters may facilitate sugar uptake by the cells from the environment. Thus, the aforementioned GHs, GTs, and sugar transporters are worthy of further examination to gain a possible explanation for the limited carbon uptake behavior of strain AF/04T.The AF/04JXTH00000000. The version described in this paper is the first version, JXTH01000000.This whole-genome shotgun project has been deposited in DDBJ/EMBL/GenBank under the accession no.


Periprosthetic joint infection (PJI) is a serious complication of total knee arthroplasty. Two-stage revision is the most widely used technique and considered as the most effective for treating periprosthetic knee infection. The one-stage revision strategy is an emerging alternative option, however, its performance in comparison to the two-stage strategy is unclear. We therefore sought to ask if there was a difference in re-infection rates and other clinical outcomes when comparing the one-stage to the two-stage revision strategy.Our first objective was to compare re-infection (new and recurrent infections) rates for one- and two-stage revision surgery for periprosthetic knee infection. Our second objective was to compare between the two revision strategies, clinical outcomes as measured by postoperative Knee Society Knee score, Knee Society Function score, Hospital for Special Surgery knee score, WOMAC score, and range of motion.Systematic review and meta-analysis.MEDLINE, EMBASE, Web of Science, Cochrane Library, reference lists of relevant studies to August 2015, and correspondence with investigators.Longitudinal (prospective or retrospective cohort) studies conducted in generally unselected patients with periprosthetic knee infection treated exclusively by one- or two-stage revision and with re-infection outcomes reported within two years of revision surgery. No clinical trials comparing both revision strategies were identified.Two independent investigators extracted data and discrepancies were resolved by consensus with a third investigator. Re-infection rates from 10 one-stage studies (423 participants) and 108 two-stage studies  were meta-analysed using random-effect models after arcsine transformation.The rate  of re-infection was 7.6% (3.4–13.1) in one-stage studies. The corresponding re-infection rate for two-stage revision was 8.8% (7.2–10.6). In subgroup analyses, re-infection rates remained generally similar for several study-level and clinically relevant characteristics. Postoperative clinical outcomes of knee scores and range of motion were similar for both revision strategies.Potential bias owing to the limited number of one-stage revision studies and inability to explore heterogeneity in greater detail.Available evidence from aggregate published data suggest the one-stage revision strategy may be as effective as the two-stage revision strategy in treating infected knee prostheses in generally unselected patients. Further investigation is warranted.PROSPERO 2015: CRD42015017327 One of the most serious complications of total knee arthroplasty (TKA) is deep periprosthetic joint infection (PJI). Cure of PJI is not possible by antibiotic treatment alone in the majority of cases and surgical treatment is required. Options include: debridement, treatment with antibiotics and retention of the prosthesis; one-stage revision; two-stage revision; resection arthroplasty; or arthrodesis or amputation as a last resort , 2. MostTo date, no randomized controlled trial has compared the effectiveness of the one- and two-stage revision procedures. However, a number of reviews based on observational evidence have assessed re-infection outcomes (recurrent and new infections) comparing both revision strategies and have mostly reported inconclusive results. In 2009, Jamsen and colleagues in their review of a total of 31 studies, reported overall infection eradication rates of between 73 to 100% and 82 to 100% in one- and two-stage revision strategies respectively [The current evidence does not conclusively support a superior revision strategy for periprosthetic knee infection. In addition, several features of these previous reviews existed which limited the generalisability and validity of the findings. First, all of the reviews were characterised by a small number of one-stage revision studies (< 10 studies), which limited reliable comparability of the two revision strategies. Second, the heterogeneous periods of follow-up for re-infection outcomes in the individual studies were considered, which did not enhance comparability and interpretation of the findings. Third, none of the reviews explored for potential sources of heterogeneity among the contributing studies. Fourth, assessment of publication bias or small study bias was not conducted. Fifth, none of the reviews conducted any subgroup analysis across important study-level and clinically relevant characteristics . Sixth, apart from the study by Jamsen and colleagues  which waIn line with the uncertain evidence and recommendations of previous reviews , 9, therOur review has been registered in the PROSPERO prospective register of systematic reviews (CRD42015017327) and was conducted using a predefined protocol and in line with PRISMA  who were treated exclusively by one-stage or two-stage revision with a follow-up duration of at least two years for re-infection outcomes (recurrent and new infections). We excluded: (i) studies that reported case series of methods in selected group of patients (such as patients with a specific infection); (ii) studies that did not include patients with less than two years of follow-up; and (iii) studies with less than 10 participants as these were more likely to be case series which did not include consecutive patients.After an initial screen of abstracts by one reviewer (S.K.K.), potentially relevant articles were acquired. Each article was assessed by two independent reviewers  using the inclusion criteria and any discrepancies regarding eligibility of an article was discussed, and consensus reached with a third author (M.R.W). One author (S.K.K.) independently extracted data and performed quality assessments using a standardized data collection form. A second reviewer checked data with that in the original articles. Data were extracted on study design, year of publication, geographical location, mean baseline age, proportion of males, period of follow-up following revision surgery, type of fixation used for re-implantation used, use of and type of spacer, number of re-infection outcomes and participants, and clinical characteristics such as preoperative and postoperative Knee Society Knee score, Knee Society Function score, Hospital for Special Surgery knee score, WOMAC score, and range of motion. For multiple publications involving the same study, the most comprehensive study was used. We corresponded with study investigators to provide missing information. Information on the methodological quality of included studies was assessed based on the Methodological Index for Non-Randomised Studies (MINORS), a validated instrument which is designed for assessment of methodological quality of non-randomized studies in surgery  and has 2 statistic [The rate of re-infection  with 95% confidence intervals (CIs) was used as the summary measure and primary outcome across studies. The Freeman-Tukey variance stabilising double arcsine transformation  was usedtatistic  were usetatistic , 22. We tatistic . In the tatistic . Though tatistic , we empltatistic . Given ttatistic , this waOur computer search and manual screening of reference lists of relevant studies identified 12,392 potentially relevant citations. After initial screening based of titles and abstracts, 244 articles remained for further evaluation. We excluded 135 articles following detailed assessments (Appendix D in P < 0.001)  was not explained by any study-level characteristics explored . Among the higher quality studies, the pooled re-infection rate (95% CI) was 6.4% , which was similar to the main finding. In further exploration of heterogeneity, on exclusion of the single largest study comprising of 118 participants (with 20 re-infections) [I2 = 48%, 95% CI: 0–76%; P = 0.053) and the pooled re-infection rate (95% CI) was 6.2% . There was no statistically significant evidence of publication bias using the Egger test (P = 0.516), consistent with the absence of selective reporting when studies were grouped by size  reported on re-infection outcomes in patients using the one-stage surgical revision strategy . The poo< 0.001) . The 95%ections) , heterogP < 0.001) , which was unexplained by any of the study-level characteristics assessed , which was similar to the main finding. The rates of re-infection were generally similar across study relevant characteristics. There was no evidence of heterogeneity , when we restricted the analysis to studies of the highest quality. Among the higher quality studies, the pooled re-infection rate (95% CI) was 6.1 .There was evidence of publication bias (Egger’s P = 0.008) and Duval and Tweedie’s trim-and-fill method resulted in no additional imputed studies  . The corClinical outcomes as measured by postoperative Knee Society Knee score, Knee Society Function score, and range of motion following revision arthroplasty, were similar between both revision strategies ; howeverGiven the uncertainty regarding the performance of the one-stage revision strategy in comparison to the two-stage strategy when treating periprosthetic knee infection, we sought to ask if there was a difference in re-infection rates and other clinical outcomes when comparing the one-stage to the two-stage revision strategy. Using a systematic and meta-analytical approach, we aimed to compare the effectiveness of the one- and two-stages revision strategies, using re-infection rate as a primary outcome and other clinical outcomes as measured by postoperative Knee Society Knee score, Knee Society Function score, Hospital for Special Surgery knee score, WOMAC score, and range of motion following revision arthroplasty. We found similar re-infection rates following one- or two-stage surgical revision for infected knee prostheses. For both revision strategies, our findings also showed that re-infection rates were generally similar  across several study relevant characteristics. The findings for other clinical outcomes were similar for both revision strategies; however, in the context of the limited data for one-stage revision studies, these findings should be interpreted with cautionSome of our findings are consistent with that of previous reviews on the topic. We also provide several findings that have not been previously reported. Our findings suggest the one-stage as an equivalent revision strategy to the two-stage in terms of effectiveness for treating periprosthetic knee infection, consistent with the results of some previous reviews , 9. HoweGiven that the control of infection and maintenance of joint function are considered as main criteria for a successful outcome following one- or two stage revision , 30, ourWith the establishment in the treatment of hip periprosthetic joint infection of the one-stage revision strategy by Buchholz and colleagues over four decades ago , its useThe strengths of the current review deserve mention. First, given the large number of studies included (twice as many one- and two-stage studies than the most recent previous review ), we hadThe limitations also deserve consideration. We acknowledge the limited number of one-stage revision studies, which precluded the ability to robustly compare re-infection rates and other clinical outcomes between the two interventions. We could not conduct detailed subgroup analyses by relevant subgroups such as co-morbidities  and duration of antibiotic therapy, given the limited data. We aimed to include only studies that that did not involve selected patients, however, this may not have been possible in some instances given the earlier phase of selection related to management without further replacement in some studies. Though we aimed to include studies that reported re-infection outcomes within two years of revision surgery, there is a possibility some re-infection outcomes may have occurred outside this period as some authors did not respond to requests for further information. Our findings are comprehensive, important and timely, but should be interpreted with caution in the context of the level of evidence. Indeed, to robustly compare the effectiveness of one-stage and two-stage revision strategies, will require evidence from a carefully designed randomized clinical trial.Available evidence from aggregate published data suggest the one-stage revision strategy may be as effective as the two-stage revision strategy in treating infected knee prostheses in generally unselected patients. Further investigation is warranted.S1 File(DOC)Click here for additional data file.S2 File(CSV)Click here for additional data file.


Concurrent infection with multiple types of Human Papillomavirus (HPV) is associated with an increased risk of cervical cancer; yet, little is known about risk factors for concurrent HPV infection in Vietnam. This study investigated the prevalence of and risk factors for high-risk-type HPV and multi-type HPV infections among women in Ho Chi Minh City, Vietnam.Data were collected from a population-based survey of 1,550 women , using a multi-stage sampling process. Socio-demographic and behavioral variables were obtained by self-report. HPV genotypes in cervical specimens were identified using PCR protocols.The prevalence of any high-risk HPV infection was 9.0%, and of multi-type HPV infection was 1.9%. In the HPV+ subsample, the percentage of high-risk HPV was 84% and of multi-type HPV was 20%. All multi-type HPV infections were high-risk-type. Lifetime smoking and older age of first sex were significantly associated with any high-risk and multi-type HPV infections. Regular condom use was inversely associated with high-risk and multi-type HPV infection.Risk factors for high-risk and multi-type HPV infections were similar. Further research and intervention are needed to reduce HPV infections in order to prevent HPV-related cancers. Human Papillomavirus (HPV) infection, particularly persistent infection with high-risk types, is a major preventable causal agent of cervical cancer ,2. More Concurrent infection with multiple HPV types is common. In a pooled analysis in 15 areas worldwide, the prevalence of multi-type HPV infection ranged from 0.3–11.8% . Among HAlthough a few studies have reported risk factors associated with general HPV infection in HCMC, Vietnam , little This study employed data from a population-based household survey of 1,550 women in HCMC, which was conducted from April 2008 to January 2009 to examine the predictive values of using an HPV test and/or a Pap smear in cervical cancer screening and diagnosis. Participants were selected through a two-stage sampling process. First, 10 districts (out of 24) and two communes (out of an average of 16) in each district in HCMC were randomly selected. Then, in each district, individuals were sampled where the probability of being selected was proportional to the size of the ward, based on the commune police registration lists. Women were eligible if they ever had sexual intercourse, were 18–69 years old, were registered residents of HCMC, and did not suffer from mental impairment. Exclusion criteria included women who were pregnant, had undergone a hysterectomy or a treatment for potential cervical cancer; had abnormal vaginal bleeding, or had any obstetrical/gynecological emergency. Selected women were fully informed about the purpose of the parent study, and the benefits/risks of participation. Women who agreed to participate provided written informed consents, and were invited to come to the commune health stations for a brief 15-minute interview and a gynecological examination, including collecting specimens for HPV tests and Pap tests. Interviews to obtain participants’ demographic and behavioral characteristics and medical history were conducted in Vietnamese in a private place  at the commune health stations. Cervical specimens were then collected by trained gynecologists. Each participant received compensation  for their time and transportation. Women who had a Pap result of ASCUS or higher  were referred to OB/GYN hospitals in HCMC for further examination and diagnosis. The parent study protocol was approved by Ethical Review Committees of the University of Medicine and Pharmacy in HCMC and of the Department of Science and Technology in HCMC. Given the objectives of the parent study, a desired sample size of 1,566 was identified. A total of 1,566 eligible women were contacted, of whom 1,550 agreed to participate (response rate = 99%). Fifty participants who had no HPV test results were excluded from this analysis, resulting in a total sample size of 1,500.Socio-demographic and behavioral variables used in this analysis were obtained from self-reported data via brief face-to-face interviews. These were participants’ factors and their husbands’ factors. Participants’ factors included age, parity, education level, marital status, age of first sexual intercourse, history of sexually transmitted infections (STIs), smoking history, lifetime number of sexual partners, and overall regular condom use. The husbands’ factors included education level, smoking history, and lifetime number of sexual partners. Current vaginitis or cervicitis was obtained from participants’ gynecological examination records. Specimens for HPV testing were obtained by cervical swab, placed in a sterile tube, and transferred to the Biology-Cell Laboratory of the University of Medicine and Pharmacy in HCMC on a daily basis for HPV DNA testing. L1 consensus PCR (MY09/11) was used to screen for HPV DNA. This test procedure could identify 25 HPV genotypes, including 8 low-risk types , 16 high-risk types , and one type with risk undetermined .To account for the complex survey design, the data used in this analysis were weighted for the population sizes of the primary sampling units , aided by survey procedures in Stata 11 . Frequency distributions were used to examine the prevalence of HPV infection with any types, high-risk types, and multiple types. Chi-square and binary logistic regression were used to examine associations between demographic/behavioral characteristics and high-risk-type HPV infections. The bivariate association between each demographic/behavioral characteristic and multi-type HPV infection was examined by an ordinal logistic regression , in whicOf the 1,500 surveyed respondents who had HPV test results, the mean age of participants was 42.4 years (SD = 9.5 years). About half of participants had two children and the highest number of children was nine . Participants’ smoking status was strongly and significantly associated with the two HPV-infection outcomes. Using no HPV infection as the reference group, the odds of being infected with high-risk-type HPV were 24.2 in women who ever smoked compared to those who never smoked. Smoking also increased the odds of being infected with multiple types of HPV (OR = 15.4). Regular condom use was significantly associated with a lower likelihood of multi-type HPV infection (p = .032). When we further compared 50 multi-type high risk cases with 99 single-type high risk HPV cases, the results were comparable to previous findings.Our study results revealed that the prevalence of HPV in a population-based sample of women in HCMC, Vietnam was 9.0% for infection with high-risk types, and 1.9% for infection with multiple types of HPV. The prevalence of high-risk HPV infection in our study is comparable to previous results of vaginal-cervical HPV infection in a similar population in HCMC ,7; howevIntervention or management to reduce high-risk HPV infection is important because of its oncogenic potential. Several studies have examined risk factors of high-risk HPV infection at the vaginal or cervical sites; however, evidence regarding risk factors other than sexual behavioral risks is inconsistent . AlthougSimilar to several previous studies ,24, our Although the proportions of multi-type HPV infection were not statistically different by most demographic and behavioral characteristics , the significant odds ratios of ordinal logistic regression suggested that irregular condom use and smoking increased the risk of being infected with multiple HPV types. In other words, risk factors of multi-type HPV infection in this study were very similar to the risk factors of high-risk type HPV infections. Although previous studies suggested that multi-type HPV infection was particularly more common in young women and women with multiple sexual partners ,8,26, thOur study has some limitations. Given the cross-sectional nature of the data, causality between risk factors and HPV outcomes cannot be established. However, most genital HPV infection is current and transient ; so HPV Because in our study multi-type HPV infection included only high-risk types, future studies should investigate multi-type HPV infection which comprises of multiple high-risk only, multiple low-risk only, and multiple with both high-and low-risk. Despite our relatively large sample size, the low HPV prevalence, particularly with multiple types, limited statistical power to detect associations and hence generated wide confidence intervals. Future prospective cohort studies are also needed to longitudinally investigate risk factors of multi-type HPV infection, interactions, and persistence.Our population-based survey suggested that risk factors for multi-type HPV infection in women in HCMC, Vietnam, were similar to risk factors for high-risk-type HPV infections. Risk factors, which showed a statistically strong association, included women’s smoking status, and older age of first sexual debut. Regular condom use was inversely associated with high-risk and multi-type HPV infection. Future research and intervention projects  are needed to reduce high-risk-type and multi-type HPV infections in order to prevent consequent HPV-related cancers.


Biological proteins have unlimited potential for use as pharmaceutical products due to their various biological activities, which include non-toxicity, biocompatibility, and biodegradability. Recent scientific advances allow for the development of novel innovative protein-based products that draw on the quality of their innate biological activities. Some of them hold promising potential for novel therapeutic agents/devices for addressing hepatic diseases such as hepatitis, fibrosis, and hepatocarcinomas. This review attempts to provide an overview of the development of protein-based products that take advantage of their biological activity for medication, and discusses possibilities for the therapeutic potential of protein-based products produced through different approaches to specifically target the liver  in the treatment of hepatic diseases. Taking advantage of these data, certain biological proteins, such as albumin, fibrinogen, and immunoglobulin, are now routinely used in clinical situations as the gold standard for the treatment of severely ill patients. Furthermore, they have unlimited potential for further use in a variety of clinical situations. A number of studies have reported on the innate biological characteristics of biological proteins, and protein-based products are currently under development. One of the benefits of using proteins for medications is that they have higher biocompatibility and biodegradability than polymeric drugs that are based on synthetic polymers. Thus, biological proteins can be useful as biologics and/or carriers for other bioactive agents. In fact, an albumin–paclitaxel nanoparticle (Abraxanecarrier) ,2. Many The liver is well known for its ability to take up high amounts of exogenous substances, because liver Kupffer cells make up approximately 80% of the macrophages in the entire human body . Such ceAlbumin is an approximately 67 kDa monomeric protein produced by hepatocytes and has been shown to be nontoxic, non-immunogenetic, biocompatible, and biodegradable, thus making it a versatile protein with potential for use in the production of protein-based products . In addiPichia pastoris expression system [+) on CD68+ Kupffer cells [+ Kupffer cells can produce relatively high levels of ROS, which play a major role in the progression of liver pathologic conditions [The use of mannosylated albumin is one of the suitable strategies for liver-selective targeting via a mannose receptor. In a previous study, we genetically prepared mannosylated-recombinant HSA (Man-rHSA) using a n system . This hin system . Intereser cells . This menditions . In factnditions .During the course of a liver disease, HSCs transdifferentiate into extracellular matrix-producing, highly proliferative myofibroblasts that promote hepatic fibrogenesis . Thus, Het al. prepared sodium ferulate (SF)-loaded BSA nanoparticles using a desolvation procedure and showed a much higher hepatic delivery of SF in SF-loaded BSA nanoparticles than in SF solutions [et al. [et al. [Albumin nanoparticles are ideal for encapsulating lipophilic drugs within them due to the high protein binding of lipophilic drugs to albumin, and a large variety of protocols for preparing albumin nanoparticles have been established ,20. Therolutions . Furtherolutions . As the  [et al.  and Sant [et al. .et al. prepared glycyrrhetinic acid (GA)-modified HSA nanoparticles (GA-HSA nanoparticles) for the targeted delivery of doxorubicin to liver tumors [in vitro cell uptake study and an in vivo biodistribution study revealed a promising new vehicle for targeting liver tumor chemotherapy in which doxorubicin-loaded GA-HSA nanoparticles increased cytotoxic activity in HepG2 cells in vitro and exhibited a much higher level of tumor accumulation in hepatoma (H22 cell)-bearing mice. Similarly, other groups prepared surface-modified HSA/BSA nanoparticles, such as hemato-porphyrin and particles modified with galactosamine, for the targeted delivery of anti-cancer drugs to hepatocellular carcinomas [Albumin nanoparticles could serve as a rational tumor-targeted drug delivery system because such nanoparticles would be expected to accumulate in solid tumors via the enhanced permeability and retention (EPR) mechanism when the size range is regulated at around 100 nm . Recentlr tumors . The resrcinomas ,28,29. Tet al. investigated the potential of HSA nanoparticles as contract agents for the detection of hepatocellular carcinoma by magnetic resonance imaging [in vitro and in vivo study. This suggests that albumin nanoparticles have the potential for use as a promising diagnostic tool.Watcharin  imaging . They prPichia pastoris, and the structural, physicochemical, and pharmacokinetic properties of rHSA were found to be identical to those of HSA derived from plasma [The advancement of recombinant DNA technology enables two genetically fused protein molecules to be produced. In addition, rHSA has been successfully produced using m plasma ,32, leadm plasma ,34).Our group designed and successfully prepared a fusion protein of thioredoxin-1 (Trx) and HSA (HSA-Trx), and the resulting HSA-Trx preserved the therapeutic efficacy of Trx (antioxidant and anti-inflammatory effect) . Trx hasInterferon (IFN)-α has stimulated a revolution in the treatment of chronic hepatitis C (HCV), and the current standard of HCV care is a combination of PEGylated IFN-α with ribavirin and boceprevir/telaprevir . AlbinteTo further enhance the quality and efficiency of drug delivery substances, they are frequently modified with polyethylene glycol (PEG) . There iin vivo. Katsumi et al. used albumin as an NO-traffic material, and developed a PEGylated albumin-based NO donor in which 10 NO molecules were covalently bound to PEGylated BSA through S-nitrosothiol linkages (SNO-PEG-BSA), and SNO-PEG-BSA exceeded the extent of the release half-life of NO by compared to S-nitrocylated BSA (SNO-BSA) [in vitro and showed a long circulation time in the plasma after intravenous injection in mice. Furthermore, PEG-BSA-SH showed therapeutic potential for the treatment of fulminant hepatic failure that was induced by an intraperitoneal injection of d-galactosamine /lipopolysaccharide (LPS) into mice [NO delivery is expected to achieve therapeutic effects in hepatic injury, but NO gas as a therapeutic agent is limited because of its short half-life SNO-BSA) . As a loSNO-BSA) . FurtherSNO-BSA) . PEG-BSAnto mice . These f®) is currently the most effective non-biological liver support device and can effectively remove protein-bound and water-soluble substances such as ammonia, bilirubin, bile acids, and medium- and short-chain fatty acids from the circulation [® and the results of clinical trials have been reported elsewhere [® applications where the removal of bilirubin and any other protein binding toxins from the body would be desirable.The molecular adsorbents recirculatory system  is an acidic glycoprotein hormone with a molecular weight of approximately 30 kDa that is synthesized predominantly in the kidneys in response to erythropoietic stress such as tissue hypoxia . Biologi3 kinase ,90. Theset al. reported that perioperatively administered EPO and G-CSF enhanced liver regeneration in a rat study [et al. performed a prospective study, a single-center randomized trial, involving a series of patients with decompensated cirrhosis who were randomly assigned to groups and given G-CSF and EPO (darbopoietin α) or a placebo [In animal studies, it was clearly shown that systemically administrating EPO increased liver regeneration and enhanced survival after a partial hepatectomy ,92,93. Iat study . More re placebo . The res1-Acid glycoprotein (AGP) is an acute phase protein in the blood. AGP is comprised of 183 amino acid residues and contains five N-linked oligosaccharides, with a molecular weight of approximately 44 kDa [*S and A variants  [et al. found that AGP inhibits apoptosis of hepatocytes induced by TNF/galactosamine and TNF/actinomycin D in mice via suppressing the activation of caspase 3 and 7, which is a key factor in inducing apoptosis [et al. demonstrated that treatment with AGP reduced multifocal necrosis in the liver in concanavalin A-induced hepatitis model mice [αy 44 kDa . AGP exivariants , and the effects . Kagaya benzene) . In addipoptosis ,101. Furdel mice . These fet al. prepared NF-κB inhibiting decoy oligodeoxynucleotide-loaded gelatin nanoparticles, and clearly showed their therapeutic effects against d-GalN/LPS-induced fulminant hepatic failure injury and concanavalin A-induced hepatitis [Gelatin is a denatured protein that is made of animal collagen; it is clinically used as a plasma expander and included as a stabilizer in a number of protein formulations due to its biocompatibility, biodegradability, and low cost . These aepatitis . Moreoveepatitis , and achepatitis ,106 and epatitis .et al. administered CO-bound liposomal Hb to hemorrhagic shock model rats as a resuscitation fluid [Hemoglobin (Hb) consists of four subunits  and four heme moieties A, and inon fluid . The reson fluid . Similaron fluid ,116.in vitro and targeted ribavirin delivery to the liver in an in vivo study [in vitro and altered the course of hepatitis virus infections in vivo as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease in mice [Since native Hb generated from lysed RBCs is scavenged by macrophages via the CD163 scavenging receptor ,118, somvo study ,121. Fur in mice . These r®), will be clinically developed for use in treating a variety of hepatic diseases.Numerous protein-based products have been developed in attempts to achieve their clinical use as pharmaceutical products, but fewer protein-based products have been approved for clinical use than other low-molecule drugs. Recent advances in scientific technologies such as recombinant protein engineering, biochemical analysis, and analytical instrumentation technique provide novel functional aspects and insights into not only proteins but also the liver to further develop innovative protein-based products for the treatment of hepatic diseases. In the near future, it is expected that novel protein-based products, similar to albumin–paclitaxel nanoparticles (Abraxane


N = 70) endorsed fewer delusion-like beliefs than non-clinical individuals with psychotic-like experiences (N = 12), they scored highest on delusional conviction, distress and preoccupation, followed by non-clinical individuals with psychotic-like experiences, and then healthy controls (N = 642). Self-serving bias was found in patients and non-clinical individuals with psychotic-like experiences, but not in healthy controls. Personalizing bias for negative events was not significantly different across the three groups. When compared with healthy controls, non-clinical individuals with psychotic-like experiences had an exaggerated self-serving bias, but were not more marked in personalizing bias. Self-serving bias and personalizing bias were both associated with delusional dimensions. However, the association between self-serving bias and number of delusion-like beliefs was stronger among patients than non-clinical participants. Future research could investigate the extent to which self-serving bias, in combination with an appraisal of delusional ideation as convincing, distress, and preoccupying, contributes to the development of clinical delusions.This study compared delusional dimensions and attribution biases along the continuum of psychosis. Participants completed questionnaires on delusion-like beliefs and attributions. Although patients with first-episode psychosis ( The view of psychosis as a continuum has been supported by two main lines of research—that psychotic symptoms are reported across clinical and non-clinical populations, and that psychosocial factors that predict the development of psychotic symptoms in patients also exert similar impacts in non-clinical individuals –8.Studies assessing delusions multi-dimensionally found that dimensions/ aspects of delusional experience, especially distress and preoccupation, are more important than number of delusions in distinguishing patients from community samples –11. Howeth percentile) did not differ from healthy controls in personalizing bias. Using a screening instrument to identify community individuals with a high risk of psychosis, this study hypothesizes that there will be stronger SSB and PB in clinical patients than in non-clinical individuals and explores the association between attributions and delusionality across groups.Previous research has shown that patients with delusions tend to attribute positive events to the self and negative events to external causes , especially to other people  –15, withResearch ethics was approved by the Kowloon West Cluster Clinical Research Ethics Committee in Hong Kong. Chinese outpatients with a case note diagnosis of schizophrenia spectrum disorder according to the Diagnostic and Statistical Manual of Mental Disorders  were rect tests and chi-square tests revealed no significant group difference (p > .05) in age , years of education , and gender .A total of 70 patients with FEP and 654 non-clinical, community participants were recruited to this study. Formal psychiatric diagnosis was available in 38 clinical patients . On average, they had been receiving psychiatric service for 20.2 months (range: 0–48). The clinical and non-clinical participants were matched on the key demographic variables. Independent-sample Non-clinical, community individuals were recruited from schools and universities, community organizations, and the Internet. Exclusion criteria were as follows: Personal or family history of mental illness, current or previous substance use, history of brain injury or organic mental disorders.Upon written consent, participants completed the following self-reported questionnaires individually, with researcher’s assistance when required.On the Internal, Personal and Situational Attributions Questionnaire , particThe SSB score was obtained by subtracting the percentage of internal attributions for negative events from the percentage of internal attributions for positive events, with an SSB score >0 indicating the presence of SSB.The PB score is the number of external-personal attributions for negative events divided by the total number of external-personal and external-situational attributions for negative events. A PB score of 0.5 or above indicates the presence of PB .r = 0.82; [The Peters et al. Delusions Inventory  consist = 0.82; ).The Community Assessment of Psychic Experiences  is a quCutoff scores of the positive subscale have been reported for reliable detection of ultra-high risk for psychosis . AccordiAll participants completed IPSAQ and PDI, whereas CAPE was completed by non-clinical participants only.Statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 19.0 . DelusioN = 724), included both SSB and PB as IVs, and the following PDI scores as DVs respectively: number of beliefs, mean level of conviction, mean level of distress, and mean level of preoccupation. Significance level of regression analysis was corrected for the number of models tested. Where SSB or PB showed a significant prediction of a PDI score, a second set of regression models were tested, which included Group, Group x SSB and Group x PB interaction effects as IVs. This was to ascertain whether the predictive effect of the attributional biases differs between clinical (N = 70) and non-clinical (N = 654) individuals.Relationship between attributional biases (SSB and PB) and delusional dimensions was analyzed using linear regression models (forced entry method). The first set of models, using data from the whole sample .The PDI scores across groups are shown in NC-P endorsed the greatest number of delusion-like beliefs, followed by FEP, and then NC-NP.p > .05).Within the clinical group, there was no significant correlation between duration of psychiatric service received and any of the PDI scores  and NC-P . The difference between the NC-P and FEP groups did not reach statistical significance . The NC-NP group also had a significantly lower proportion of individuals showing an SSB (35.8%) than both the FEP  = 19.48, p < .001) and NC-P , p < .001) groups.As shown in p > .025). PB for negative events was stronger in FEP than NC-NP group . The difference between the FEP and NC-P groups  and that between the NC-P and NC-NP groups  did not reach statistical significance.There was a significant group difference in PB. However, after correcting for the number of comparisons (i.e. 2), the overall group difference no longer remained significant (N = 724) reached statistical significance (p < .05). PDI number of beliefs was positively associated with both SSB  and PB , which remained significant after correcting for the number of tests. The Group x SSB interaction effect was significant , with a stronger association between number of beliefs and SSB in patients than in healthy individuals  and PB , which remained significant after correcting for the number of tests. The association between conviction and either bias was not significantly different between groups  and PB , which remained significant after correcting for the number of tests. The Group x SSB interaction effect fell out of the corrected significance level  and PB , which remained significant after correcting for the number of tests. The association between preoccupation and either bias was not significantly different between groups . On the other hand, SSB alone did not contribute to clinical delusions leading to need for care. Rather, both SSB and an evaluation of the delusional ideation as convincing, distressing and preoccupying distinguished patients from the high-risk group. The suggestion that SSB, in combination with delusional dimensions, contributes to the development of clinical delusions is a hypothesis that needs to be considered with caution because our study was limited by a cross-sectional design and use of self-reported measures of delusionality and attributions. It is also noteworthy that our healthy group reported a weaker SSB than previous studies. Although this is consistent with the view that SSB is more robust in the Western cultures and is smaller in Asian samples –35, we dN = 12). The small size of this group limited the power of group comparisons, especially for differences that had a moderate effect size but did not reach statistical significance due to the small sample size. Whilst we identified non-clinical individuals with psychotic-like experiences according to an established psychometric criterion using the CAPE, a more reliable screening method would be a comprehensive diagnostic interview. Moreover, the CAPE cut-off score for psychotic-like experiences used in this study was developed based on help-seeking clinical samples. Since there is a much lower base rate of psychosis in the community compared to the clinics, we cannot assume that the sensitivity and specificity of the scale would be the same in the community. In addition, we did not have the patients’ complete symptom profile. This limits the generalizability of our results in general, and makes it harder to interpret the PB results in particular, because PB has previously been linked more specifically to persecutory delusions than other subtypes of delusions. This study also lacked comprehensive assessment of emotional distress, which has been suggested to contribute to the development of delusions [One of the limitations of this study was the small group of non-help-seeking individuals with a high risk of psychosis (elusions –38. TherS1 File(XLSX)Click here for additional data file.