Free vascularized fibular grafts have been widely used for the reconstruction of long bone defects. However, the use of a vascularized tibial graft is precluded by its weight-bearing function and unacceptable donor site morbidity.We present a rare case of using a vascularized tibia-fibular composite graft taken from a 6-year-old Chinese boy’s ipsilateral lower leg to reconstruct a large bony defect of his traumatic femur. Hypertrophy of the tibial graft, good remodeling of the femoral shaft, and atrophy of the unloaded fibular graft were noted at the 10-year follow up. He was able to participate in outdoor activities such as basketball while wearing his prosthesis.The 10-year follow up demonstrates the feasibility of this salvage procedure for a floating knee injury with neurovascular compromise. Since Taylor  reportedA 6-year-old Chinese boy sustained a crush injury in a motor vehicle accident resulting in extensive damage to his right lower limb with comminuted fractures of his right femur and his right tibia-fibula. His right femur was a Gustilo type IIIC fracture with sciatic nerve and femoral artery tears associated with a 9cm bony fragment lost during the trauma Figure A. His riEscherichia coli and Streptococcus bovis. On the 7th postoperative day, bone scanning using technetium-labeled methylene diphosphonate was performed which demonstrated positive uptake on both ends of the donor tibia-fibular graft. Because the right leg was not stable enough, no specific physical therapy or temporary prosthesis was used. The wound at the medial and posterior aspect of the right thigh became erythematous and purulent discharge was noted 11 days after the initial operation. Debridement of the necrotic muscle and tissue was performed and the wound was then closed loosely. The antibiotics were changed to cefamandole 250mg every 8 hours and ampicillin 500mg every 6 hours, based on the culture data. The stump of the below-knee amputation also became necrotic and was debrided 26 days after the initial surgery. The skin and wound condition were stabilized thereafter.Postoperatively, the patient was treated with intravenous antibiotics using cefazolin 500mg every 8 hours and gentamicin sulfate 20mg every 8 hours. No anticoagulants were used postoperatively in this patient. Subsequent wound cultures grew The patient was discharged 6 weeks after the operation, with the wound clear and the infection under control. Non-weight-bearing crutch walking was started 5 weeks after the surgery and partial-weight-bearing was allowed 2 months later when the patient used 50% weight-bearing with the aid of a below-knee prosthesis. Unfortunately, delayed callous formation at the distal femoral-graft junction and pin tract infection in the distal femur were noted at 4 months after surgery Figure A. ClinicSevere open fractures are surgical emergencies that should be thought of as incomplete amputations . The onlet al. [Free vascularized fibular grafting has been reported many times in the literature for use in the salvage of massive bony defects, and that hypertrophy of the free vascularized fibular graft can also increase the limb’s weight-bearing capacity ,6-10,14.et al. . The traFor a segmental bone gap of 6cm or less, traditional bone grafting techniques may suffice. For a defect greater than 6cm, a fibula is preferable as a free vascularized bone graft -5,8-10 bDelayed callus formation was found in our patient, because we initially used Hoffmann’s external fixation for a leg that sustained a high-energy trauma with potential skeletal infection. We were concerned whether the transferred distal tibial epiphyseal plate would influence the ultimate length of the femur, alignment, and host-donor bony union. The second-staged operation using dynamic compression plating supplemented by an iliac bone graft rigidly aligned the host-donor bones and achieved early union. The transferred epiphyseal plate of the distal tibia and fibula were removed at that time because there was no length discrepancy of the injured femur. On the standing scanogram at the 10-year follow up, the limb proved to be on the same axis as the normal leg, and the knee and hip joints were both at the same level Figures A and 3B.To the best of our knowledge, the transfer of a tibia-fibular graft containing the zone of injury from high-energy trauma to reconstruct a defect in the ipsilateral femur has not been reported. In our case, the alignment and length of the remodeled femur were maintained due to the successful microsurgery and secondary rigid fixation. The long-term result demonstrates the feasibility of using a microvascular transfer of a vascularized tibia-fibular graft to reconstruct a massive femoral bony defect in a severe floating knee injury with neurovascular compromise.Written informed consent was obtained from the patient’s legal guardians for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.S-HC participated in the case management and was a major contributor in writing the manuscript. TW participated in data collection, literature review and draft writing. M-CY participated in the surgical management of vascularized flap reconstruction. C-HP and J-YK participated in the trauma management of fracture and surgical consultation. All authors read and approved the final manuscript.


Iconic Egyptian bas-reliefs and graphic hieroglyphic and cuneiform texts portray the proximate cause of the collapse as the invasions of the “Peoples-of-the-Sea” at the Nile Delta, the Turkish coast, and down into the heartlands of Syria and Palestine where armies clashed, famine-ravaged cities abandoned, and countrysides depopulated. Here we report palaeoclimate data from Cyprus for the Late Bronze Age crisis, alongside a radiocarbon-based chronology integrating both archaeological and palaeoclimate proxies, which reveal the effects of abrupt climate change-driven famine and causal linkage with the Sea People invasions in Cyprus and Syria. The statistical analysis of proximate and ultimate features of the sequential collapse reveals the relationships of climate-driven famine, sea-borne-invasion, region-wide warfare, and politico-economic collapse, in whose wake new societies and new ideologies were created.The Late Bronze Age world of the Eastern Mediterranean, a rich linkage of Aegean, Egyptian, Syro-Palestinian, and Hittite civilizations, collapsed famously 3200 years ago and has remained one of the mysteries of the ancient world since the event’s retrieval began in the late 19 From this crisis arose new societies and new ideologies Compared to the Last Glacial period, the amplitude of Holocene climate fluctuations is less pronounced. Nevertheless, climate fluctuations on multi-centennial to millennial time-scales and rapid shifts occurred during the Holocene Before the LBA crisis ca. 1200 BC), the Eastern Mediterranean hosted some of the world’s most advanced civilizations. In the Aegean, the Mycenaean culture was flourishing with powerful urban centres such as Mycenae and Tiryns in Argolis, Pylos in Messenia, Athens in Attica, Thebes and Orchomenus in Boeotia, Iolkos in Thessaly, and Knossos in Crete 0 BC, theth–9th centuries BC, could not be without consequences on Eastern Mediterranean and West Asian environments where dry farming agro-production, pastoral nomadism and fishing were the primary or secondary subsistence systems. Reduced precipitation probably affected the outlying nomad habitats, and led rain-fed cereal agriculturalists to habitat-tracking when agro-innovations are not available Despite the abundant literature devoted to the Sea peoples, we still do not know exactly who they were, where they came from, why they attacked, and, finally, where they disappeared to after their raids. Some scholars are even uncertain whether the Sea People’s existence was a cause or an effect of the decline of the LBA. Recent studies However, the debate about the role of climate in shaping ancient societies has emerged because a direct causation fails to be proven 14C) date for the LBA crisis and the Sea People raid. Cyprus and Syria had a long and rich story of commercial relationships before the Sea People event. They now meet through a common climate story to decipher the environmental roots of the LBA crisis.Here, we focus on Cyprus, an island located at the heart of the ancient civilizations and trade routes of the Eastern Mediterranean during the LBA 22  was sampled in the Larnaca Salt Lake, near Hala Sultan Tekke, in southeastern Cyprus. No specific permissions were required for this location and this type of activity because the lake belongs to the European Union and is free of access for European citizens. The field studies did not involve endangered or protected species. The layers identified in the cores were radiocarbon dated by accelerator mass spectrometry (AMS) 14C on short-lived samples  calibration: 3580–3450 cal yr BP); the middle core at 3140±30 14C yr BP . The top at 820±30 14C yr BP . Terrestrial plant remains are scarce in the core, limiting an extended chronology.The continuous core B samples . Convent−3). The fire history was retrieved by counting the pollen-slide charcoal particles (50–200 µm) and expressed as concentrations (fragments per cm−3). Concentrations have been plotted on a linear depth-scale. The upper part of the core (250–0 cm depth) is sterile in bioindicators  A total of 84 samples were prepared for pollen analysis using the standard palynological procedure for clay samples. Pollen grains were counted under x400 and x1000 magnification using an Olympus microscope. Pollen frequencies (%) are based on the terrestrial pollen sum excluding local hygrophytes and spores of non-vascular cryptogams. Aquatic taxa frequencies are calculated by adding the local hygrophytes-hydrophytes to the terrestrial pollen sum. Dinoflagellate cysts were counted on pollen-slides, and are presented as concentrations (cysts per cmLDCC). The NJ method is an alternative process for hierarchical cluster analysis, finding hierarchical groupings in multivariate data sets. Here, it is based on pollen-type time-series (presence/absence and abundance). NJ analysis was used to compute the lengths of branches of a tree, using branches as ecological distances between groups of taxa (descending type) correlation as similarity measure and final branch as root. The pollen-types from each cluster were summed to create pollen-derived vegetation patterns (PdVs). A PCA was then performed to test the ordination of samples by assessing major changes in PdV-frequencies. The main variance is loaded by the PCA-Axis1. PCA-Axis1 scores have been plotted on a linear depth-scale  analysis, principal components analysis (PCA), cluster analysis, and linear detrended cross-correlations  were computed . The PCA-Axes1 time-series have been cross-correlated to ascertain the maximal match in time and the potential delay between the two time-series. The CC is then plotted as a function of alignment position. This numerical approach is well-adapted to detect and quantify potential links between environmental data. Positive correlation coefficients are considered, focusing on the Lag0 value (with +.50 as significant threshold). Negative correlations are also assessed to test the inverse- or non-correlation between the two time-series (with −.50 as a significant threshold). Non-significant values indicate a complete lack of correlation.To disentangle if climate proxies from Cyprus and Syria are chronologically linked, computed . The LDCThe Larnaca Salt Lake Complex, one of the most important natural standing water bodies in Cyprus, consists of four main lakes Posidonia oceanica fibers and rhizomes  Morhange et al. rhizomes  with pearhizomes  in the l22 pollen record. The two main PdVs  has been integrated in a matrix of radiocarbon data obtained from the destruction debris (2) test . The weighted average date (2963±13 14C yr BP) gives a 1 σ calibrated age range of 1215–1190 cal yr BC with 33.3% relative probability and another age range of 1180–1160 cal yr BC with 24.3% relative probability, using Calib-Rev. 6.0.1 14C yr BP, with a 1 σ calibrated age range of 1215–1190 cal yr BC with 34.3% relative probability and another age range of 1180–1160 cal yr BC with 26% relative probability. The numerical comparison of 2963±13 14C yr BP and 2962±14 14C yr BP indicates that the two pooled mean ages are statistically the same at the 95% confidence . The weighted average date obtained by combining these two pooled mean ages is 2962±9 14C yr BP with no changes in the calibrations. This indicates that the LBA crisis, the Sea People raids, and the onset of the drought period are the same event.As both archaeological and climatic events (in Cyprus and Syria) were dated by radiocarbon chronology, we choose an objective mathematical approach to propose an unequivocal fit. The first date for the climate event and the fall of crop yields in Syria , we can say that the LBA crisis was a complex but single event where political struggle, socioeconomic decline, climatically-induced food-shortage, famines and flows of migrants definitely intermingled.By combining data from coastal Cyprus and coastal Syria, this study shows that the LBA crisis coincided with the onset of a ca. 300-year drought event 3200 years ago. This climate shift caused crop failures, dearth and famine, which precipitated or hastened socio-economic crises and forced regional human migrations at the end of the LBA in the Eastern Mediterranean and southwest Asia. The integration of environmental and archaeological data along the Cypriot and Syrian coasts offers a first comprehensive insight into how and why things may have happened during this chaotic period. The 3.2 ka BP event underlines the agro-productive sensitivity of ancient Mediterranean societies to climate and demystifies the crisis at the Late Bronze Age-Iron Age transition.


Known associations between diabetes and cancer could logically be attributed to hyperglycemia, hypersecretion of insulin, and/or insulin resistance. This study examined the relationship between initial glycemic biomarkers among men and women with impaired fasting glucose or undiagnosed diabetes and cancer mortality during follow up.The cohort included subjects aged 40 years and above from the Third National Health and Nutrition Examination Survey (NHANES III) with fasted serum glucose >100 mg/dl without the aid of pharmaceutical intervention . Cancer mortality was obtained from the NHANES III-linked follow-up database . A Cox regression model was applied to test for the associations between cancer mortality and fasting serum glucose, insulin, glycosylated hemoglobin (HbA1c), C-peptide, insulin like growth factor (IGF-1), IGF binding protein 3 (IGFBP3) and estimated insulin resistance.A total of 158 and 100 cancer deaths were recorded respectively from 1,348 men and 1,161 women during the mean 134-month follow-up. After adjusting for the effect of age and smoking in women, all-cause cancer deaths  and lung cancer deaths  were specifically associated with serum C-peptide concentrations. Similar associations in men were not statistically significant. Serum glucose, HbA1c, IGF-1, IGFBP3 and HOMA were not independently related to long-term cancer mortality.C-peptide analyses suggest a modest association with both all-cause and lung cancer mortality in women but not in men. Further studies will be required to explore the mechanisms. The association between type 2 diabetes and several types of cancer has been widely reported The extended debate regarding mechanisms that link type 2 diabetes and cancer remains unresolved. The mitogenic effects of elevated insulin and the energetic effects of elevated glucose were logical candidates as risk factors for cancer Thus, this study was designed to test the hypothesis that one or more early glycemic biomarkers for type 2 diabetes are specifically associated with cancer mortality on follow-up among the middle-aged men and women with impaired fasting glucose (IFG) or undiagnosed diabetes in the general US population. To accomplish this aim, a collection of initial glycemic biomarkers  were analyzed for independent associations with long-term cancer outcomes within a nationally representative sample assembled from the Third National Health and Nutrition Examination Survey (NHANES III).The Third National Health and Nutrition Examination Survey (NHANES III), conducted by the National Center for Health Statistics (NCHS) and the Centers for Disease Control and Prevention from 1988 through 1994, was the seventh in a series of surveys based on a complex, multi-stage sample design 2). Subjects with serum cotinine values greater than 14 ng/ml were classified as current smokers, otherwise as nonsmokers Data were collected at all study sites by trained personnel according to standardized procedures. Social and demographic information such as age, sex, and race/ethnicity was collected during household interviews Of the adult NHANES III participants aged 40 and above, 99.9% were eligible for mortality follow-up by linkage with the National Death Index Continuous variables were reported as median and interquartile range. Categorical data were reported as percentages and standard error of the mean (SE). The cancer mortality analysis includes both cancer mortality and a subset of cancer incidence. A Cox proportional hazard model was used to calculate the hazard ratios (HR) in the evaluation of cancer mortality risk associated with fasted serum glucose, HbA1c, C-peptide, insulin resistance for all cancer and specifically for lung cancer mortality. Other site-specific cancers, such as colorectal cancer, prostate cancer in men, and breast cancer in women were not further evaluated due to limited mortality sample sizes. As widely accepted predictors of cancer outcomes, age and smoking status were added into the model as covariate adjustments, as well as race/ethnicity and body mass index Due to the differences in cancer epidemiology among men and women, the cancer mortality analysis was stratified by sex. A sample weight was thus used to adjust for the unequal probabilities of selection to represent the U.S. population The NHANES III survey updated the data on insulin like growth factor (IGF-1) and IGF binding protein-3 (IGFBP3) in October 2006. Both of these proteins have been the subject of attention due to potential associations with cancers A total of 1,348 men and 1,161 women aged 40 years and above with pre-diabetes or undiagnosed diabetes were included for analysis. The baseline demographic characteristics of participants stratified by sex are summarized in In men, age and smoking were independently associated with all-cause cancer deaths and with lung cancer deaths. However, none of the following biomarkers, fasting serum glucose, HbA1c, HOMA-IR, and serum C-peptide, were related to either all-cause cancer deaths or to lung cancer deaths  however, the association between smoking and cancer mortality remained statistically significant for lung cancer , but not for the larger category of all-cause cancers. In addition, for women only, there was a positive association between serum C-peptide concentrations and both all-cause cancer deaths  and lung cancer deaths . And, as with men, there was no statistically significant association between serum glucose, HbA1c, and HOMA-IR with either all-cause or lung cancer mortality. Of note, the relationship between fasting serum glucose and the risk of dying from lung cancer did approach statistical significance in women and may thus require more extensive future analysis in a larger cohort  , despite of borderline statistical significance. The association between serum C-peptide concentrations and lung cancer death remained significant in women .Valid values for IGF-1 and IGFBP3 were available from only a sub-sample of 1,355 people. Neither IGF-1 nor IGFBP3 was associated with either all cancer death or lung death among men or women in the multivariate analysis .The results of this study have demonstrated that among glycemically vulnerable subjects, serum C-peptide concentration was associated with a modestly increased risk for long-term overall cancer mortality and lung cancer mortality in women. Since the majority of insulin is removed in the first pass through the hepatic circulation, C-peptide concentrations are presumed to better reflect insulin secretory rates than circulating insulin. A similar association between C-peptide and cancer mortality risk was not observed in men. Neither serum glucose nor estimated insulin resistance was related to long-term cancer outcomes in this selected cohort of subjects with pre-diabetes and undiagnosed diabetes. Though the increased risk associated with C-peptide is modest, the clinical outcome is serious and hyperinsulinemia includes a large and rapidly growing segment of our population.A recent analysis on the NHANES 1988–1994 survey in which 15594 people (aged 20–89) with metabolic syndrome were followed an average of 8.5-years, demonstrated that for every 50 mg/dl increase in plasma glucose, there was a 22% increased risk of overall cancer mortality, and insulin resistance was associated with a 41% increased risk of overall cancer mortality The results of the analysis above imply that C-peptide concentrations may help to identify a risk of long-term cancer mortality in women prior to the appearance of overt symptoms of malignancy. Prior analyses from our group suggest that the metabolic syndrome poses a significant increase in non-cardiovascular mortality risk primarily in postmenopausal women and not in men C-peptide is a direct biomarker of endogenous insulin secretion. The link between C-peptide, hyperinsulinemia, other metabolic disturbances and cancer risk is very likely complex and the precise mechanisms involved remain largely unknown The pathway linking insulin production to cancer outcomes independent of glycemic control and insulin resistance is suggested to involve tumorigenesis driven by increased insulin, IGF 1 and IGF 2, collectively signaling through both insulin and IGF-1 receptors Despite the general agreement that obesity is a strong predictor for insulin resistance The exclusion of cancer deaths identified in the early follow-up helped to eliminate the potential influence of undiagnosed cancer cases at baseline. The association between serum C-peptide concentrations and all-cause/lung cancer death in women remained similar to those estimated from the original analysis. The results from the time-lag analysis helps to confirm the temporal sequence in the associations of interest and make the possibility of reverse causation less likely The first limitation of the current analysis is that IGF-1 and IGFBP3 were available on only a small portion of the NHANES data set. Thus, the power to demonstrate the effect of IGF-1 and IGFBP3 may have been insufficient as mentioned above. Moreover, the analysis relied on single one time measurements for each of the glycemic markers. Those adults with untreated diabetes and serum glucose values greater than 100 mg/ml were very likely to have subsequently been treated with insulin, oral hypoglycemics or other drugs. Such treatment may have moderated the risk during the follow-up period. The effect of subsequent oral hypoglycemic agents and insulin could not be accounted for in the current analysis. Furthermore, the analysis was restricted to men and women aged 40 years and above characterized as pre-diabetics and unrecognized diabetics but not currently exposed to any anti-diabetic medication. Despite selecting a presumably cancer-prone sub-population, the number of cancer deaths was still too small to develop a reliable prediction model. The final analysis set did not have sufficient power to evaluate the association with specific cancers other than those of the lung. Finally, the association between C-peptide and cancer mortality is modest at best. The hazard ratio is 1.96 per each increment of 1 pmol/mL in C-peptide. But the interquartile range in the population is only 0.7 pmol/ml (0.61–1.31), so the relative risk from 25th to 75th percentile is low. The association was not found in men, thus, differences in sex hormones may play a role. This is of course speculation and the mechanism is unclear.In conclusion, the results of this study have demonstrated that circulating C-peptide concentrations are associated in women with a modest risk of both long-term all-cause cancer mortality and in this limited cohort specifically with mortality from lung cancer. Similar associations were not found in men. The relationship of C-peptide with cancer at other specific sites could not be reliably examined due to limited analyte sample numbers and site specific mortality events. Additional basic and clinical studies will be required to further validate the current findings and explore the mechanisms underlying the associations of interest.


This study aims to examine the association between inflammatory biomarkers and dyslipidemia and its components among Mongolians in China.Data were obtained from 2544 Mongolians via standard questionnaires and blood samples in Inner Mongolia, China. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) as well as blood lipids were examined.Individuals with dyslipidemia had higher levels of hsCRP, sICAM-1 and sE-selectin than those without dyslipidemia . Compared to the lowest quartile of inflammatory biomarkers, individuals with the highest quartile were more likely to have dyslipidemia . Moreover, hsCRP was associated with all the components of dyslipidemia, whereas, sICAM-1 was not related to high density lipoprotein cholesterol (HDL-c) or triglycerides (TAG). Additionally, sE-selectin was just associated with TAG.Our study indicated that elevated plasma levels of hsCRP, sICAM-1 and sE-selectin were positively and significantly associated with increased risk of dyslipidemia among Mongolians. However, the associations were not identical for different inflammatory biomarkers with the components of dyslipidemia. With the remarkable improvement of people’s living standard and associated lifestyle changes in China, dyslipidemia has become more prevalent during the last decades. According to the results from the Chinese National Nutrition and Health Survey in 2002 (CNHS 2002), the prevalence of dyslipidemia in Chinese adults was 18.6% Meanwhile, atherosclerosis is widely recognized as a chronic inflammatory vessel disorder and the most important single contributor to the growing burden of cardiovascular disease. Clinical and epidemiological studies across different ethnic groups demonstrated that biomarkers of inflammation were associated with atherosclerosis, leading to myocardial infarction (MI) and stroke A cross-sectional study was conducted between 2002 and 2003 in Inner Mongolia, an autonomous region in north China. The methods for selection of study participants and data collection have been described elsewhere This study was approved by the Institutional Review Board at the Soochow University. Written informed consent was obtained for all study participants.. The mean of these three blood pressure measurements was used in the data analysis. Height and body weight were measured by trained staff using a balance beam scale after subjects removed their shoes and were wearing light clothing. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters (kg/m2). Waist circumference was measured at the level of 1 cm above the umbilicus.A standard questionnaire was used to obtain data on demographic characteristics, lifestyle risk factors, family history of cardiovascular disease and personal medical history by trained staff. Smoking was defined as having smoked at least one cigarette per day for 1 year or more. The information regarding amount and type of alcohol consumed during the past years was collected, and alcohol drinking was defined as consuming at least 50 g distillate spirits  per day for 1 year or more. Three sitting blood pressure measurements were taken for each participant using a mercury sphygmomanometer according to a standard protocol, and there were 30 s intervals between two BP measurementsBlood samples were collected in the morning after at last 8 h of fasting. All plasma and serum samples were frozen at −80°C until laboratory testing. Fasting blood was measured using a modified hexokinase enzymatic method. The value of hsCRP was determined by an immunoturbidimetric assay on a Beckman Synchron CX5 Delta Clinical System using commercial reagents. The value of sICAM-1 and sE-selectin was measured by an ELISA assay  which employed the quantitative sandwich enzyme immunoassay technique. Concentrations of TC, HDL-c and TAG were assessed enzymatically on a Beckman Synchrony CX5 Delta Clinical System  using commercial reagents, and LDL-c concentration was calculated by means of the Friedewald equation for participants who had less than 400 mg/dL TAG t test for normally distributed continuous variables; Wilcoxon rank-sum test for variables that did not follow a normal distribution and chi-squared test for categorical variables. Logistic regression was used to examine the association between dyslipidemia and the biomarkers of inflammation, and odds ratio (OR) and 95% CI of dyslipidemia were calculated for higher quartiles of hsCRP, sICAM-1 and sE-selectin compared with the lowest quartile. Finally, multivariable-adjusted mean concentrations of individual components of the dyslipidemia were calculated according to quartiles of hsCRP, sICAM-1 and sE-selectin and linear trends were tested. Gender, age, smoking, drinking, systolic blood pressure, diastolic blood pressure, fast plasma glucose were adjusted in multivariable models. All p values were two-tailed and statistical significance level of 0.05 was used. Statistical analysis was conducted using SAS statistical software (version 9.1).The participants were initially categorized into two mutually exclusive groups with and without dyslipidemia. Descriptive statistics for demographic variables, components of dyslipidemia and inflammatory biomarkers were calculated separately for the two groups. The average levels of continuous variables and the prevalence of categorical variables were calculated for the two groups. Mean and 95% confident interval (95% CI) were used to describe normally distributed variables; if the variables were not normally distributed, median and interquartile ranges were used; frequencies were used to describe categorical variables. Differences between the two groups were tested using The descriptive characteristics of 2,544 study participants according to lipid status are shown in The unadjusted and multivariable-adjusted OR (95% CI) of dyslipidemia according to the quartiles of inflammatory biomarkers are presented in In this cross-sectional study among residents of Inner Mongolia, we found that elevated hsCRP, sICAM-1 and sE-selectin levels were positively and significantly associated with dyslipidemia. Individuals with dyslipidemia had higher levels of hsCRP, sICAM-1 and sE-selectin compared to those without dyslipidemia. In addition, individuals with higher levels of hsCRP, sICAM-1 and sE-selectin were at an increased risk of dyslipidemia compared to those with lower values. However, the above biomarkers demonstrated different profiles with regard to which components of dyslipidimia they were associated with. For example, hsCRP was associated with all the components of dyslipidemia with a dose-response relationship, whereas the positive linear association was only identified between sICAM-1 and LDL-c and TC as well as between sE-selectin and TAG, after adjusting for multivariables.Our study confirms findings from several previous investigations that have reported a significant association between elevated CRP and dyslipidemia Adhesion and transendothelial migration of circulating leukocytes are critical early events in the pathogenesis of atherosclerosis, soluble Cell Adhesion Molecules (sCAMs) such as soluble vascular cellular adhesion molecule-1 (sVCAM-1), sICAM-1 and sE-selectin play pivotal roles in the adhesion of monocytes to endothelial cells. Numerous studies have shown a close association between sCAMs and dyslipidemia The underlying mechanisms for the risk factor role of inflammation in dyslipidemia are not fully understood. Epidemiological data have indicated that subjects with dyslipidemia are in a proinflammatory state, which is distinguished by elevated levels of cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-6 and could further promote the expression of hsCRP and CAMs We acknowledge that several limitations of this study should be mentioned. First, this was a cross-sectional study, therefore no causal relationships could be precisely delineated. Secondly, approximately 25% of the eligible population from these villages chose not to participate which may have introduced some selection bias. However, we believe this bias is minimal because it is unlikely that participants chose not to participate due to their lipid levels which they did not know. Furthermore, several important biomarkers of inflammation, such as TNF-α, IL-6 and VCAM-1, were not measured in our study.In conclusion, our study indicated that elevated plasma levels of hsCRP, sICAM-1 and sE-selectin were positively and significantly associated with increased risk of dyslipidemia among Mongolian residents of Inner Mongolia. However, the associations were not identical for different inflammatory biomarkers with the components of dydlipidemia. Our results suggest that different inflammatory biomarkers may have distinct mechanisms in the pathogenesis of lipoprotein subclass abnormalities.


P < 0.01) and in patients with a history of Stevens-Johnson syndrome (P < 0.05) from penicillin. Allergists are more willing to confirm penicillin allergic status, more likely to carefully administer penicillin even after negative skin test, but less concerned for the potential cross-reactivity with 3rd and 4th generation cephalosporins, compared to non-allergists. The lack of penicillin skin test reagents, the reliability of penicillin allergy history, and medicolegal problem were the main reasons for prescribing alternate antibiotics without confirmation of penicillin allergic status. In summary, the different management of penicillin allergy between allergists and non-allergists was significantly demonstrated in patients with a history of severe non-immediate reaction and in patients with a history of an immediate reaction when a penicillin skin test is available.The purpose of this study was to compare the management of patients with a history of penicillin allergy between allergists and non-allergists in Thailand. A questionnaire was distributed to Thai physicians by online survey. The answers from 205 physicians were analyzed. The discrepancy of penicillin allergy management between allergists and non-allergists was clearly demonstrated in patients with a history of an immediate reaction in the presence of penicillin skin test ( Penicillin allergy is one of the most commonly reported drug allergies worldwide. About 10% of the general population report suspected allergic reactions to penicillin . In realIn clinical practice, the confirmation of penicillin allergic status is not always feasible, which results in unnecessary avoidance of beta-lactam antibiotics in patients who are overdiagnosed . It is wIt is understandable that doctors in other specialties may have limited knowledge and different perspectives about managing allergic disorders, as compared to allergists . Their pThe lack of allergists and standard skin test reagents for the diagnosis of penicillin allergy makes the confirmation of penicillin allergic status not always possible –17. TypeThe purpose of this study was to comparatively survey the management of penicillin allergy between allergists and non-allergists in Thailand in patients with different patterns of penicillin-induced suspected allergic reactions. The awareness of cross-reactivity among beta-lactam antibiotics as well as the knowledge and attitudes towards penicillin allergy management was also determined. The impacts of areas of expertise, types of medical practice settings, and duration of clinical practice on penicillin allergy management were also analyzed.http://dx.doi.org/10.1155/2014/214183.This study was a cross-sectional survey on the management of patients with a suspected history of penicillin allergy in Thailand. After approval by the Ethics and Research Committee of Faculty of Medicine at Chulalongkorn University, the web-based questionnaire was created by using Google Docs and e-mailed to 1,000 Thai physicians  throughout the country. The questionnaire was focused on four aspects: (1) the management of patients with a history of penicillin-induced immediate reactions in the presence and absence of penicillin skin test reagents, (2) the management of patients with a history of penicillin-induced non-immediate reactions, (3) the prescription of other beta-lactams in patients with a history of penicillin allergy, and (4) the fundamental knowledge of penicillin allergy skin testing and attitudes towards the management of patients with a history of penicillin allergy in Thailand. Details of the web-based questionnaire are available in Supplemental Appendix Ain Supplementary Material available online at P values < 0.05 were considered statistically significant.The online survey responses were automatically collected and subsequently analyzed using SPSS 17.0 for Windows . The actual rates of penicillin allergy in patients with a suspected history estimated by physicians were calculated by using class interval arithmetic means. Chi-square test and multinomial logistic regression were used for univariate and multivariate analysis. A total of 205 completed surveys were received (a 20.5% response rate) from the online questionnaire. 14.1% were adult or pediatric allergists, while 26.3%, 40.5%, and 19.0% were general practitioners, internists or pediatricians , and other specialists, respectively. Almost half (45.9%) of the responders worked for an academic institute  and 19.0% worked in a primary care hospital, 22.9% in a general/provincial hospital, and 12.2% in the private practice sector. About 45.9% of the responders have less than 5-year experience in clinical practice, while 30.2% and 23.9% of them have 5–10 years and more than 10 years of practice experience, respectively .P value = 0.06) but was clearly demonstrated if the penicillin skin test was negative   . 79.3% oP values < 0.01). If a penicillin skin test was not available, the management of patients with a history of penicillin-induced severe immediate reaction (anaphylaxis) between allergists and non-allergists was still different , but no longer different  in patients with a history of penicillin-induced mild immediate reaction (urticaria and/or angioedema).A question was addressed whether the severity of the immediate reaction influenced patient management in the presence or absence of penicillin skin test reagents . The difIn patients with a history of anaphylaxis, 83.5–84.7% of non-allergists would avoid both penicillin and cephalosporins regardless of skin testing availability. In contrast, 34.5% of allergists would perform a penicillin skin test if available, and 20.7% considered prescribing penicillin using a desensitization technique in patients requiring penicillin therapy. In patients with a history of penicillin-induced urticaria or angioedema, 82.8% of allergists would perform penicillin skin testing first, while only 25.0% of non-allergists would do so. However, if the penicillin skin test was not available, the majority of physicians  would avoid both penicillin and cephalosporins.P value = 0.03), borderline different in drug reaction with eosinophilia and systemic symptoms , but not statistically different in maculopapular exanthema   . Only 3.P values < 0.01) but not with other drugs .Regarding basic knowledge of penicillin skin testing for diagnosis of an immediate reaction, less than half of non-allergists (29.1%) have accurate knowledge on the appropriate recommended skin test reagents (penicilloyl-polylysine and minor determinants) and only 5.1% of them know how to correctly interpret penicillin skin test results according to the ENDA recommendation  . It is wP value = 0.04). While the majority of allergists (69.0%) favored penicillin skin tests over penicillin avoidance (24.1%), both approaches were equally elected by the non-allergist group (39.2–40.3% each). The reasons for prescribing an alternate drug without confirming penicillin allergy status were not statistically different between allergists and non-allergists . The easy availability of alternate antibiotics was the main reason, followed by a convincing drug allergy history. Interestingly, the medicolegal problem was another main concern for Thai physicians, especially among non-allergists.A difference in opinion between allergists and non-allergists was observed. The preferred approach to manage patients with a history of an immediate reaction to penicillin was significantly different between allergists and non-allergists . After multivariate analysis, penicillin allergy management by allergists was significantly different from non-allergist counterparts .Non-allergists preferred to confirm an allergic history by means of skin tests in patients with a history of penicillin-induced urticaria and anaphylaxis, much less than allergists would do , and less likely to administer penicillin with graded challenge technique (0.10-fold) in patients with a suspected history of penicillin allergy after negative skin test, compared to allergists. In contrast, non-allergists were more likely to avoid not only penicillin but also cephalosporins in patients with a history of penicillin-induced anaphylaxis and SJS than allergists would do so . Interestingly, they avoided first generation cephalosporins much less than allergists (0.17-fold) in patients with a history of penicillin allergy. Probably due to limited knowledge in penicillin skin test procedure and interpretation, non-allergists rather preferred to avoid penicillin (7.29 folds) than to confirm allergic status (0.14 fold), as compared to their allergist counterparts.Clinical practice duration also had some influence since physicians with less than 5 years of experience in practice were more in favor of penicillin allergy confirmation (4.65-fold) than those practicing medicine longer than 10 years and were less likely to avoid cephalosporins in patients with a history of penicillin-induced DRESS (0.11-fold).Although allergists are primarily responsible for the management of patients with a history of a drug allergy, in the real life, these patients are often cared for by doctors in other specialties due to the shortage of certified allergists in some areas. This study surveyed how the problem of penicillin allergy in different circumstances was managed by allergists and non-allergists, including their knowledge and attitudes towards this problem.Our study shows that allergists are more willing to confirm the status of penicillin allergy and more inclined to use a desensitization procedure in patients with a history of penicillin-induced immediate reaction, as compared to non-allergists. The study also shows that the limited availability of penicillin skin tests clearly impacts their clinical judgment. If the penicillin skin testing was not available, the discrepancy of patient management between allergists and non-allergists in patients with a history of penicillin-induced urticaria or angioedema would no longer be observed, since allergists also avoided penicillin ± cephalosporins in these cases. Interestingly, the majority of allergists were very cautious when prescribing penicillin in patients with a suspected history even after a negative penicillin skin test, while half of non-allergists would prescribe penicillin normally in a similar circumstance.Different views on beta-lactam cross-reactivity between allergists and non-allergists were noted. Interestingly, allergists were more reluctant to prescribe first generation cephalosporins in penicillin allergic patients while being less concerned about third/fourth generation cephalosporins, as compared to their non-allergist counterparts. Current data indicates that the potential cross-reactivity with penicillin is noteworthy only in first generation cephalosporins . In termRegarding knowledge and attitudes towards penicillin allergy management, it was clear that non-allergists have limited knowledge regarding penicillin skin test reagents and interpretation as compared to certified allergists. Even though both allergists and non-allergists agreed that majority of patients with a history of penicillin allergy are not truly allergic, the allergists' estimated rate of penicillin allergy in these patients was significantly lower than that of their non-allergist counterparts. Surprisingly, less than half of Thai allergists could correctly interpret penicillin skin test results as well. A refresher course for allergists on drug allergy testing should be organized. The appropriate modalities of allergological work-up in patients with suspected beta-lactam hypersensitivity should be finalized. The lack of penicillin metabolites (penicilloyl-polylysine and minor determinant mixture) could potentially be replaced by the soluble forms of the suspected beta-lactams or other beta-lactams from the same classes, along with benzylpenicillin and aminopenicillin, as skin test reagents since they are more easily available and have good predictive values in clinical practice .While penicillin skin testing was more favoured among allergists, many non-allergists still preferred penicillin avoidance. The availability of alternate drugs and the convincing drug allergy history were the main factors for prescription of alternate antibiotics instead of the confirmation of penicillin allergy status. It is worth mentioning that the medicolegal problem from harmful reactions, which are possible after a drug rechallenge, was one of the major concerns for not confirming the status of penicillin allergy particularly among non-allergists. The launch of a national standard practice guideline to manage patients with a history of penicillin allergy would be helpful to prevent medicolegal problems. Health economics and outcome research regarding the confirmation of penicillin allergy in patients with a suspected history should be carefully investigated.The study demonstrates the diversity of management in patients with a history of penicillin allergy among Thai physicians, although most of them knew that only a minority of these patients are truly allergic. Although the duration of medical practice may also play a role, the results of our study emphasize that the area of expertise was the most important factor determining penicillin allergy management. As the different opinions between allergists and non-allergists were statistically significant in patients with a history of severe non-immediate reaction and in patients with a history of mild immediate reaction if penicillin skin test reagents are available, we recommend that these patients are managed by allergists. Nevertheless, penicillin skin test reagents should be provided to practice allergists and the accurate skin test procedure emphasized. In contrast, it might be possible that non-allergists should be allowed to handle patients with a history of penicillin-induced mild non-immediate reaction (simple MPE) if no certified allergist is available. According to our study, the current approach between allergists and non-allergists in this patient group is already similar. In fact, graded challenge test is the recommended procedure for any physicians knowledgeable in treating adverse drug reactions to manage these patients, since the risk to develop severe reaction is small . In thisThere are some limitations to this study. The ratio of non-allergists to allergists was 6 : 1 due to the limited number of allergists in the country. In fact, the number of allergists who replied to this survey was already one-fifth of total certified allergists in Thailand. The response rate was rather low but still within a similar range to prior studies , 9. DataThe different management of penicillin allergy between allergists and non-allergists was mainly observed in patients with a history of severe non-immediate reaction and in patients with a history of an immediate reaction, particularly in the patients who have been skin-tested with penicillin reagents. Pitfalls in penicillin allergy management by both allergists and non-allergists are addressed. The possible role of non-allergists in the management of patients with a history of penicillin-induced mild non-immediate reaction has been raised.The Supplementary Material demonstrates the survey questionnaire about penicillin allergy management emailed to Thai physicians in this study (Appendix A) and factors affecting penicillin allergy management among Thai physicians in different scenarios (Appendix B)Click here for additional data file.


Fresh-frozen plasma (FFP) may contain antibodies to hepatitis B surface antigen . These anti-HBs may lead to a misinterpretation of the actual hepatitis B immune status. Furthermore, they may not only confer protection against hepatitis B virus (HBV), but may also favor the selection of HBsAg mutants.We report a case of de novo HBV infection in a HBV-naïve recipient with alcoholic liver disease, who received a liver from a donor with antibodies to hepatitis B core antigen  and anti-HBs.A lookback investigation revealed the following: 1) Due to anti-HBs passively acquired through FFP, the recipient was considered immune to HBV and did not receive anti-HBV prophylaxis. 2) Within 1 year after transplantation he developed hepatitis B in absence of any elevated liver enzymes after the anti-HBs by FFP declined. 3) Despite an infection with HBV-containing wild-type HBcAg, the patient did not seroconvert to anti-HBc positivity. 4) The replicating HBV encoded two HBsAg mutations, first sQ129R and 4 months later sP127S. They map to the highly conserved “α” determinant of the HBsAg loop.1) Passive transfer of anti-HBs from FFP led to an erroneous pretransplant diagnosis of HBV immunity when the patient was in fact HBV-naïve. 2) HBsAg mutations might have been selected in escape from donor's actively produced anti-HBs and the recipient's anti-HBs by FFP might have favored this selection. 3) It is doubtful whether hepatitis B immunoglobulin could have prevented the reactivation. 4) Antiviral prophylaxis would have been crucial. The shortage of organs urges many transplantation centers to use marginally suitable grafts for orthotopic liver transplantation (OLT), for example, from donors with antibody to hepatitis B core antigen (anti-HBc), which is a marker of past hepatitis B virus (HBV) infection. However, transplanting such organs requires special caution. After a resolved HBV infection, the viral genome can persist as covalently closed circular DNA (cccDNA) in the liver. The expression and replication of these occult genomes is kept at a low level by the immune system, but the virus may reactivate in the graft during immunosuppressive therapy.In August 2006, a 52-year-old man suffering from alcoholic liver cirrhosis (Child-Pugh Score B) presented with upper gastrointestinal bleeding from esophageal varices. After alcohol misuse for many years, he had been abstinent since February 2006. No risk factors for hepatitis B were known. Over the following 3 days he received solvent/detergent-treated (S/D) fresh-frozen plasma (FFP)  and 10 red blood cell (RBC) units. Serum taken on Day 4 contained total antibodies to hepatitis A virus  and a low level of 28.1 IU/L anti-HBs; all other HBV markers were negative  was not detected, but anti-HAV was still present  but no anti-HAVM. HBV DNA was not detectable in the donor's serum at a detection limit of 12 IU/mL. Histology of the graft revealed mild macrosteatosis (approx. 20%) and focal perisinusoidal fibrosis without evidence of active hepatitis or septal fibrosis. The findings suggested past HBV and HAV infection. The recipient did not have HBsAg, anti-HBc, anti-HBs, anti-HAVG, or anti-HAVM just before OLT  and even increased significantly to 284,000 IU/mL on June 21, 2010. After the follow-up on January 14, 2011, the daily dose of 0.5 mg of entecavir was increased to 1 mg. This was followed by a transient decrease of HBV DNA to 1632 IU/mL on February 28, 2011. However, at the last follow-up on September 19, 2011, the viral load was at 2898 IU/mL. Switching to tenofovir was considered. To date, the patient has been in good health on antiviral and immunosuppressive treatment with entecavir and tacrolimus-mycophenolate mofetil.Therapy with entecavir was initiated in February 2010. Within 4 weeks the serum HBV DNA decreased to values of less than 10We found that the decline of anti-HBs after transplantation to values of less than 10 IU/L was mirrored by the increase of HBV DNA and HBsAg in the recipient  the patient was erroneously considered immune to HBV and HAV. The (serologic) vaccination status was not reviewed on the first visit to the transplant center (March 2007), or the status was reevaluated when the patient was waitlisted for transplantation (June 2007), in contradiction of the guidelines.Physicians should be aware of this pitfall. The quantity, origin, and specificity of relevant antibodies should be assessed in all transplantation candidates. Not only prophylactic or therapeutic immunoglobulin preparations, but also FFP and plasma-containing products such as RBC or thrombocyte concentrates, may cause misleading serologic results in the recipient. In contrast to active immunity, passively acquired antibodies slowly disappear. Therefore, antibodies should be assayed repeatedly, and the results should be interpreted together with the transfusion history of the patient to ensure that they persist and represent true active immunity. Other pitfalls in serology include cross-reacting antibodies, nonspecific reactions, and polyclonal B-cell stimulation, which may mimic specifically induced antibodies. Therefore, the results should be checked by a second method. Ideally, a patient's status should be assessed long before transplantation, to vaccinate patients with nonviral CLD.To date, there is no standardized HBV prophylaxis regimen in the transplantation setting. Hepatitis A or B in patients with CLD and in adults aged 40 years or more is associated with a more severe clinical course and higher mortality.10Optimal antiviral prophylaxis after OLT in recipients of grafts from anti-HBc–positive donors is the subject of debate.During and after transplantation the patient received FFP from single Swiss donors. The anti-HBs content in the FFP is not known, but the appearance of anti-HBs after OLT showed that at least one of the donors was anti-HBs positive. Since anti-HBc was not transferred by FFP at detectable levels, it is probable that the anti-HBs in the FFP were induced by vaccination. The prevalence of anti-HBc in the Swiss donor population has been reported as less than 2%.This case also demonstrates that it is very important to recognize occult HBV infection in a liver donor. After exposure to HBV, anti-HBc usually persists irrespective of ongoing hepatitis or resolution.18HBcAg is the most immunogenic HBV component,The clinical course of the reactivated HBV infection in the graft was surprisingly mild in spite of very strong replication. HBV reinfection of an originally HBV-negative graft in a HBV-infected recipient often causes rapid deterioration of the liver. Such recipients have experienced severe immunopathogenesis before transplantation and have obviously retained enough cytotoxic memory cells to retain the potential for immunopathogenesis when reinfection occurs. Obviously, the absence of any active immune reaction against HBV antigens in the patient described here favors a benign course.In view of no detectable liver damage before and during entecavir therapy one could ask whether this therapy is necessary. It has only been partially successful and leaves viremia at relatively high levels of approximately 5000 IU/mL. The already very high HBsAg concentration in serum increased significantly during the therapy. This suggests that HBV continues to spread within the liver. Antiviral treatment blocks reverse transcription, genome maturation, and, thus, generation of new cccDNA, but it cannot diminish production of viral antigens. The high amount of HBsAg suggests that the liver contained a very high load of cccDNA which was fully expressed at the level of transcription and translation. The limited effect of the antiviral therapy is obviously the consequence of a very high production of RNA pregenomes, DNA polymerase, and immature core particles, which finally results in a relatively large amount of secreted and infectious HBV particles. Currently, the only recognizable benefit of entecavir in this case is the reduction of infectivity of the blood to levels not dangerous for normal household contact.We are convinced that the transient anti-HAV in 2006 and anti-HBs in 2006 and 2009 were passively transferred by FFP: anti-HAV and anti-HBs were absent in 2001 and shortly before transplantation. The antibody content in the FFP in 2006 was high: anti-HAV and anti-HBs was immediately detectable after administration of FFP in 2006 and 2009 and anti-HBs steadily declined thereafter. Anti-HBs have no longer been detectable since January 2010. Surprisingly, anti-HAVG did not decline after transplantation . There i12In summary, humoral immunity against microbial agents should be interpreted with caution after administration of FFP or blood products. To ensure active immunity, protective antibody levels should be assessed repeatedly over time. Patients with CLD should be immunized early against preventable diseases. Early prophylaxis should be given if the liver graft may contain occult HBV. Anti-HBc is not a reliable screening marker for ongoing HBV infection in immunocompromised patients.


We describe temporal trends in the mortality rates and factors associated with AIDS and non-AIDS related mortality at the Evandro Chagas Clinical Research Institute (IPEC), Oswaldo Cruz Foundation (FIOCRUZ).Adult patients enrolling from 1986 through 2009 with a minimum follow up of 60 days were included. Vital status was exhaustively checked using patients’ medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm. The CoDe protocol was used to establish the cause of death. Extended Cox proportional hazards models were used for multivariate modeling.A total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased; median follow up per patient was 3.9 years (interquartile range 1.7–9.2 years). The dramatic decrease in the overall mortality rates was driven by AIDS-related causes that decreased from 9.19 deaths/100PYs n 1986–1991 to 1.35/100PYs in 2007–2009. Non-AIDS related mortality rates remained stable overtime, at around 1 death/100PYs. Immunodeficiency significantly increased the hazard of both AIDS-related and non-AIDS-related causes of death, while HAART use was strongly associated with a lower hazard of death from either cause.Our results confirm the remarkable decrease in AIDS-related mortality as the HIV epidemic evolved and alerts to the conditions not traditionally related to HIV/AIDS which are now becoming more frequent, needing careful monitoring. Highly-active antiretroviral therapy (HAART) had a dramatic impact on the AIDS epidemic; in particular, it has greatly changed the mortality profile for human immunodeficiency virus (HIV)-infected individuals. In the pre-HAART era there was a clear predominance of AIDS-related conditions whereas, currently, the mortality profile is more diverse, including cardiovascular diseases, non-AIDS-related-malignancies and other end-organ diseases such as end-stage liver and renal diseases In Brazil, mono and dual antiretroviral therapy started being provided in the early 1990s and HAART has been made available since 1996. Local studies have shown an increased survival of HIV-infected individuals and, more recently, an increased frequency of non-AIDS-related causes of death among HIV-infected individuals IPEC is a national reference center for infectious diseases and has been a reference center for care, research, and training related to HIV/AIDS since 1986. The AIDS program at IPEC is one of the largest providers of primary, specialty, and tertiary care for HIV infected individuals and AIDS patients in Rio de Janeiro State.A longitudinal observational clinical database has been maintained on patients receiving HIV care at IPEC. Cohort procedures have been described and results published The study population included adult patients (age ≥18 years) who enrolled in the IPEC cohort and had a minimum follow up of 60 days, from September 12, 1986 (the date of the first enrollee) through October 30, 2009 . End of follow up was defined as the earlier of death or December 31 2009 when administrative censoring was applied. Information regarding vital status was exhaustively checked up until December 31 2009 using the patients’ medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm http://www.cphiv.dk/CoDe/) was used to revise near death patient information. The CoDe method is a uniform coding system that includes detailed data collection on the causes of death and contributing factors and a centralized review process of the collected data. The Portuguese translated CoDe case report forms were completed by two physicians specialized in HIV care. The central review process followed the CoDe guidelines and was performed independently by two qualified reviewers also specialized in HIV care. If agreement on the immediate and underlying causes of death was reached, the cause of death was established. If there was disagreement between the two reviewers, the specific case was referred to one additional reviewer who reviewed the CoDe case report and the CoDe review forms and then established the cause of death.For all deaths that occurred in the study period, the CoDe (“Coding of Death in HIV”) method (The cause of death was given by the underlying cause of death. Groups of causes of death were defined based on the categories present in the CoDe review form as follows: AIDS-infection (CoDe 01.1), AIDS-malignancy (CoDe 01.2), AIDS-not specified (CoDe 01), non-AIDS infection (CoDe 02), liver-related (CoDe 03), non-AIDS malignancy (CoDe 04), diabetes mellitus (CoDe 05), pancreatitis (CoDe 06), toxicity , cardiovascular , primary pulmonary hypertension (CoDe 11), lung embolus (CoDe 12), respiratory disease , renal failure (CoDe 15), violence (CoDe 16), psychiatric , substance abuse (CoDe 19), hematological disease (CoDe 20), endocrine disease (CoDe 21), central nervous system (CNS) disease (CoDe 23), digestive system disease , skin and motor system disease (CoDe 27), urogenital disease (CoDe 28), obstetric complication (CoDe 29), congenital disorders (CoDe 30) and unknown . Of the above mentioned causes of death, those with two deaths or less were combined in the “Other causes” group.Age at enrolment was calculated as the difference between date of birth and date of enrolment. Age at the end of follow up was calculated as the difference between date of birth and end of follow up as defined above. Race/ethnicity was based on the provider’s report and was categorized into white and non-white. Education was self-reported and categorized according to the number of years in school into three groups: ≤5 years, 6–9 years, and ≥10 years. Presumed HIV exposure category were self-reported and categorized hierarchically into injection drug use , men who have sex with men , heterosexual and other/unknown. Baseline CD4 cell count was defined within a window of 180 days of enrolment, and, if more than one measurement was available, the value closest to the date of enrolment was chosen. HAART use was defined as the use of at least three antiretroviral drugs: two nucleoside reverse transcriptase inhibitor and either one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor, and categorized into those who, at any given point in time, used HAART for more than 12 weeks, and those who never used HAART (never used or used for 12 weeks or less). AIDS-diagnosis (CDC 1993 definition) at baseline was defined by the occurrence of an AIDS-defining illness at or before cohort enrolment.Descriptive statistics for demographic and clinical variables were compared for four groups defined as a function of vital status and category of underlying cause of death . Kruskal-Wallis and Chi-squared tests were used to access differences among groups for continuous and categorical variables, respectively. Incidence rates of death per 100 person-years were calculated for all causes, and for AIDS-related and non-AIDS-related causes of death. For the calculation of the rates, the study period was divided into three-year periods, except for the first period, to allow for a more precise description and assessment of temporal trends. Temporal trends over periods were tested by exact mid-P values calculation.To explore the factors associated with AIDS or non-AIDS related causes of death, we used extended Cox proportional hazards models, accounting for competing risks, as described elsewhere This study was conducted according to the principles expressed in the Declaration of Helsinki. This study was approved by the ethics committee of the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation. Participants provided written informed consent.During the study period, a total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased. Some demographic and clinical characteristics were significantly different across the groups alive, death due to non-AIDS related and death due to AIDS-related causes of deaths , such asThe remarkable changes in the relative frequency of causes of death are shown in Among the specific causes, the percentage of deaths due to AIDS-infection decreased from 66.4% in 1986–1991 to 34.9% in 2007–2009. The top three causes of death within the AIDS-infection group were tuberculosis , cytomegalovirus , and cryptococcosis . In contrast, the percentage of deaths due to AIDS-malignancy increased from 1.8% in 1986–1991 to 10.7% in 2007–2009. The top two causes of death within the AIDS-malignancy group were Kaposi’s sarcoma  and non-Hodgkin lymphoma .Non-AIDS infection was the most frequent non-AIDS cause of death with 5.2% (45/868) of all deaths . Sepsis Mortality rates from all causes decreased remarkably from over 10 deaths/100 person-years (PYs), to almost 2/100PYs during the study period . This deThe cumulative incidence functions for AIDS-related, non-AIDS related and unknown causes of death are shown in the figure for the entire cohort  and for We retrospectively assigned a defined cause of death to 97.7% of the 868 deaths occurring among the 3530 individuals followed at IPEC from 1986 to 2009. We showed that mortality rates from AIDS-related causes of death dramatically decreased over time from 9.19 deaths/100 PYs in 1986–1991 to 1.35 deaths/100 PYs in 2007–2009. In contrast, mortality rates from non-AIDS-related causes showed no trend over time, oscillating at 1 death/100 PYs. Moreover, remarkable changes in the relative frequency of AIDS-related and non-AIDS-related causes of death were observed with AIDS-related causes decreasing from 87% to 62%  in the periods 1986–1991 and 2007–2009, respectively. These results are in agreement with reports from Brazil and other countries that show a remarkable decrease in AIDS-related causes of death as the HIV epidemic progressed through time and corroborates the observation that conditions that are not traditionally related to HIV/AIDS are now becoming relatively more frequent, as reflected in our findings We found that patients who died from AIDS-related causes of death had poorer immunological profile at cohort enrollment compared to those who remained alive or died of non-AIDS-related causes of death. Median CD4 cell counts at baseline for patients who died of AIDS-related infections and AIDS-related malignancies were, respectively, 117 and 146 cells/mm3, as opposed to 296 cells/mm3 for patients who died of non-AIDS related causes. Additionally, a significantly higher percentage of those who died of AIDS related causes had AIDS diagnosis at enrollment. Indeed, AIDS diagnosis at enrollment and lower CD4 cell count were significantly associated with a higher hazard of death from AIDS-related causes in the multivariate analysis. In previous analyses, we have shown that late presentation to care is a major problem in our setting We also found that HAART use was significantly associated with a lower hazard of death from AIDS-related and non-AIDS related causes. In a scenario where antiretroviral treatment has been shown to dramatically reduce mortality rates attributable to HIV-infection and where improvements in antiretroviral treatment have further reduced mortality rates among HIV-infected individuals, the significant association of lower CD4 cell counts with higher rates of death due to AIDS and non-AIDS related causes supports the numerous arguments for earlier initiation of antiretroviral treatment AIDS-infection remained the most frequent cause of death throughout the 25 years evaluated in the present study. This finding has also been reported in several other cohorts from the developed and developing world In the adjusted analysis, we found that older age, lower education, and lower CD4 cell counts significantly increased the hazard of death from non-AIDS related causes. Compared to those who died from AIDS-related conditions, patients who died of non-AIDS-related causes of death were older at cohort enrolment and at the time of death. An aging HIV-infected population presents new challenges that include the monitoring and handling of drug interactions resulting from the treatment of chronic co-morbid conditions and HIV infection.Among non-AIDS-related deaths, non-AIDS-infections were the most frequent cause of death. We have previously shown that infections play a major role in early mortality Cardiovascular disease was the second most frequent cause of death among non-AIDS related causes. Similar to several other HIV-associated co-morbidities, cardiovascular disease stems from the interplay of multiple risk factors, including both traditional risk factors and those specific to HIV infection, such as impaired immune function disease Our results also show that the proportion of deaths attributable to both AIDS-malignancy and non-AIDS-malignancy increased over time. The most common AIDS-related malignancies were Kaposi’s sarcoma and non-Hodgkin lymphoma while the most frequent non-AIDS malignancy was lung cancer. Malignancies are important causes of morbidity and mortality among HIV infected individuals. Due to declining mortality from AIDS-related infections, malignancies account for a growing fraction of deaths Our study has strengths and limitations that are worth mentioning. A strength was to the use of a standardized method of assessing the causal link between a disease or condition and death, namely the CoDe method Our results show a dramatic decreasing trend in the mortality rates from AIDS-related causes of death among HIV-infected patients from Rio de Janeiro, Brazil. It also shows that, in recent years, similar rates of death from AIDS-related and non-AIDS-related causes were observed. This finding evidences the complexity of HIV-infected patient management that is now clearly beyond the scope of care traditionally provided in most HIV specialized services and that calls for an integrated approach to treatment and prevention. Estimates of the burden of non-AIDS co-morbidities in populations affected by HIV and evidence from effective care delivery models would improve planning capabilities for better use of scarce resources. Furthermore, HIV testing targeting populations at increased risk coupled with linkage to care and early initiation of HAART are now, ever more, the cornerstone of the fight against HIV/AIDS. As for Brazil, this dramatic decrease of AIDS related causes of death happens in the midst of the country’s demographical and epidemiological transitions, where the burden of communicable and non-communicable diseases co-exist


Network motifs, recurring subnetwork patterns, provide significant insight into the biological networks which are believed to govern cellular processes.We present a comparative network motif experimental approach, which helps to explain complex biological phenomena and increases the understanding of biological functions at the molecular level by exploring evolutionary design principles of network motifs.N-ethylmaleimide-sensitive factor activating protein receptor) system in exocytic membrane fusion in yeast and neurons, we find that the SM-SNARE network motifs of yeast and neurons show distinct dynamical behaviors. We identify the closed binding mode of neuronal SM (Munc18-1) and SNARE (syntaxin-1) as the key factor leading to mechanistic divergence of membrane fusion systems in yeast and neurons. We also predict that it underlies the conflicting observations in SM overexpression experiments. Furthermore, hypothesis-driven lipid mixing assays validated the prediction.Using this framework to analyze the SM (Sec1/Munc18)-SNARE (Therefore this study provides a new method to solve the discrepancies and to generalize the functional role of SM proteins. Cellular processes are governed by complex molecular interaction networks where the molecular components and the interactions between them are represented by nodes and edges, respectively. Intensive studies of local and global organizing principles of the networks show the inherent simplicity of biological networks: modularity and reusability -5. TheseHowever, whereas studies have mainly focused on modeling or analysis of topological or kinetic features of network motifs in a single cell type or species, network motifs can be used to reflect dynamical and evolutionary adaptations to meet physiological variances over a time course. Integrating the dynamics across species is particularly important in modeling cellular processes through protein interaction networks. Many of the biological processes mediated by protein interaction networks are highly evolutionarily conserved or related across species. The evolutionary dynamics of biological processes shape the network structure over large time scales. For instance, protein interaction networks are believed to evolve through genetic sequence mutation or gene duplication ,10. The We developed an analysis framework on the basis of comparative network motif design Figure . Given aWe applied the framework to study SM-SNARE-mediated exocytic membrane fusion processes in yeast and neurons. As for many essential biological processes, intracellular membrane fusion is mediated by interactions among a series of evolutionarily conserved proteins. SNARE proteins are viewed as a critical component in execution of vesicle membrane fusion with the target plasma membrane, forming a helical-bundle complex termed a SNAREpin through interactions of v-SNAREs (vesicle - associated SNARE proteins) and t-SNAREs (target membrane associated SNARE proteins) ,13. SM (in silico mutation experiments confirmed that the bifurcation behaviors resulted from the closed binding mode of Munc18-syntaxin-1. Our reconstitution lipid-mixing assay experiments based on wildtype and mutant SNARE proteins confirmed the prediction that the closed binding mode of Munc18-syntaxin-1 (one tSNARE protein) in neuronal SSNM explains d the divergence of yeast and neuronal SM-SNARE system behaviors. Therefore it reconciles s the discrepancy y in studies of over-expressed SM protein from a system regulation point of view. To test the robustness and extensibility of the model, we further expanded the neuronal SSNM with other exocytic proteins, which may regulate SM and SNARE proteins.Applying our modeling framework, we comparatively constructed two ensemble SM-SNARE network motifs (SSNM) in the exocytic network based on the binding mode information curated from current literature: the cascade-like SSNM in yeast and the feedback-loop-like SSNM in neuronal synaptic pathways. Comparative dynamical analysis revealed bifurcation behavior in the neuronal system which was different from hyperbolic response behaviors in the yeast system and provides a way to explain the conflicting experimental observations of SM overexpression in neuronal systems. Furthermore, the comparative topological analysis revealed that the closed binding mode of Munc18-syntaxin-1 in neuronal SSNM may be the critical factor that brings the complexity to synaptic exocytosis in terms of network topology and system behaviors compared to yeast exocytosis. Furthermore, in vitro experiments with in silico network motif modeling. The strategy is shown in Figure in silico experiments link the molecular architecture to cellular function and demonstrate system behaviors. It can identify key factors which may introduce the divergence of system behaviors and provide predictions regarding underlying regulatory mechanisms of the target system. Third, experiments are designed to verify the predictions and new components are included to test the robustness and extensibility of the model.For comparative modeling of network motifs for the complicated molecular machinery of exocytic membrane fusion, we outlined a three-step strategy, integrating prediction-driven trans to cis SNAREpin complex [We first constructed SM-SNARE network motifs because SM proteins and SNAREs play central positions in the protein interaction network of intracellular membrane fusion. Two SM-SNARE network motifs are reconstructed for yeast and neuronal synaptic exocytosis because they represent two fundamental types of exocytosis: constitutive and regulated Figure . We deve complex .In yeast, the exocytosis pathway operates continually supplying vesicles containing lipids and proteins for the plasma membrane. Yeast exocytic SNAREs Sso1p (yeast syntaxin/t-SNARE), Sec9p (yeast SNAP25/t-SNARE) and Snc1/2p (yeast synaptobrevin/v-SNARE) mediate the vesicular fusion process. Sso1p and Sec9p preassemble into the t-SNARE complex. Then, Snc1/2p associates with the complex to form the SNAREpin complex, which acts as an engine to release biochemical energy to drive the vesicular and plasma membranes together. The yeast SM protein, Sec1p, regulates the SNARE complexes and the fusion rate by directly binding to the assembled SNAREpin (pattern 2) ,29.In neurons, the synaptic exocytosis pathway is highly regulated in time and space, and it controls specialized neuron communication and the release of neurotransmitters contained by synaptic vesicles in response to calcium signals. Despite the regulation, the core molecular machinery of the synaptic exocytosis pathway is evolutionarily related to that of yeast. For example, neuronal t-SNAREs, syntaxin-1 and SNAP25 pre-assemble into a t-SNARE complex. The complex later reacts with VAMP (synaptobrevin/vesicle associated membrane protein) to form an assembled SNARE complex/SNAREpin. The neuronal SM protein Munc18-1 also binds to the assembled SNAREpin (pattern 2) to facilitate membrane fusion. Munc18-1 has an extra binding mode (closed mode of binding of Munc18-syntaxin) with syntaxin-1 (pattern 1), which stabilizes syntaxin-1 in the closed conformation, blocking the formation of the SNAREpin complex . FurtherWe investigated system behavior in response to SM regulation both in yeast and neurons, using the system models described above.The first simulation models system behaviors of the cascade-like yeast SM-SNARE network motif with respect to the ySM protein concentration and the results show yeast SM stimulates fusion. The ySM positively regulates the fusion process as the amount of fusion shows a hyperbolic response to the ySM protein concentration. Figure in vivo because of the fact that syntaxin-1(tSNARE) outnumbers Munc18-1(nSM)[The neuronal SSNM model allows computational exploration of the system behaviors in the feedback-loop-like neuronal SM-SNARE network motif with respect to the nSM protein concentration and the results show that SM stimulates fusion in neurons but in a more complex ways than in yeast. A bifurcation behavior is observed in the neuronal SSNM model where nSM can play either a positive or negative role depending on the dose Figure  and 3d: 18-1(nSM),17.To extract the critical factor which underlies the divergence and complexity in the yeast and neuronal exocytic systems, we next investigated the two SM-SNARE network motifs from yeast and neurons. Network comparison analysis explores the differences with respect to network structure, since the topological diversity of biological networks usually reflects the diversities of function, evolutionary selection, and regulation mechanism of cellular processes ,6,9. TheThe neuronal SM-SNARE binding mode (closed mode of binding of Munc18-syntaxin) radically changes the topology of the SM-SNARE network in neurons compared with that in yeast, even as it conserves the cascade-like branch. This predictively suggests that the binding mode drives the divergence of the SM-SNARE network motif regulation in the secretory pathways in the different systems, and introduces the complexity into the neuronal system.in silico to eliminate the neuronal nSM binding to closed nSyx (closed mode of binding of Munc18-syntaxin)  may be the key factor in inducing the structural divergence of SM-SNARE network motif in yeast and neurons.To test this prediction, we next performed a perturbation experiment To further test the predictions by our model, we utilized fluorescence resonance energy transfer-based lipid fusion assays, in which neuronal SNAREs are reconstituted into liposomes at physiologically relevant surface densities and when fusion occurs between the fluorescent donor and unlabeled acceptor vesicles the fluorescent intensity can reflect the dynamics of lipid fusion. More importantly, the reconstitution lipid mixing assay allows us to investigate the fusion event by precisely controlling the concentration ratio of SNARE proteins or other regulatory proteins.To test whether there is bifurcation behavior in neuronal SM-SNARE network motif, we firstly employed the lipid mixing assay for the wildtype SNARE-SM system. The tSNAREs syntaxin-1 and SNAP25 were separately expressed. The dynamics of fusion showed the exact bifurcation behavior with respect to Munc18-1(nSM) initial concentration which we observed in the network motif modeling -syntaxin-1, we employed the lipid mixing assay in a mutant SNARE-SM system as previously reported , where pm Figure  and 5d.The confirmed bifurcation behavior of the neuronal SM-SNARE system provides a mechanistic explanation for the discrepancies observed in SM overexpression experiments. The overexpression of SM protein inhibited synaptic exocytosis in flies but increased exocytosis in chromaffin cells, PC12 cells and motor neurons, and had no effect on exocytosis in some studies ,30-33. FIn addition to SM and SNARE, many other important regulatory proteins are involved in exocytic membrane fusion, especially in neurons, such as Munc13-1, complexin, and synaptotagmin . These pThis work developed a comparative strategy to facilitate network motif modeling for complex biological processes. Applying the method to SM-SNARE systems in exocytic membrane fusion, we connect the regulation mechanism of SM-SNARE to the network motif structure of the protein interaction and to the evolutionary dynamics of the network motifs. This comparative analysis indicated that the topological shift of the network motifs from yeast to neuron is a force underlying the complicated behavior of the neuron system. The prediction-driven lipid mixing assays were then designed in wildtype and mutant neuronal systems to test the findings produced by the comparative system modeling. The result further confirmed the bifurcation behavior in neuronal systems. Specifically, the bifurcation behavior of the neuronal system in response to different SM concentrations provides a new perspective on discrepancies observed in SM overexpression experiments.in silico can explore the dynamical behaviors and controlling mechanism of the systems and infer potential functional roles of system elements such as SM proteins under different conditions. The prediction-driven comparative wet experiments in the trafficking systems can then be specifically designed under different conditions to test the conclusions and therefore offer a mechanistic understanding for the complex biological systems in an effective manner. Many other important regulatory proteins are involved in exocytic membrane fusion. Deciphering this complex network remains challenging, however our comparative network motif modeling offers an extensible and robust experimental framework to understand the dynamics of large-scale network in terms of elementary network patterns.This analysis also showed that the closed mode of binding of Munc18-1 to syntaxin-1 is a potentially critical contributor to divergence of network motif structure topology between yeast and neurons in exocytic membrane fusion. This binding mode is not observed in yeast exocytic membrane fusion but was recently discovered in endosomal trafficking in yeast . Recent Plasmid construction, mutagenesis, protein expression and purification for neuronal SNAREs have been described elsewhere . Brieflysn-glycerol-3-phosphatidylcholine (POPC) and 1, 2-dioleoyl-sn-glycerol-3-phosphatidylserine (DOPS) (molar ratio 65:35) with a lipid/protein ratio of 100:1. The v-SNARE synaptobrevin was reconstituted with another 10 mM liposome containing POPC, DOPS, NBD-PS ) and rhodamine-PE ) (molar ratio 62:35:1.5:1.5) with the lipid/protein ratio of 100:1. Two reconstituted liposomes were dialyzed overnight using dialysis buffer  to remove detergent OG. After dialysis, the solution was centrifuged at 10000 x g to remove protein and lipid aggregates.The procedure was described elsewhere . BrieflyTo measure the lipid mixing, dialysised v-SNARE liposomes were mixed with dialysised t-SNAREs liposomes in the ratio of 1:1 and 4.5 μM concentration. For the fusion reaction performed with Munc18, at the beginning, different ratios of t-SNAREs liposomes and Munc18 were incubated at 4°C for about 2-3 h. Then the mixture was mixed with v-SNARE liposomes again to perform in vitro liposome fusion assay. The final reaction volume for each assay was 100 ul with total 1 mM lipids in Hepes buffer. Fluorescence intensity was monitored with the excitation and emission wavelengths of 465 and 530 nm, respectively. The fluorescence signal was recorded by a Varian Cary Eclipse model fluorescence spectrophotometer using a quartz cell of 100 ul with a 2-mm path length. All of the lipids mixing experiments were performed at 35°C.Based on previously work, fusion levels were transformed to fusion round ,41,42.http://vrac.iastate.edu/~jlv/cytomodeler/. The kinetics simulation and bifurcation analysis were completed in CytoModeler and Systems Biology Toolbox. Differential equations were solved using the ODE23s routine.To perform comparative network motif modeling, we develop a Cytoscape  plug-in For robustness analysis of parameters, the work used the Latin Hypercube Sampling method. 2000 random parameter sets were generated with +/-30% variance relative to their original values .The concentrations of reactant proteins are given in molar units. For the SNARE proteins such as SNAP25 and syntaxin, we followed the studies ,44 whichin vivo and in vitro biochemical experiments for parameter values [in vivo/in vitro and also approaches to estimating unknown parameters. It should be stressed that these available rate constants are measured independently and under different secretion systems which may be different quantitatively. However, because the exocytosis process is highly conserved between different cell types, we integrated these rate constants into our kinetic equations which aim at providing insights into fundamental regulatory mechanisms of protein interaction among two essential protein families (SM and SNARE) during almost every type of exocytosis process [In our models, where available, we have relied on r values ,44-49. Ir values  which pr process ,16. TherThe authors declare that they have no competing interests.TX, JST, XG, and JAD conceived the study. TX, XG and JAD coordinated the project and the manuscript preparation. JST and SSR carried out lipid mixing assay. TX carried out the data analysis and drafted the manuscript. All authors read and approved the final manuscript.Supplements for yeast and neuronal SM-SNARE network modeling. The file includes: System reactions, equations and parameters used in the models for the in silico experiments and parameter robustness analysis [analysis ,48,50-56Click here for file


Improvement of patients quality of life is one of the main goals in the treatment of AIS. There are well known instruments to estimate the treatment outcomes for patients with AIS, such as SRS questionnaires. Although widely used with patients with AIS, there are still some important aspects of QOL less covered in those instruments. The KIDSCREEN-52 quality-of-life (KIDSCREEN-52-HRQOL) is a relevant, worldwide tool used for assessing the health-related quality of life in children and adolescents, and to compare the QOL of treated patients with healthy peers at the same age.To describe and characterize health-related quality of life in girls with idiopathic scoliosis, after spine surgery, with the KIDSCREEN-52-HRQOL questionnaire.Patients with idiopathic scoliosis completed an age-appropriate health-related quality of life questionnaire KIDSCREEN-52 test approved at country the research provided. The study involved 50 patients with AIS. Patients were 12-16 years old girls, post surgery. The results from this sample were compared with general population norms, taken from freely chosen peers without any orthopedic condition.The results where similar in the following blocks - ""feelings"", ""family and home"", ""leisure"", ""school"" and a ""bad mood"". AIS group had a higher scores at blokes as ""to be happy as you are"" ""feeling happy at home"" , ""feel satisfied with life"" and ""happy to be alive"". In the question blocks as ""physical activity"", ""Self esteem” and “Money” AIS patients revealed lower results with statistically significant difference 24.8% , 16.3%  and 22,8%  respectively.By using questionnaire KIDSCREEN 52, it is possible to compare HRQOL of AIS patients, after surgery, with the QOL of healthy peers, and reveal some aspects, not covered by widely used questionnaires, for estimation of treatment outcomes of AIS.


Silicon nanoribbons (Si NRs) with a thickness of about 30 nm and a width up to a few micrometers were synthesized. Systematic observations indicate that Si NRs evolve via the following sequences: the growth of basal nanowires assisted with a Pt catalyst by a vapor-liquid-solid (VLS) mechanism, followed by the formation of saw-like edges on the basal nanowires and the planar filling of those edges by a vapor-solid (VS) mechanism. Si NRs have twins along the longitudinal < 110 > growth of the basal nanowires that also extend in < 112 > direction to edge of NRs. These twins appear to drive the lateral growth by a reentrant twin mechanism. These twins also create a mirror-like crystallographic configuration in the anisotropic surface energy state and appear to further drive lateral saw-like edge growth in the < 112 > direction. These outcomes indicate that the Si NRs are grown by a combination of the two mechanisms of a Pt-catalyst-assisted VLS mechanism for longitudinal growth and a twin-assisted VS mechanism for lateral growth. One-dimensional nanostructures have attracted much attention in the research community owing to their novel physical and chemical properties and due to their easy manipulation as building blocks for nanoscale devices. In particular, nanoribbons (NRs) are of interest on account of their geometrical shape, comprised of a rectangular cross-section on a nanometer scale that can provide unique properties for optical, mechanical, and electrical devices. Limited experiments on III-V and oxide semiconductor NRs have already shown promising properties, such as the wave-guiding of photons, lasing action, nonlinear polarization, Aharonov-Bohm interference, and high mechanical flexibility -5. MeanwTwo different methods to prepare Si NRs have been reported. The top-down approach uses lithography and etching procedures to create the NRs from wafers, which affords a well-defined morphology and crystalline orientation . Meanwhi2 (99.9999%) and an Ar (99.9999%) flow of 100 and 100 standard cubic centimeter per min (sccm), respectively. SiCl4  was then supplied for 10 min by bubbling with H2 as a carrier gas at 20 sccm. The carrier gas was then turned off and the reactor was cooled to room temperature.Si NRs were synthesized on Si (111) substrates using CVD process. Conventional wet chemical cleaning processes were performed to remove any residual components from the substrates. Pt thin film (0.5 nm) was deposited as catalyst by using the electron-beam evaporator. The substrates were then placed in a hot-wall horizontal reactor and heated to the reaction temperature of 1,000°C under a HThe structural properties of the Si NRs were characterized using scanning electron microscopy (SEM)  and transmission electron microscopy (TEM) . To prepare the samples for TEM observation, the NRs were dispersed via the ethanol solution. A small droplet of the solution was then dropped onto the copper TEM grid. To prepare the samples for cross-section TEM observation, the saw-like edged NRs were dispersed via ethanol solution onto Ge substrates coated with 30 nm of Au film. The cross-sectional samples were produced by FIB (Nova 600 Nanolab) and a lift-out technique  slicing and a lift-out process with a micromanipulator  from the basal nanowires by the VS mechanism. In fact, previous studies suggest that twins have critical roles in the crystal growth. For example, the presence of a twin can drive the growth in a specific direction by what is known as classical "reentrant twin mechanism" ,21. IndeRegarding the role of the twin on the lateral growth, it is also noted that the twin creates distinct surface energy anisotropy in the basal nanowire. As shown in Figure The triangular configurations of the saw-like edges are due to the nucleation of two-dimensional islands during the epitaxial growth on the Si 111) surface ,24. On t11 surfacFigure The bulk of previous studies have reported the growth of one-dimensional Si nanostructures  via the VLS or the VS mechanism, respectively ,15,26,27The authors declare that they have no competing interests.TEP carried out the main part of synthesis, the structural analysis, and drafted the manuscript. KYL and IK participated in the structural analysis. JC participated in the discussion of the cross-sectional TEM sampling. PV participated in the discussion of the growth mechanism. HJC participated in the design of the study, draft preparation and coordination. All authors read and approved the final version of the manuscript.Combinatorial Growth of Si Nanoribbons. Supporting InformationClick here for file