To evaluate progression rate of Bosniak category IIF complex renal cysts andthe malignancy rate among surgically resected cysts.We performed a database search for complex renal cysts classified as Bosniakcategory IIF on computed tomography or magnetic resonance imaging betweenJanuary 2008 and April 2016. Follow-up examinations (computed tomography ormagnetic resonance imaging) were used in order to evaluate progression(Bosniak category reclassification) and stability, the latter being definedas remaining stable for a minimum of six months. Pathology reports were usedas the reference to assess the malignancy rate of surgically resectedcysts.A total of 152 cysts in 143 patients were included in the final analysis.Seven cysts (4.6%) were reclassified on follow-up studies, and mean time toprogression was 20 months . Three cysts weresurgically resected. All three were diagnosed as low-grade malignant renalcell carcinomas (RCCs): one clear cell RCC and two papillary RCCs. Theremaining 145 cysts remained unchanged after a mean follow-up period of 28months .The progression rate in Bosniak category IIF cysts was low. Even lesions thatwere upgraded on follow-up remained stable, indicating an indolent behavior.Our data support the idea of conservative management of Bosniak IIF renalcyst. Most renal cysts are acquired lesions, areasymptomatic, and are incidentally diagnosed on routine tests such as ultrasound,computed tomography (CT), and magnetic resonance imaging (MRI).Renal cysts are the most common incidental finding in the daily practice ofradiology, with an estimated prevalence of 50% in patients over 50 years ofageThe majority of renal cysts are benign. Simple cysts are easily characterized byroutine imaging methods and do not require histopathological analysis. However,certain features, such as septa, wall thickening, areas of enhancement, and muralnodules, increase the complexity of a cyst and consequently the risk of malignancy.In patients with complex renal cysts, CT and MRI play an important role, not only inthe characterization of the cysts but also in guiding their appropriatemanagement.(1-8). To standardize communication between radiologistsand urologists, Bosniak initially described four categories. Cysts classified ascategory I or II were considered presumably benign, therefore not requiringfollow-up or surgical management; those classified as category III or IV wereconsidered to have an increased risk of malignancy, therefore requiring surgicalmanagement(1-8). In 1993, Bosniak introduced a new category (IIF),in an attempt to stratify category III cysts, category IIF being applied to thosethat were likely benign but more complex than category IIcysts(2). Minimally complicated cysts, such as thosecontaining numerous thin septa or thick calcifications, and hyperattenuating cyststhat are completely parenchymal and larger than 3.0 cm were included in the IIFcategory, therefore requiring follow-up to confirm theirstability(9-11).The Bosniak classification system, created in 1986, established morphological CTcriteria to differentiate between cysts that are probably benign and those that arelikely to be malignant. Although there have been many studies evaluatingthe malignancy rates of category III and IV cysts, few studies haveevaluated the malignancy rates and progression of category IIF cysts. Previousstudies of category IIF cysts have had small sample sizes, have involved shortfollow-up periods(5), or have produced discrepantresults(1-5). Therefore, the objective of the present study wasto evaluate Bosniak category IIF cysts, in terms of their progression and themalignancy rate after surgical resection, in a large cohort of patients.The Bosniak classification system has been widely used by radiologists andurologists, having recently been found to be also suitable for use in the evaluationof renal cysts on MRI scansThis was a single-center retrospective study. We searched the radiology database ofour institution for CT or MRI reports that contained the term "Bosniak IIF" and wereissued between January 2008 and April 2016. The study was approved by theinstitutional review board. Because of the retrospective nature of the study, therequirement for written informed consent was waived.Examinations were prospectively read in consensus by two board-certified abdominalradiologists with 3 to 20 years of experience, and all cases included in this studywere reviewed by one of the authors. Discrepant cases were reviewed in consensuswith a senior author with 15 years of experience in abdominal radiology. For imageinterpretation, cases were read on an integrated Picture Archiving and CommunicationSystem and radiology information system that included multiplanar reconstructiontools .CT examinations were performed in several different 16- to 32-slice multidetectorCT scanners, with a collimation of ≤ 2 mm, including protocols forroutine abdominal imaging, abdominal pain, renal masses, and urography, all ofwhich involved, at a minimum, an unenhanced phase and a contrast-enhanced venousphase  or nephrographic phase .Iodinated contrast medium (1-2 mL/kg of body weight) was delivered intravenouslyvia a power injector at a rate of 2.0-3.0 mL/s.MRI examinations were performed in several different 1.5 or 3.0 T scanners. At aminimum, axial and coronal fast spin-echo T2-weighted images, chemicalshift-based images, diffusion-weighted images, and unenhanced andcontrast-enhanced T1-weighted sequences were obtained, in all cases , of the area extendingfrom the diaphragm to below the inferior renal pole. Gadolinium-based contrastmedium (0.2 mL/kg of body weight) was injected at a rate of 2 mL/s.The inclusion criterion was having renal cysts that were classified as BosniakIIF on CT or MRI and were reclassified on a subsequent examination ordemonstrated stability for at least 6 months in follow-up studies. The exclusioncriteria were severe artifacts degradation on imaging examinations, cystssmaller than 1.0 cm, and follow-up studies of stable cysts performed after lessthan 6 months.Our initial search generated 428 reports of Bosniak category IIF cysts. Of those428 reports, 276 were excluded, for the following reasons: no follow-upexaminations (n = 233); cyst size < 1.0 cm (n = 19); and a follow-up periodshorter than 6 months (n = 24).(1-8). The first follow-up examination demonstratingsuch reclassification was considered a reference point for determining the timeto progression. If conservative management was chosen, the latest availablefollow-up study was considered in order to evaluate stability. If surgery wasperformed, pathological reports were evaluated. None of our category IIF cystswithout progression were submitted to biopsy or surgery. During the follow-upperiod, none of those cysts were reclassified as being in a lower category.Progression was defined as the appearance of new worrisome characteristics in acyst, leading to its reclassification as Bosniak category III orIVThe initial imaging modality employed was MRI in 88 patients (65 follow-upexaminations with MRI and 23 follow-up examinations with CT) and CT in 64patients (21 follow-up examinations with MRI and 43 follow-up examinations withCT).The final sample included 152 Bosniak category IIF cysts in 143 patients , as depicted in During the follow-up period, seven (4.6%) of the Bosniak category IIF cysts werereclassified: two as category III and five as category IV. The mean size of thereclassified cysts was 1.9 cm , and the mean time toprogression was 20 months : two cysts showed progressionbefore 6 months of follow-up ; four cysts showedprogression between months 11 and 36; and one cyst showed progression after 48months of follow-up. The mean growth rate of the reclassified cysts was 0.04 cm: the size of one cyst increased by 1.1 cm; and two cystsshowed a reduction in size but developed new worrisome features . Of the seven reclassified cysts, three were surgically resected at our facility. Ofthose three cysts, all of which had been reclassified as Bosniak category IV, onewas found to be a clear cell renal cell carcinoma (RCC) and two were found to bepapillary RCCs. The postoperative follow-up period ranged from 16 months to 30months , and there was no evidence of recurrence. Two of thoseseven patients were followed clinically: one was 86 years old and had a Bosniakcategory IV cyst that remained stable after one year of follow-up; and the other hadcirrhosis and hepatocellular carcinoma and a Bosniak category III cyst that alsoremained stable after one year of follow-up. The last two patients with category IIFcysts that were reclassified  werelost to follow-up.The remaining 145 Bosniak category IIF cysts remained unchanged on follow-up studiesand were not reclassified. The growth rate of those cysts ranged from 0.1 cm to 4.1cm , one having grown more than 4 cm over 6 years, without significantchanges in morphology. The mean follow-up was 28 months .Comparisons between the stable and reclassified cyst groups are summarized in (1-8). For category I and II cysts, no specificrecommendation is made, because such cysts are presumably benign. For category IIIand IV cysts, surgery is often considered, given the high risk of malignancy,although some authors believe they are less aggressive than are non-cystic renalneoplasms. For category IIF cysts, the length of follow-uprequired is still under debate. The American College of Radiology suggests CT or MRIfollow-up examination every 6-12 months for up to 5 years after the initialdiagnosis(2). The revised Bosniak system proposed that IIF cystswith fewer complex features  could befollowed for two years after initial diagnosis, whereas those that were more complex should be followed for up to fouryears(7).The authors of another study suggested that, in addition to morphological features,patient age should be taken into consideration when deciding how long the follow-upperiod should be(16): five years for patients 50-60 years of age andlonger for younger patients.The Bosniak system for classifying renal cysts into five categories is wellestablished, and the specific management strategies recommended for each categoryhave been widely adopted(17) addressed the Bosniak classificationin CT in terms of its diagnostic performance and the malignancy rates for thevarious categories. The review showed that malignancy rates were higher in studiesthat used histopathology alone as the reference standard than in those that used acombination of histopathology and clinical follow-up. In the present study, the rateof progression for Bosniak category IIF cysts was 4.6%, which is slightly lower thanthat reported in previous studies(1-5), including a recent study that reported a rate of10.9%(2).However, in the present study, the histopathology showed that all of the resectedcysts were malignant RCCs.A recent systematic review and meta-analysis. Particularlyhyperattenuating or heavily calcified on CT may benefit from MRI, given the highercontrast resolution for tissue characterization on T2-weighted images andpost-contrast sequences with digital subtraction. For both of the cystsmentioned above, what appeared to be rapid progression was more likely related totheir reclassification on MRI rather than to true progression. We believe that thoselesions were already category III/IV cysts, and their reclassification beingsecondary to an initial underestimation of the septal enhancement in one and tobetter characterization of the small nodule in the subsequent MRI of the other.Despite the short time to progression in both of those cysts, no metastases wereseen in the follow-up studies. In fact, cystic neoplasms presenting as category IIFare more likely to be less aggressive neoplasms than to be conventionalRCCs(19-23). Two of the cysts that were reclassified in ourstudy (one as category III and one as category IV) were managed through conservativefollow-up, because both patients had comorbidities and one was of advanced age, bothcysts remaining stable at 12 months. Three of the seven reclassified cysts weretreated surgically; all three were subsequently identified as malignant RCCs,although they were early stage, low-grade RCCs.Of the seven cysts that were reclassified in our study, two were reclassified withinthe first six months of follow-up, and the five remaining cysts were reclassifiedbetween month 11 to month 48. One of the two rapidly progressing cysts had shownthin septa on the initial MRI and measurable septal enhancement on a subsequent MRI,therefore being reclassified as Bosniak category III. The other fast progressingcyst was likely related to higher contrast resolution of MRI when compared to CT. Inthe initial examination (by CT), it appeared as a 2.7 cm hyperattenuating cyst withquestionably thickened walls classified as category IIF. An MRI scan one month latershowed a small mural nodule and the cyst was therefore reclassified as category IV.As previously reported, multiple septa, septal thickening, and small solidcomponents are more evident on MRI scans than on CT scansOur study has some limitations. First, the majority of the Bosniak category IIF cystsidentified were excluded due to lack of follow-up, which could have introduced aselection bias. Second, stability during follow-up is not necessarily indicative ofbenignity. Third, there were very few cases in which there was histologicalconfirmation of malignancy, which precluded a more detailed analysis of progressionrates.The progression rate in Bosniak category IIF cysts was low. Even lesions that wereupgraded on follow-up remained stable, indicating an indolent behavior. Our datasupport the idea of conservative management of Bosniak IIF renal cyst.


We previously reported that perinatal dioxin exposure increased autistic traits in children living in dioxin-contaminated areas of Vietnam. In the present study, we investigated the impact of dioxin exposure on children’s eating behavior, which is often altered in those with developmental disorders.A total of 185 mother-and-child pairs previously enrolled in a birth cohort in dioxin-contaminated areas participated in this survey, conducted when the children reached 3 years of age. Perinatal dioxin exposure levels in the children were estimated using dioxin levels in maternal breast milk after birth. Mothers were interviewed using the Children’s Eating Behaviour Questionnaire (CEBQ). A multiple linear regression model was used to analyze the association between dioxin exposure and CEBQ scores, after controlling for covariates such as location, parity, maternal age, maternal education, maternal body mass index, family income, children’s gestational age at delivery, and children’s age at the time of the survey. A general linear model was used to analyze the effects of sex and dioxin exposure on CEBQ scores.p-dioxins/furans (TEQ-PCDDs/Fs) and CEBQ scores in boys, although significant associations between some eating behavior sub-scores and 1,2,3,4,6,7,8,9-octachlorodibenzofuran were observed. In girls, there was a significant inverse association between levels of TEQ-PCDFs and enjoyment of food scores and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Two pentachlorodibenzofuran congeners and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with a decreased enjoyment of food score, and seven PCDF congeners were associated with a decreased desire to drink score. The adjusted mean enjoyment of food score was significantly lower in children of both sexes exposed to high levels of TEQ-PCDFs. There was, however, a significant interaction between sex and TEQ-PCDF exposure in their effect on desire to drink scores, especially in girls.There was no significant association between most dioxin congeners or toxic equivalencies of polychlorinated dibenzo-Perinatal exposure to dioxin can influence eating behavior in children and particularly in girls. A longer follow-up study would be required to assess whether emotional development that affects eating styles and behaviors is related to dioxin exposure.The online version of this article (10.1186/s12887-018-1171-2) contains supplementary material, which is available to authorized users. We found that dioxin levels in maternal breast milk in contamination hotspots in southern Vietnam were 3–4 times the levels in unsprayed areas of northern Vietnam, even though four decades had passed [Dioxin contamination in Vietnam has had a long-term impact on the environment and human health, particularly in hotspots of high contamination –4. This d passed . As bread passed , lower cd passed , and lowd passed .When our cohort reached 3 years of age, we performed a health impact survey to determine whether there was an association between perinatal dioxin exposure and autistic traits measured using the Autism Spectrum Rating Scales (ASRS), and found that perinatal TCDD exposure increased social emotional difficulties in these children . We alsoAnimal studies have reported that dioxin exposure affected brain regions in the limbic system such as the hypothalamus, nucleus accumbens, amygdala, and orbitofrontal cortex –16 that The study was conducted in the Thanh Khe and Son Tra districts of Da Nang City near Da Nang airbase, where extremely high dioxin levels have been recorded in soil and sediment samples collected in 2006  [In 2008–9, a total of 241 mother-and-newborn pairs (159 pairs in Thanh Khe and 82 in Son Tra) were recruited in district hospitals. These pairs were selected based on the following criteria: i) Mothers resided in Thanh Khe or Son Tra at least during their pregnancy; ii) babies were born at term; iii) mothers had no birth complications. Breast milk samples (20 mL) were collected from these mothers 1 month postpartum with the assistance of midwives and were stored in sterile polyethylene containers at − 4 °C at local health centers.A total of 198 mother-child pairs (82.2%) participated in the survey when the children reached 3 years of age. Forty-one other pairs were lost to follow-up owing to relocation or failure to appear at the examination; two infants died in their first postnatal month. There were no significant differences in the characteristics of mothers and children or dioxin levels in breast milk between study participants and the 43 pairs lost to follow-up. Some demographic information was missing for 13 of the mothers, so the final sample for analysis included 185 mother-child pairs, representing 76.8% of the original sample.At the follow-up surveys at 4 months, 1 year, and 3 years of age, neurodevelopmental measurements were obtained using the Bayley Scales of Infant and Toddler Development, Third Edition  to assess infant development in the areas of cognition, language, and motor functions. The findings were reported in our previous studies –9. At thp-dioxins/furans (PCDDs/Fs) were lipid-base calculated. Toxic equivalency factors (TEFs) for each congener were referenced from the World Health Organization 2005-TEF list [p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCDDs/Fs were calculated by multiplying each congener concentration by its TEF and summing the values. The values of the concentrations that were below the limit of detection were set to equal half of the limit of detection for the analysis. Table Breast milk samples were frozen after collection and transported to the High Technology Center, Kanazawa Medical University, Japan to analyze concentrations of 17 2,3,7,8-substituted dioxin congeners. After extracting fat from 10 mL of sample and a series of purifying operations, measurement was performed using a gas chromatograph  equipped with a high-resolution mass spectrometer . The established analytical method has been described in detail previously . ConcentTEF list . Toxic eLower TEQ levels of dioxin-like polychlorinated biphenyls (dl-PCBs) measured in the present study were compared with levels in samples collected in unsprayed areas in northern Vietnam, although dl-PCB levels were measured in only four samples . Those fStructured questionnaires were used to obtain information related to childbirth and the growth and neurodevelopment of children  and to maternal demographics at the 4-month survey. Maternal height and weight were obtained from medical records in the hospitals’ obstetrics departments. Table Mothers were asked about the children’s eating behavior in face-to-face interviews using the CEBQ, a multi-dimensional, parent-reported questionnaire . This scInformed consent to participate in the present study was obtained from all mothers. The Institutional Ethics Boards of Medical and Epidemiological Studies at Kanazawa Medical University and Vietnam Military Medical University approved the study design. The Department of Health and Prevention of Diseases of Da Nang City government reviewed and approved the informed consent process.Statistical analysis was performed using SPSS ver. 11.0 for Windows . Concentrations of PCDDs and PCDFs congeners and TEQ levels of PCDDs, PCDFs, and PCDDs/Fs in breast milk were used for analysis after base-10 logarithmical transformation to improve normality. A linear regression model was used to analyze the association between each CEBQ score (a response variable) and congener concentration and TEQ in breast milk (a predictor variable) after adjusting for the following covariates: Location (Thanh Khe or Son Tra), maternal age, parity, body mass index (BMI) during pregnancy, maternal education, family income, gestational weeks to delivery, and children’s age at the time of the survey. Regression analysis was stratified by sex because we previously found that the effects of dioxin exposure on growth and neurodevelopment differed between boys and girls in this cohort –10. Nextp-dioxin in boys were inversely associated with the fussiness score , suggesting a connection between this dioxin congener and decreased food avoidance behavior.Tables In girls, we found significant inverse associations between levels of TEQ-PCDFs and enjoyment of food scores, and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Among PCDF isomers, two pentachlorodibenzofuran isomers with high TEFs and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with lower enjoyment of food scores, and seven PCDF isomers were associated with lower desire to drink scores in girls Table . In addip = 0.009), without a significant effect by sex. The adjusted mean enjoyment of food score was 3.8, significantly lower in the high-exposure TEQ-PCDF group than in the low-exposure group (4.1). The effect of TEQ-PCDFs on the desire to drink score was borderline significant , but interaction between sex and TEQ-PCDF levels was significant , with a lower adjusted mean in the high-exposure TEQ-PCDF group (2.8) than in the low-exposure group (3.5) in girls.The findings suggested significant associations between exposure to dioxin, as indicated by TEQ-PCDF and/or TEQ-PCDD/F values, and enjoyment of food and desire to drink scores, with sex-specific differences. We therefore analyzed the effects of the two main factors, sex and dioxin type  on enjoyment of food and desire to drink scores using the general linear model after adjusting for covariates . BMI was not associated with CEBQ scores, and a decrease in positive eating score was not related to emaciation. In boys, while dioxin exposure was not related to eating behavior, BMI was positively associated with enjoyment of food scores and inversely correlated with satiety responsiveness scores, suggesting that eating behavior affects BMI.In our previous study performed in the same cohort, we reported that perinatal exposure to TCDD was associated with an increase in autistic traits, particularly in boys . Childrep-dioxin and octachlorodibenzo-p-dioxin, were associated with eating behaviors; this suggests that the mechanism altering eating behavior in these children may not be the toxicity of TCDD-like aryl hydrocarbon receptor agonists. A similar study in areas contaminated by PCDFs and high-chlorinated PCDD isomers in other countries than Vietnam would be required to validate the effects on eating behavior in young children.In the present study, TEQ-PCDFs of congeners with comparatively lower TEFs than PCDDs were associated with decreased CEBQ scores. Some high-chlorinated PCDD isomers with lower TEF values, such as heptachlorodibenzo-We conducted the present study to assess whether dioxin exposure might alter eating behaviors in children. Animal studies have linked perinatal dioxin exposure with poor neurodevelopment. Pretreatment with TCDD was reported to completely block the effects of lesions in the ventromedial hypothalamus of the rat brain, leading to hypophagia and weight loss, suggesting that TCDD exposure affects neurological control of appetite . Food inPrevious studies have suggested that perinatal dioxin exposure affects taste preference in rats, particular in females. Perinatal TCDD and dioxin-like PCB exposure altered the expression of saccharin preference behavior in adult female rats . NishijoGrowth restriction has been reported in infants with Yusho disease whose mothers ingested rice oil contaminated with PCDDs/Fs and PCBs during pregnancy, and particularly in boys . In our In children, eating behaviors have been targeted in preventing obesity and over-eating. One study reported that boys were more inclined to have a post-meal snack than girls, a habit leading to weight gain . A studyWe found that TEQ-PCDFs contributed more to increased FAPP scores in girls than TEQ-PCDDs, including TCDD. Our previous study of dioxin exposure sources indicated that PCDF levels may increase with increased intake of marine food sources such as shrimp and with longer residency in contaminated areas . OngoingPerinatal exposure to dioxin affected eating behavior in 3-year-old children and particularly in girls. Future research should clarify the effects of dioxins on emotional development that affects eating styles and behaviors, leading to health problems such as emaciation or obesity in later life.Additional file 1:Data of CEBQ and dioxins in 3-year-old Vietnamese children . (XLSX 43 kb)


Objectives: Masked hypertension (MH) is not uncommon in the youth and may increase risks of long-term cardiovascular impairment. However, little is known about the subclinical heart damage in this group of patients. Currently, 3-layer speckle tracking imaging based on two-dimensional echocardiography is feasible to detect the early signs of myocardial damage. We therefore aimed to investigate whether subtle changes of cardiac function occurred in the young MH patients by using advanced quantification with layer-specific speckle tracking.Methods: A total of 40 adolescents with MH  and 40 age-, gender-, race-, and height-matched normotensive volunteers were enrolled in our study. MH was defined as one or more of the ambulatory blood pressure (BP) parameters  higher than ≥ 95th percentile for gender and height according to the local reference. Both comprehensive two-dimensional echocardiography with layer-specific strain analysis and 24-h ambulatory BP monitoring were performed. Longitudinal strain and circumferential strain in endocardial, mid-myocardial, and epicardial layers were determined accordingly with the dedicated software .Results: Compared with normotensive controls, youths with MH had higher ambulatory pulse rate and left ventricular mass index, and were more obese. Interestingly, similar ventricular volumes and ejection fraction were observed in the study groups, but further analysis with layer-specific strains revealed that endocardial and mid-myocardial longitudinal and circumferential mechanical function were decreased in the young MH subjects when compared to normotensive individuals . However, there were no difference regarding radial strain and apical rotation derived from traditional speckle tracking analysis.Conclusion: Subclinical change of LV mechanic function assessed by layer-specific speckle tracking is present in youth with MH despite considered as normal with conventional ways.Thus, MH in youth should be monitored closely instead of labeling as an entirely benign entity. Masked hypertension (MH) has recently become a topic of interest in youths; it refers to a condition in which office blood pressure (BP) is normal but being elevated during ambulatory BP monitoring . ActuallTwo-dimensional (2D) speckle-tracking echocardiography (STE), capable of obtaining quantitative measurements of whole-layer longitudinal, circumferential, and radial directional deformation without the angle dependency of one-dimensional techniques, has been well recognized to allow easily early detection of myocardial damage while left ventricular (LV) ejection fraction (LVEF) is still preserved in various pathologies –9. RecenThus, this study for the first time provided the new insight to LV mechanical function in youths with MH, and assessed the occurrence of early echocardiographic signs of subclinical left ventricular dysfunction in this young group, using advanced quantification with layer-specific 2D speckle tracking.This was a community-based cohort study, which initially enrolled 1445 ethnic Chinese students for surveying 24-h ambulatory BP in Hong Kong during 2011/2012. The presented local reference was used for the definition of MH in Chinese adolescents as one or more of the ambulatory BP parameters  were higher than 95th percentile for age, gender and height, and the office BPs were normal . TotallyAnthropometric measurements  and laboratory analyses  were obtained from all the subjects included in the study. Body mass index (BMI) and body surface area (BSA) were calculated for each subject. The study was approved by the Joint the Chinese University of Hong Kong and New Territories East Cluster Clinical Research Ethics Committee and the Ethics Committee of the Department of Health of the Hong Kong Government (CRE-2013.563). Informed consent was obtained from the participants and their parents before commencement of the monitoring.Conventional BP measurements were obtained by measuring the average value of the 3 consecutive measurements in the sitting position, at least 1 min apart and after 5 min of rest, using the Datascope Accutorr Plus , which has been validated in our local Chinese children and adolescents , 18. AppAll the participants underwent a 24-h BP monitoring. The non-invasive 24-h ambulatory BP monitoring was performed on the non-dominant arm during a weekday with typical activities, using a portable non-invasive oscillometric recorder . The ABP readings will be obtained every 30 min over a 24-h period. Only ABP profiles with at least 40 recordings, including at least eight readings during sleep, will be accepted. Individual mean systolic, diastolic and mean arterial BP will be calculated for wake and sleep periods. All readings taken during 24 hours will be used to calculated mean 24-h, mean daytime and mean night-time SBP and DBP, in accordance with the method proposed by Soergel et al. . Local r2.7 , within 2–3 days after 24-h BP monitoring. Routine 2D cine loops of three consecutive cardiac cycles were obtained at end-expiratory apnea from parasternal long-axis and short-axis views and the standard three apical views  by the same operator. Grayscale recordings were optimized for LV evaluation at a frame rate between 50 and 70 fbp and saved for subsequent strain analyses. LV volume and LVEF were calculated with biplane Simpson method. Left ventricular mass index was determined according to the corrected method of the American Society of Echocardiography (ASE) and indexed to body height2.7 .All data of 2D speckle tracking were analyzed off-line using the dedicated EchoPAC V201 software . The advanced software automatically tracked the contour of endocardium to cover the myocardial thickness of the entire LV wall at an end-diastolic frame, similarly to traditional 2D-STE method, but allowing investigation of three myocardial layers for longitudinal and circumferential strain: endocardial, mid-myocardial and epicardial level. Adequate tracking could be verified in real time and corrected by manual to ensure optimal tracking of endocardium and epicardium and inclusion of the entire LV thickness including endocardial, mid-myocardial and epicardial layers in all observed echocardiographic views .t-tests for continuous variables, as well as the chi-square test and Fisher's exact test for categorical variables. The P < 0.05 was considered statistically significant.Collected data were computerized and analyzed using the IBM SPSS Statistics, version 20 (IBM) software. Continuous variables are expressed as mean ± SD and nominal variables as percentages. Data were compared between 2 groups using the independent sample None of subjects was found to be primary or secondary hypertensive. Patient characteristics are presented in Table 2.7 was significantly higher in cases than in normotensive individuals. There was no significant difference in the LV wall thickness, ventricular volumes and LVEF between the observed groups. Interestingly, young subjects with MH had lower mitral E/A ratio and mitral annulus e′ when compared with normotensive individuals , but no difference in E/e′.Routine echocardiographic features of the study population were shown in Table 2D-STE derived LV global LS and CS were significantly lower in youth with MH than in controls. Moreover, comparing with true normotensives, LV systolic and early diastolic longitudinal strain rates in MH subjects were significantly decreased, while late diastolic strain rates tended to increase in MH, although without statistically significance Table . Howeverp < 0.05)  to validate the layer-specific strain determined by 2D-STE. However, Altiok E et al. reported that the layer-specific strain using cardiac MRI demonstrated good correlations with the layer-specific strain using 2D echocardiography . Of noteWith layer-specific 2D-STE, subclinical impairment of LV mechanical function in different myocardial layers is present in youth with MH, despite considered as normal with conventional ways. Thus, periodic follow-up and early detection of LV functional deterioration in young MH patients may help to prevent the natural progression of the disease.M-CY, H-KS, and FF conceived and designed the experiments. X-XL, H-KS, and YZ organized the database. X-XL and YS performed the echocardiographic images analysis and statistical analysis. X-XL wrote the first draft of the manuscript. X-XL, YS, QG, and JS wrote sections of the manuscript. All authors have read and revised the manuscript, which was coordinated by FF and YZ, who also produced the final draft for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aim of this study was to determine the association between patient-reported outcome measures (PROMs) six months following femoral neck fracture after a low fall and future arthroplasty, and the factors associated with this. Six-month post-fracture PROMs were collected from the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR) for patients aged >55 years who were admitted for a femoral neck fracture after a low fall between March 2007 and June 2015. These cases were linked with those registered by Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) up to October 2016. Multivariable analysis was performed using a Cox proportional hazards model to determine factors associated with future arthroplasty, including six-month PROMs. Of the 7077 hip fracture patients registered by VOTOR during the study period, 2325 met the inclusion criteria. Internal fixation being used for the initial hip fracture surgery, being younger and having no pre-injury disability were all independently associated with future revision or conversion to arthroplasty. Out of all PROMs, reporting pain and discomfort six months post-fracture was associated with a 9.5-fold increase in the risk of future arthroplasty . The value of clinical registries can be enhanced via data linkage, in this case by using PROMs to predict arthroplasty following femoral neck fracture. Hip fractures are significant injuries that lead to reduced quality of life and increased mortality, especially in older patients ,2. In maPrevious research has established that re-operation rates are lower for arthroplasty compared to internal fixation (approximately 10% compared to 40%) ,6. HowevIn the past, research on predictive factors for re-operation has relied on demographics, pre-fracture health status and post-operative radiological findings ,8. WhileTo assess outcomes that matter most to patients, patient-reported outcome measures (PROMs) are being increasingly adopted following orthopaedic surgery . The incAll hip fracture patients registered by the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR) from 1 March 2007 to 30 June 2015 were included. The VOTOR is a sentinel site registry which, since March 2007, has included four trauma hospitals within the state of Victoria (population 6.3 million) : two majTo determine the incidence of arthroplasty following hip fracture, the VOTOR hip fracture dataset was linked with the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) dataset for the period 1 March 2007 to 31 October 2016. The AOANJRR includes data on almost all arthroplasty procedures performed in Australia since 2002. Data are validated against patient-level data provided by each of the state and territory health departments in Australia with use of a sequential, multilevel matching process .Ethical approval was obtained for this study from each of the four VOTOR hospitals via the multi-site ethics review process (HREC16Alfred/92), as well as the Monash University Human Research Ethics Committee (CF16/2058 - 2016001024). Both VOTOR and the AOAJNRR use an opt-out method of consent, with the opt-out rate currently at <3% for VOTOR, while the AOANJRR has had only 46 patients opt out in 16 years (1.2 million procedures) ,15.The study population consisted of all patients registered by VOTOR with a hip fracture who: (i) were aged 55 years and over, (ii) had sustained a fractured neck of femur  diagnostic codes: S72.00–S72.05, S72.08, S72.10) , and , mapped from ICD-10-AM codes) ; date ofSix-month PROMs were extracted from VOTOR for all patients surviving to six months post-injury. These data were captured over the telephone by trained interviewers who contacted patients or their next of kin . For this study, the following six-month PROMs were included based on their relevance to the hip fracture population: (i) place of residence  and (ii) Three-Level European Quality of Life-Five Dimensions (EQ-5D-3L) measure. The EQ-5D-3L asks patients to score their mobility, activity, pain and discomfort, anxiety and depression, and self-care, as “no problems”, “some problems” or “severe problems” . AdherinFollowing VOTOR case selection, unique patient identifiers including name, date of birth, medical record (UR) number and date of index surgery were securely transferred to the AOANJRR, where probabilistic linkage was carried out. Probabilistic linkage takes into account a wide range of potential identifiers  to ensure a potential case match. When there is a probability above a certain threshold that two given records refer to the same case, the two records are considered to be matches. For each linked case with a future arthroplasty, the following AOANJRR variables were added to the dataset: date, type and diagnosis/reason for arthroplasty, components inserted, bearing surface for components inserted, diameter of femoral head and whether cement was used on the femoral and acetabular side.After the linked dataset was returned to VOTOR, a medical record review was undertaken for each linked patient at each of the four VOTOR hospitals to determine the laterality of the original hip fracture . This step was necessitated by the reliance of VOTOR on diagnostic coding via the ICD-10-AM, which does not include laterality. Subsequently, fractures were matched with any subsequent arthroplasties according to laterality. The ICD-10-AM does not record fracture displacement, nor did we conduct radiological reviews; therefore, we were unable to determine fracture displacement.p < 0.25) [p < 0.05). The reduced model was compared with the initial model using likelihood ratio tests and the remaining variable coefficients were assessed to ensure that they had not substantially changed, indicating potential confounding. This process was repeated until a parsimonious final model was achieved [Descriptive statistics were used to summarise the characteristics of the sample. Chi square analyses were carried out to compare patient characteristics  and index procedures between those with complete and incomplete follow-up data. Chi square analyses were also carried out to determine univariable associations between patient characteristics, index procedures, six-month EQ-5D-3L and residential outcomes, and future arthroplasty. A multivariable analysis was performed using a Cox proportional hazards model, where the primary outcome was the time from the initial hip fracture surgery to the first arthroplasty procedure  or time to the revision arthroplasty (if the index procedure was an arthroplasty) within the follow-up period. Patients were followed until censoring  or until death. The proportional hazards assumption was evaluated statistically based on Schoenfeld residuals and a log–log Kaplan–Meier survival plot against time. The variables included in the multivariable analysis were the significant factors identified in the univariable analysis ( < 0.25) . Non-sigachieved .To account for the mapping of EQ-5D-3L data from SF-12 data in 2007 and 2008, a sensitivity analysis was carried out comparing results from the unmapped dataset (2009 onwards) to the dataset containing mapped data. All analyses were conducted within Stata  and alpha was set at 0.05.The flow of patients and hip fractures through the study is shown in Seventy-seven patients required an arthroplasty six months or more after their initial surgery . Main reA sensitivity analysis was carried out, comparing these results to those from a subset of data restricted to those patients with a date of injury from 2009 onwards (including only unmapped EQ-5D-3L data) . All finThe aim of this study was to link two clinical registries to determine the association between PROMs six months post femoral neck fracture and future arthroplasty, and other factors associated with this. Consistent with previous research, the risk of revision arthroplasty or conversion to arthroplasty six months after initial hip fracture surgery was highest among patients undergoing internal fixation, relative to total hip arthroplasty and hemiarthroplasty. The risk was also higher for patients who were younger and reported no pre-injury disability. Patients reporting pain and discomfort six months post-injury had an almost ten-fold higher risk of future arthroplasty compared to those with no pain.While there is a small body of literature investigating PROMs as predictors of subsequent revision following arthroplasty, to our knowledge, this is the first study to investigate PROMs predicting arthroplasty following hip fracture. Our major finding was the strong association between pain and discomfort six months post hip fracture and future arthroplasty. Similar to this, previous studies have shown associations between low Oxford Hip Scores (OHSs)  at both six months and five years post arthroplasty, and subsequent revision ,24. LikeAnother key finding was that further surgery was more common in younger patients and those reporting no pre-injury disability. These findings are supported by previous research reporting greater revision rates following arthroplasty in younger patients ,28,29,30Notably, after adjusting for confounding, we found no association between pre-injury comorbidity and future arthroplasty. This finding contradicts previous research demonstrating a greater risk of revision in patients with higher degree of pre-injury comorbidity, possibly due to susceptibility to post-surgical infection or poor bone quality ,32. The A key limitation of this study was the small number of patients undergoing internal fixation, as their index procedure may have been revised using further internal fixation surgery or implant removal, and these data were not available. However, revision via arthroplasty is the recommended management for patients over 60 years of age , who conDespite these limitations, there were several strengths to our study. Using data from two high-quality registries provided access to PROMs with high follow-up rates in a large volume of hip fracture cases. This provided the first strong evidence of post-fracture PROMs predicting future arthroplasty. These methods also provide access to baseline (pre-revision) PROMs in order to quantify the level of improvement post-revision. Another strength was our use of a standardised and widely-used outcome measure, the EQ-5D-3L. This outcome measure has been recommended for use following both fracture and arthroplasty, and is currently used in several arthroplasty registries ,12,20. OWhile there has been extensive research investigating predictive factors for revision arthroplasty following femoral neck fracture, these have focused on patients’ pre-fracture health, surgical techniques and radiological findings. This study linked two large clinical registries: an orthopaedic registry collecting PROMs and a national clinical quality registry of joint replacement procedures, providing the first opportunity to determine the association between PROMs six months post femoral neck fracture and future arthroplasty, and the factors associated with this. Patients reporting pain and discomfort six months post-injury had an almost ten-fold higher risk of future arthroplasty compared to those with no pain. We acknowledge that this may be an intuitive finding for those who commonly treat patients undergoing revision arthroplasty. However, this is the first study to provide empirical evidence of the association between pain and revision arthroplasty after hip fracture and the first to quantify the magnitude and timing of that association. Furthermore, this study has also demonstrated which PROMs may have less predictive capacity for future revision, specifically mobility, self-care, usual activities and anxiety/depression. Consequently, our findings reinforce the importance of pain as a critical outcome to collect, and act on, following femoral neck fracture.


Influenza causes an estimated 3000 to 50,000 deaths per year in the United States of America (US). Timely and representative data can help local, state, and national public health officials monitor and respond to outbreaks of seasonal influenza. Data from cloud-based electronic health records (EHR) and crowd-sourced influenza surveillance systems have the potential to provide complementary, near real-time estimates of influenza activity. The objectives of this paper are to compare two novel influenza-tracking systems with three traditional healthcare-based influenza surveillance systems at four spatial resolutions: national, regional, state, and city, and to determine the minimum number of participants in these systems required to produce influenza activity estimates that resemble the historical trends recorded by traditional surveillance systems.We compared influenza activity estimates from five influenza surveillance systems: 1) patient visits for influenza-like illness (ILI) from the US Outpatient ILI Surveillance Network (ILINet), 2) virologic data from World Health Organization (WHO) Collaborating and National Respiratory and Enteric Virus Surveillance System (NREVSS) Laboratories, 3) Emergency Department (ED) syndromic surveillance from Boston, Massachusetts, 4) patient visits for ILI from EHR, and 5) reports of ILI from the crowd-sourced system, Flu Near You (FNY), by calculating correlations between these systems across four influenza seasons, 2012–16, at four different spatial resolutions in the US. For the crowd-sourced system, we also used a bootstrapping statistical approach to estimate the minimum number of reports necessary to produce a meaningful signal at a given spatial resolution.In general, as the spatial resolution increased, correlation values between all influenza surveillance systems decreased. Influenza-like Illness rates in geographic areas with more than 250 crowd-sourced participants or with more than 20,000 visit counts for EHR tracked government-lead estimates of influenza activity.With a sufficient number of reports, data from novel influenza surveillance systems can complement traditional healthcare-based systems at multiple spatial resolutions.The online version of this article (10.1186/s12879-018-3322-3) contains supplementary material, which is available to authorized users. Every year influenza epidemics are responsible for substantial clinical and economic burdens in the United States of America (US) . ConsequOver the past decade, Internet-based technologies have been explored as new ways to monitor influenza activity and provide more immediate estimates of disease activity. These Internet-based technologies include systems such as Yahoo , Google https://insight.athenahealth.com/flu-dashboard-2016). Flu Near You is an online crowd-sourced surveillance system that allows volunteers in the US and Canada to report weekly if they have experienced ILI symptoms [In this paper, we evaluate two novel influenza-tracking systems, athenahealth, a cloud-based EHR-based system, and Flu Near You (FNY), a crowd-sourced system. Founded in 1997, athenahealth is a provider of cloud-based services and mobile applications for medical groups and health systems. Similar to traditional health-care based surveillance systems, athenahealth collects data on individuals who seek medical care. Because athenahealth’s network is cloud-based, the proportion of patients with ILI symptoms in their national network of providers can be estimated in near real-time, potentially providing estimates of influenza activity faster than the national surveillance systems . For the analysis presented in this paper, ILI was defined as Unspecified Viral or ILI Visit Count, which included the number of visits where the patient had an unspecified viral diagnosis, an influenza diagnosis, or a fever diagnosis with an accompanying sore throat or cough diagnosis. Influenza-Like Illness rates for a given location were calculated by dividing the Unspecified Viral or ILI Visit Count by the total number of visits.Weekly state-aggregated counts of total visits, influenza vaccine visits, influenza visits, ILI visits, and unspecified viral or ILI visits were provided by the athenahealth research team for the time period of 2012–16 (https://flunearyou.org/). [Flu Near You was created in 2011 through collaboration between HealthMap of Boston Children’s Hospital and the Skoll Global Threats Fund (u.org/).  This syshttps://www.cdc.gov/flu/weekly/overview.htm) [Information on patient visits to health care providers for ILI is collected through the US Outpatient Influenza-like Illness Surveillance Network  . For thiVirological influenza surveillance data is collected through participating US World Health Organization (WHO) Collaborating Laboratories and National Respiratory and Enteric Virus Surveillance System (NREVSS) laboratories located throughout the US. The number of specimens testing positive for influenza was used in these analyses .The Boston Public Health Commission (BPHC) has operated a syndromic surveillance system since 2004. All nine acute care Boston hospitals electronically send limited data for all emergency department (ED) visits every 24 h. Data sent includes visit date, chief complaint, zip code of residence, age, gender, and race/ethnicity. Influenza-Like Illness visits were defined as fever and a cough or sore throat using chief complaints. Greater Boston was defined as zip codes associated with Suffolk, Norfolk, Middlesex, Essex, and Plymouth counties. These zip codes are associated with over 90% of Boston ED visits. Influenza-Like Illness rates for Greater Boston were calculated by using the number of ILI visits divided by the total number of ED visits.We used Pearson correlations to compare EHR and crowd-sourced ILI rates to ILI rates from ILINet along with the number of specimens testing positive for influenza from the virologic surveillance system. Correlations were calculated at the national and HHS-defined regional resolutions during the time period of October 1, 2012 through May 21, 2016, and for each of the four individual influenza seasons within this time period (MMWR weeks 40 to 20) separately. We also present comparisons of EHR to CDC ILINet for 46 states and comparisons of crowd-sourced ILI to CDC ILINet for 49 states that voluntarily provided historic data across all seasons. Finally, crowd-sourced ILI rates were also compared to ILI rates estimated from ED visits in the Greater Boston area. Boston was chosen as a pilot city because of the large FNY user base and availability of data. Electronic Health Record data at this spatial resolution was not available.Spatial resolutions were classified into three author-defined categories based on correlation values with CDC ILINet across all seasons. Spatial resolutions with correlations less than 0.5 were classified as “poor”, spatial resolutions with correlations between 0.5 and 0.70 were classified as “good”, and spatial resolutions with correlations greater than or equal to 0.70 were classified as “excellent”. Data were analyzed using R, version 3.3.2,  and descAs above, weekly ILI rates from the crowd-sourced system were compared to weighted ILI rates from CDC ILINet and the number of specimens testing positive for influenza at national and regional resolutions during the 2015–16 influenza season. State and city resolutions were not included in this analysis because the crowd-sourced user base was not large enough. At the national level, Pearson correlations were calculated for subsets of the crowd-sourced data from 0.1 to 15% of the full dataset in increments of 0.1%, and at the regional level, Pearson correlations were calculated from 1 to 100% of the full dataset in increments of 1%. This process was repeated 1000 times using sampling with replacement (bootstrapping), stratified by week at each spatial resolution. The 95% confidence intervals were calculated by ordering the Pearson correlation coefficients and selecting the 2.5th and 97.5th percentiles. This method was not performed for EHR because available data was aggregated at the state level.Pearson correlations between CDC ILINet and EHR and mean weekly visits at all spatial resolutions are shown in Additional file Pearson correlations of crowd-sourced ILI rates versus CDC ILINet and BPHC as well as mean weekly reports at all spatial resolutions are shown in Additional file Fig. Figure During the 2015–16 influenza season, a total of 401,993 crowd-sourced reports were collected in the US, corresponding to a weekly average of 12,182 reports. The Pearson correlation coefficients during the 2015–16 influenza seasons for the full crowd-sourced dataset and CDC ILINet and the number of viral-positive specimens were 0.84 and 0.92, respectively. Figure Traditional surveillance systems currently used by governmental agencies are robust, well accepted, and provide the best basis for tracking influenza activity. However, because estimates only include individuals who visit a medical care facility and there is typically a delay from onset of patient symptoms to final publication of reports, alternative data sources have the potential to minimize these delays in reporting and complement these traditional systems. Although there is still a time delay from onset of patient symptoms to presentation at a health-care provider, the EHR cloud-based system allows symptom reports to be aggregated in near-real time. On the other hand, the crowd-sourced system does not include the same time delay as health-care based systems and captures individuals who do not seek medical care. However, while participants have the option to report symptoms the same day as onset, most participants do not report until they receive the weekly reminder and data is typically aggregated once a week.For both EHR and crowd-sourced ILI, as the number of total reports increases, the correlations with traditional ILI estimates from governmental agencies also increase. However, EHR data showed higher correlations with CDC ILINet and the number of viral-positive specimens compared to crowd-sourced data at similar spatial resolutions. EHR correlations with CDC ILINet are close to one, which shows that healthcare-based influenza surveillance with different data capture strategies lead to similar ILI incidence curves. Although both EHR and the CDC use data from patients seeking medical attention, the proportion of visit settings differs slightly between the two systems, with emergency department visits being under-represented in the EHR. On the other hand, crowd-sourced correlations with CDC ILINet never reach a correlation of one. Instead, crowd-sourced correlations converge to approximately 0.8–0.9, as shown using both empirical and theoretical approaches. A similar observation was observed when comparing methods of provider recruitment in Texas . This diIn general, both crowd-sourced and EHR ILI rates showed higher correlations with CDC ILINet compared to the number of viral-positive specimens at the national and regional resolutions . However, they do not provide weekly estimates to the public of laboratory-confirmed influenza burden. Although the mechanisms of capture differ between the syndromic systems, the general seasonal trends are similar and provide valuable information about changes in influenza activity.Our findings suggest that both EHR and crowd-sourced ILI estimates correlate with ILI estimates from traditional influenza surveillance systems in various spatial resolutions with a sufficient number of visits or reports. Spatial resolutions with at least 250 mean weekly crowd-sourced reports display correlations higher than 0.5 with traditional influenza surveillance systems. Furthermore, spatial resolutions with approximately 20,000 weekly EHR visit counts consistently show correlations greater than 0.7 with traditional influenza surveillance systems. As the FNY user base and availability of EHR data are increased throughout the US, these internet-based surveillance tools may become a complementary way to timely monitor influenza activity, especially in populations who do not access health care systems, areas with limited surveillance data, and community based populations.Additional file 1Table S1. Pearson correlations between EHR and CDC ILINet and average weekly EHR visits at the national, regional, and state resolutions. Table S2. Pearson correlations between Crowd-sourced and CDC ILINet/BPHC and average weekly crowd-sourced reports at the national, regional, state, and state resolutions. Table S3. Pearson correlations between CDC number positive viral reports and EHR, crowd-sourced (FNY), and CDC ILINet. (DOCX 81 kb)


In this article, we review the existing literature on the application of 18F-FDG and 18F-NaF as PET probes in atherosclerosis and present the findings of original animal and human studies that have examined how well 18F-NaF uptake correlates with vascular calcification and cardiovascular risk.The early detection of atherosclerotic disease is vital to the effective prevention and management of life-threatening cardiovascular events such as myocardial infarctions and cerebrovascular accidents. Given the potential for positron emission tomography (PET) to visualize atherosclerosis earlier in the disease process than anatomic imaging modalities such as computed tomography (CT), this application of PET imaging has been the focus of intense scientific inquiry. Although  As a major contributor to many life-threatening and debilitating diseases, atherosclerosis is among the foremost causes of morbidity and mortality throughout the world . It is dRisk factors such as hypertension, hypercholesterolemia, diabetes, and smoking put individuals at risk of developing atherosclerosis by damaging the vascular endothelium and setting off a cascade of proinflammatory responses as shown schematically in Fig. The inflammatory process of plaque formation triggers another chain of events that gives rise to the calcification of the vascular wall . In the Given the enormous human and economic cost of atherosclerosis and its downstream effects, early and effective detection—particularly of plaques vulnerable to rupture—is paramount. Assessment of Framingham risk factors such as dyslipidemia, hypertension, and diabetes can identify those at risk of developing atherosclerotic disease, but cannot shed light on the extent or vulnerability of existing plaques. Clinical evaluations performed in symptomatic patients, such as the ankle-brachial index and cardiac stress tests, offer some insight into the presence of intraluminal stenosis, but the degree of stenosis alone has not been shown to be predictive of plaque rupture , 12. TheThe anatomic imaging modalities that have historically been used in the assessment of atherosclerosis have tended to focus on noncompositional parameters. Conventional ultrasonography and angiography techniques can be used to examine the extent of luminal stenosis, while cardiac CT can be used to produce calcium scores to quantify the calcification of the coronary vessels. However, other modalities, including multidetector CT coronary angiography, MRI, intravascular ultrasonography (IVUS), and optical coherence tomography, have begun to be implemented with the specific aim of determining plaque composition , 14. By 18F-fluorodeoxyglucose (18F-FDG), a radiolabeled glucose analog that serves as a marker of metabolic activity and, by extension, inflammation. By contrast, 18F-sodium fluoride (18F-NaF) is a specific marker of bone mineralization that has traditionally been used in diagnosing metastatic bone cancer, but has recently been applied to vascular calcification. The aim of this review was to examine the available literature on 18F-NaF PET as a diagnostic and prognostic tool in comparison with the more established method of 18F-FDG PET.Unlike their anatomic counterparts, molecular imaging modalities are capable of detecting microscopic processes such as inflammation and microcalcification. These chemical composition changes occur early in the disease process and precede the aforementioned morphologic developments Fig. . Foremos18F-FDG, the most widely utilized PET radiotracer by far, was among the first molecular probes used for the assessment of atherosclerosis and is perhaps the best studied to date. Early studies showed a correlation between 18F-FDG activity within the vasculature and atherosclerotic and cardiovascular risk factors, promoting its utility as a diagnostic agent [18F-FDG uptake and atherosclerotic disease. Studies in patients with a history of cerebrovascular accidents showed elevated 18F-FDG activity in 58–85% of carotid lesions [18F-FDG uptake in carotid plaques and macrophage staining on corresponding pathology specimens [18F-FDG-avid lesions in patients with symptomatic carotid stenosis line up with macrophage-rich areas of plaque in endarterectomy specimens [18F-FDG uptake was 27% higher in symptomatic carotid lesions than in contralateral asymptomatic lesions [ic agent –18. Furt lesions , 20. Tawpecimens . In a sipecimens . The aut lesions .18F-FDG PET imaging can be used to evaluate plaque vulnerability and the risk of associated ischemic events. Figueroa et al. found that plaques with high-risk morphologic characteristics on CT and histopathology have significantly higher 18F-FDG avidity [18F-FDG uptake have been found to be significantly more likely to go on to suffer an ischemic cardiovascular event [Other studies have provided some evidence that  avidity . Patientar event  or a cerar event .18F-FDG PET in monitoring the effects of various treatments for atherosclerotic disease has also been investigated. In a study of 43 patients undergoing 18F-FDG PET for cancer screening, Tahara et al. randomized subjects to undergo either pharmacologic intervention with simvastatin or dietary modification alone, and found that only the treatment group showed a significant decrease in plaque SUV [18F-FDG uptake significantly increased in animals in which an atherogenic diet was continued and decreased in those in which a normal diet was restored [The role of aque SUV . Ogawa eaque SUV . They alaque SUV . In a sirestored .18F-FDG activity is associated with the atherosclerotic disease process, this link is distinct from the structural changes captured by anatomic imaging modalities. Across multiple studies, 18F-FDG avidity has been shown to be highly discordant with CT findings. In a study of 85 patients, Tatsumi et al. found no correlation between 18F-FDG uptake and CT calcium score [18F-FDG uptake were generally found to be younger than those with extensive calcification, suggesting that high 18F-FDG uptake represents an earlier stage in the disease process.Although these findings strongly suggest that um score . Similarum score , 31. Pat18F-FDG is representative of the inflammatory activity of activated macrophages infiltrating the fibrous cap, which predisposes plaques to rupture [18F-FDG avidity [18F-FDG activity and levels of CD68, a measure of macrophage content [It has been postulated that uptake of  rupture . However avidity , while a content .18F-FDG as a probe for atherosclerosis is its intense uptake by myocardial tissue. The spillover from this physiologic activity obscures pathologic inflammation from atherosclerotic plaques, greatly limiting the utility of the modality in assessing the coronary vasculature. A method of mitigating this limitation is to suppress myocardial glucose metabolism by requiring the patient to fast or consume a high-fat, low-carbohydrate diet prior to image acquisition [18F-FDG is most commonly used to evaluate atherosclerosis within the carotid arteries, the aorta, and its larger offshoots. However, even during delayed imaging of these structures, the contrast resolution is limited by the retention of radiotracer in the surrounding tissues, blood pool, and vessel wall. Another limitation, which applies to 18F-FDG as well as 18F-NaF, is the spatial resolution of PET; visualization of microcalcifications in the millimeter range may be constrained by the physical limits of the modality [Perhaps the most significant limitation of uisition –36. Althmodality , 37.18F-NaF has shown considerable promise in allowing the evaluation of patients at risk of atherosclerosis. It differs from 18F-FDG PET in its molecular binding characteristics and, thus, the manner in which it illustrates disease burden. Whereas 18F-FDG is taken up by metabolically active cells and is considered a surrogate for inflammation, 18F-NaF is incorporated into areas of calcium deposition by exchanging the hydroxyl ions of hydroxyapatite crystals with radiolabeled fluoride to form fluorapatite [18F-NaF PET scans are not affected by the major limitation of myocardial uptake and can be used to assess the coronary arteries in addition to the peripheral vasculature. The uptake of 18F-NaF in bone is orders of magnitude greater than in the vasculature, and thus it is vital to focus imaging on the vasculature to minimize background bone uptake of the tracer.Although its application to vascular imaging is relatively recent, rapatite . Consequ18F-NaF is not only correlated with advancing age, but also with risk factors for atherosclerotic and cardiovascular disease [18F-NaF PET/CT after myocardial infarction [18F-NaF activity were significantly more likely to demonstrate high-risk morphologic features—namely, positive remodeling, microcalcification, and necrosis of the lipid core—on ultrasonography. It is plausible that the observed increase in NaF uptake in culprit lesions is attributable to the permeability of ruptured plaques, but there is no evidence of this to our knowledge. The fact that patients were imaged after myocardial infarction limits the ability of the study to inform risk assessment in patients prior to plaque rupture. Longitudinal NaF studies in the same subjects in the absence and presence of myocardial infarction/stenting are needed.Several studies have shown that vascular uptake of  disease –43. Thisfarction . Uptake 18F-NaF PET in comparison with existing diagnostic tools. More specifically, the distribution of vascular uptake has been compared with that of calcified plaques visualized on CT. In a retrospective study in 61 patients, Li et al. found a significant correlation between 18F-NaF uptake and calcification on CT in the coronary arteries, but not in the aorta [18F-NaF uptake and arterial calcification on CT. Notably, the vast majority (88%) of sites with 18F-NaF activity on PET were colocalized with calcifications seen on CT, but far fewer sites of calcification (12%) showed elevated 18F-NaF uptake [18F-NaF activity can indicate the presence of microcalcifications before they are large enough to be visualized on CT. Moreover, the lack of 18F-NaF uptake at sites of macrocalcification discernible by anatomic imaging techniques suggests that these plaques are no longer undergoing active calcium deposition.Recent research effort has sought to validate he aorta . Derlin F uptake . These r18F-NaF PET in atherosclerosis requires validation in large prospective studies, as much of the data that has appeared in the literature thus far has been derived from single center retrospective studies with limited sample sizes. Additional prospective studies are especially vital to determining the modality’s prognostic value, which hinges on the ability to identify plaques at risk of rupture. The specificity of 18F-NaF for this application is also worthy of investigation; although not as intense as myocardial uptake of 18F-FDG, background uptake of 18F-NaF may be sufficient in some patients to preclude differentiation between vulnerable and stable plaques.The clinical application of 18F-NaF PET for the early detection of atherosclerosis has been illustrated most vividly in animal studies. McKenney-Drake et al. and Salavati et al. used the Ossabaw miniature swine model of metabolic syndrome (MetS) to demonstrate that 18F-NaF uptake in the coronary arteries precedes the emergence of macroscopic calcification on IVUS and CT scans [The potential of CT scans –49.18F-NaF uptake in the coronary arteries to test the hypothesis that 18F-NaF PET imaging can detect CAC earlier than the current gold standard noninvasive CT scanning [To investigate NaF as a marker of early coronary artery calcium , a study was conducted in this preclinical model. The study included 13 lean (control) swine and 11 swine with MetS and early coronary artery disease (CAD). When fed a high-calorie atherogenic diet and forced to live a sedentary lifestyle, the Ossabaw swine developed progressive CAD from the stages of clinically insignificant fatty streaks through necrotic, flow-limiting lesions with macrocalcifications detectable on IVUS , 51. CACscanning –49. Detascanning .18F-NaF PET study by Beheshti et al. [18F-NaF uptake in the heart was almost 2.5-fold higher in MetS pigs than in lean pigs  [p < 0.05; Fig. These studies relied on the Alavi-Carlsen global molecular calcium score (GMCS), a quantification system pioneered in an earlier i et al. . A measui et al. , 43, 52  < 0.05)  . As expected, in MetS pigs PWC was about fivefold greater than in lean pigs —was used as a surrogate for atherosclerosis. The PWC of the proximal RCA was more variable than the percent plaque burden data. An example of early CAD , with a low percent plaque burden (about 13%), is shown as concentric wall coverage (100%) in Fig. p = 0.24; Fig. 18F-NaF uptake did not come from the ventricular tissue of the heart.Biochemical assessment revealed no significant difference in the calcium content of the left ventricle Fig. a between18F-NaF uptake in coronary arteries is a biomarker for early CAC in pigs with CAD that lack frank evidence of calcification on IVUS and CT imaging. These findings imply that 18F-NaF binds to microcalcifications too small to be detected using anatomic/morphologic imaging modalities, an interpretation that is strengthened by histopathology data revealing sparse calcifications within the proximal region of the coronary artery. The histopathology findings did not significantly correlate with 18F-NaF uptake in the coronary arteries, suggesting that histologic assessment detects macroaggregates of hydroxyapatite, but not the microcalcifications visualized on 18F-NaF PET/CT [18F-NaF PET/CT in the early detection of atherosclerosis, but validation is required in human studies.This preclinical PET/CT study demonstrated that increased F PET/CT . The finF PET/CT , 53, 54 18F-NaF PET/CT in the clinical evaluation of atherosclerosis, we analyzed 124 human subjects, including 80 healthy controls and 44 patients with chest pain syndromes. These subjects belonged to the Cardiovascular Molecular Calcification Assessed by 18F-NaF PET/CT (CAMONA) study in Odense, Denmark. All subjects underwent a 90-min 18F-NaF PET/CT scan and a 180-min 18F-FDG PET/CT scan under similar conditions. A whole-vessel analysis in axial sections was then performed for the three vascular segments of the thoracic aorta, including the ascending aorta, aortic arch and descending aorta. Measures of arterial microcalcification including average SUVmax, average SUVmean, and Alavi-Carlsen GMCS were calculated for each vascular segment as well as for the whole vessel using previously described methods. Vascular 18F-NaF uptake quantified as average SUVmax, average SUVmean, and GMCS was significantly higher in patients than in healthy controls. Of note, age was significantly correlated with average SUVmax, average SUVmean and GMCS in all vascular segments and the whole vessel, although the correlation coefficients were higher in patients with chest pain syndromes . Moreover, GMCS of the thoracic aorta was a borderline significant predictor of an unfavorable CVD risk profile as compared to average SUVmax and average SUVmean . 18F-FDG uptake in the thoracic aorta quantified as average SUVmax and average SUVmean was positively correlated with age; however, the correlation was not significant in the healthy group.To further investigate the value of mes Fig. . GMCS ofr = 0.11, p = 0.48), but was positively correlated with increasing age in patients with cardiovascular disease risk factors . These findings highly suggest that global assessment of cardiovascular microcalcification has potential applications for prompt risk stratification and therapeutic intervention in patients at high risk of cardiovascular disease. Given the evidence that 18F-NaF is able to detect arterial calcifications earlier than CT, this approach holds promise as a clinical alternative to the conventional CT-based calcium score.We also assessed the extent of cardiac microcalcification in another subset of subjects from the CAMONA study that included 40 healthy subjects and 38 patients with chest pain syndromes. To quantify cardiac microcalcification, ellipsoid ROIs were manually drawn around cardiac ventricles by an experienced physician on axial PET/CT images starting from the base to the cardiac apex excluding the aortic valve Fig. . Alavi-C18F-fluoromethylcholine [18F-FDG and 18F-NaF remain the most widely studied and compared.Once the value of molecular imaging for evaluating patients at risk of atherosclerotic disease had been demonstrated, comparisons between available PET radiotracers became an area of scientific inquiry. Although numerous radiotracers have been investigated for this indication, including lcholine , 56, a b18F-FDG and 18F-NaF activity with clinical and pathologic measures of disease have consistently found that 18F-NaF is more strongly correlated. In a prospective study in 119 subjects, Dweck et al. found that, while 18F-NaF uptake in coronary arteries and the aorta was significantly correlated with 10-year FRS, 18F-FDG uptake was not [18F-NaF activity was significantly associated with increased rates of CAD and angina, as well as with histories of coronary revascularization and major adverse cardiac events, but 18F-FDG activity was not. In a prospective study of 139 subjects , Blomberg et al. similarly found that an increased risk of cardiovascular disease as estimated by FRS was associated with vascular calcification metabolism as measured by 18F-NaF, but was not associated with 18F-FDG uptake [18F-NaF uptake occurred very reliably in culprit plaques in the coronary arteries and histologically-confirmed sites of active calcification, macrophage infiltration, apoptosis, and necrosis [18F-FDG. In both of these studies, the authors concluded that physiologic uptake of 18F-FDG by the myocardium obscured pathologic uptake in the coronary arteries, drastically limiting the ability to evaluate atherosclerotic burden using this radiotracer. Such comparisons were also extended to other cardiovascular conditions involving calcification and inflammation, producing similar results. In a study in 101 patients with aortic stenosis of varying severity and 20 controls, Dweck et al. found that uptake of both radiotracers was significantly higher in patients, but that 18F-NaF uptake was better correlated with the severity of valvular disease [Studies that have correlated  was not . LikewisG uptake . In a prnecrosis . No such disease .18F-NaF to be better correlated. In a study in 45 patients, Derlin et al. found that 18F-NaF had far superior colocalization with CT calcifications than 18F-FDG (77.1% vs. 14.5%) [18F-NaF is superior to that of 18F-FDG, as the target-to-background uptake ratio of 18F-NaF (2.3) exceeded that of 18F-FDG. Two prospective studies by Dweck et al. confirmed that 18F-NaF uptake is significantly correlated with CT calcium scores, while 18F-FDG uptake is too intense in the myocardium to enable detection of coronary pathology [18F-NaF alone.Studies comparing these molecular imaging probes with radiologic and serologic assessments of arterial calcification have also shown . 14.5%) , and alsathology , 60. The18F-NaF-based PET imaging is less prone to the complexities that are associated with PET imaging of this disorder.Increasingly, there is evidence that molecular calcification may be the initial biologic process for development of atherosclerotic plaques in the arteries , 62. Thi18F-NaF and 18F-FDG in detecting the chemical composition and vulnerability of atherosclerotic plaques. Despite possessing distinct binding properties that interrogate entirely different components of the disease process, these radiotracers were initially shown to be associated with many of the same clinical risk factors for atherosclerosis and cardiovascular disease [18F-FDG and 18F-NaF was found to be increased not only in vulnerable plaques with high-risk morphologies, but also in ruptured plaques that cause myocardial infarctions and cerebrovascular accidents [In this review, we have outlined evidence in the literature regarding the use of the molecular imaging probes  disease –41, 43. ccidents , 44.18F-NaF correlated well with these conventional measures of atherosclerotic burden, 18F-FDG demonstrated no such relationship [18F-NaF in illustrating the calcification that takes place in atherosclerotic disease is plainly evident in its correlation with CT calcium scores and colocalization with CT-detected macrocalcifications and pathologically confirmed microcalcifications. Thus, the data support the use of 18F-NaF PET as the best modality for the early detection of disease as it has been shown to pick up microcalcifications before they become visible on CT scans in humans [18F-FDG is not associated with these markers of calcification, but is linked to the inflammatory component of atherosclerosis, which is a critical risk factor for plaque rupture [18F-FDG has the unique disadvantage of intense myocardial uptake, which obscures activity in the coronary arteries, and essentially restricts the applications of 18F-FDG to the peripheral vasculature [18F-FDG and 18F-NaF have consistently shown that the latter is better correlated with clinical, pathologic, and radiologic measures of disease.However, the similarities ended when these PET probes were compared to anatomic imaging modalities, most notably CT calcium scores. While tionship , 42, 46.n humans –38. In c rupture . In addiculature , 57. Lar18F-NaF PET, as well as its comparative advantage in the early detection of microcalcifications (Fig. 18F-NaF PET could allow earlier intervention and improved outcomes, and studies combining this technique with CT calcium score or MRI may offer further sensitivity and specificity. A few early studies have already begun to demonstrate the utility of hybrid imaging for this indication [The relative specificity of dication , 64. GivIn two recent editorials, we have discussed current limitations of PET in assessing cardiovascular disorders and the suboptimal methodologies that are being employed in this structurally and biologically complicated domain , 66. In


The effectiveness of treatment after cessation of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) has not been well investigated. The aim of the present study was to clarify the clinical benefit of post-nivolumab treatment in such patients.A retrospective review was conducted on patients who received treatment after cessation of nivolumab due to disease progression or adverse events at the Toneyama National Hospital between January 2016 and April 2017.Among 64 patients treated with nivolumab, 26 patients received treatment after cessation of nivolumab due to disease progression (n = 21) or adverse events (n = 5). The median age of the patients was 68 years and 19 patients were male. Nineteen patients had performance status (PS) 1 or less at initiation of post-nivolumab treatment. Four, 20, and 2 patients were treated with platinum doublets, a single agent, and molecular targeting agents, respectively. Response rate, disease control rate, and median progression-free survival of first-line post-nivolumab treatment were 34.6% (9 patients), 73.1% (19 patients), and 2.8 months , respectively. Adverse events (≥ grade 3) and treatment cessation were observed in 57.7% (15 patients) and 19.2% (5 patients), respectively. There were no statistically significant differences for the majority of patient characteristics between the groups with (n = 26) and without post-nivolumab treatment. However, PS at cessation of nivolumab and post-progression survival (PPS) after cessation of nivolumab  were significantly different between the groups. A multivariate Cox regression analysis showed significant correlation of PS at cessation of nivolumab  and post-nivolumab treatment  with prolonged PPS after nivolumab.Median post-progression survival in patients with advanced NSCLC who received post-nivolumab treatment was approximately 1 year. Lung cancer is one of the leading causes of mortality worldwide. Cytotoxic chemotherapy has been the standard treatment of this disease for decades. Molecular targeting agents such as gefitinib, one of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), became available one and half decade ago. The introduction of EGFR-TKIs in clinical practice changed the strategy for the treatment of non-small cell lung cancer (NSCLC). Nowadays, other molecular targeting agents such as anaplastic lymphoma kinase (ALK)-TKIs have also become available. In recent years, the novel mechanism of immune checkpoint inhibitors (ICIs), that differs from conventional immunotherapies, has received great attention. Programmed cell death 1 (PD-1) inhibitors block a signal preventing activated T cells from attacking cancer cells. Nivolumab is the first PD-1 inhibitor approved in many countries for the treatment of NSCLC. Numerous pivotal studies showed a survival benefit of treatment with nivolumab in patients with NSCLC . Pembrolet al. reported a higher overall response rate to single-agent chemotherapy after immunotherapy compared with that observed in historical data from the pre-PD-1 inhibitor era [Nevertheless, more than half of NSCLC patients treated with a PD-1 inhibitor fail their treatment and require subsequent therapy. Recently, Schvartsman itor era . Moreoveitor era . HoweverA retrospective review was conducted using medical records of patients who received treatment after cessation of nivolumab due to disease progression or adverse events at the Toneyama National Hospital between January 2016 and April 2017. Nivolumab was administered based on the clinical decision by the attending physician. Dosage and schedule of nivolumab administration were 3mg per body weight and once every 2 weeks. Data collected by the end of August 2017 were used for analysis. Post-progression survival (PPS) was defined as the survival time following progressive disease (PD) during treatment with nivolumab. In the present study, definition of partial response, stable disease, and PD were based on the RECIST ver. 1.1. However, for patients in whom the RECIST criteria could not be applied, those were determined clinically. Objective response rate was defined as the ratio of patients with partial response to all study patients. Disease control rate was defined as the ratio of patients with partial response and stable disease to all study patients. Progression-free survival (PFS) and PPS were calculated from the date of initiation of post-nivolumab treatment, and the date of diagnosis of PD during treatment with nivolumab, respectively. The present study was approved by the Toneyama National Hospital Institutional Review Board . This approval allowed for retrospective chart review and anonymous reporting of the results without requiring patient informed consent.All comparisons were performed using the JMP version 8 statistical software package . Variables are expressed as means ± standard deviation or as median and range. Categorical values are expressed as numbers and percentages. Percentages are expressed in relation to the total population unless otherwise specified. Comparisons were performed using the Student’s t test for continuous variables, and Fisher’s exact test for categorical variables. Survivals were assessed using the Kaplan Meier method and determined by the log-rank test. In addition, a multivariate Cox regression model was used to examine factors that may influence survival after cessation of nivolumab administration. For all analyses, a value of p<0.05 indicated a statistically significant difference.The results of first-line post-nivolumab treatment are shown in Characteristics of patients with and without post-nivolumab treatment are shown in The treatment strategy after cessation of PD-1 inhibitor administration against NSCLC has emerged as an important clinical issue. Currently, there are limited data available to overcome this challenge.The present study showed that treatment response to first-line post-nivolumab chemotherapy in patients with advanced NSCLC, treated after cessation of treatment with nivolumab, were higher compared with that obtained from historical data with conventional chemotherapy as late-line treatment. Furthermore, median PPS after cessation of treatment with nivolumab in patients with advanced NSCLC who received post-nivolumab chemotherapy was approximately 1 year. Moreover, this median PPS was significantly longer in patients treated with post-nivolumab chemotherapy than in untreated patients regardless of the results of the best response and PFS of treatment with nivolumab . We specRecently, Schvartsman et al. reported that the response rate to single-agent chemotherapy after immunotherapy was higher than that obtained from historical data from the pre-PD-1 inhibitor era. They surveyed 26 patients retrospectively and demonstrated a response rate of 39% . This waA recent Japanese study investigated PPS after treatment failure with EGFR-TKIs such as gefitinib or erlotinib. Survival time of patients treated with second-line chemotherapy after cessation of treatment with EGFR-TKIs was 13.9 months . These pγ and transforming growth factor-β to improve antitumor immunity [Immune checkpoint inhibitors combined with chemotherapy have shown high efficacy as first-line treatment against advanced NSCLC. The objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively . The objimmunity . The admimmunity . These pThe limitations of the present study must be acknowledged. Firstly, although the treatment response was assessed based on the RECIST, the interval of radiographic examination was not uniform among patients. Thus, the response rate and PFS could not be determined accurately. Secondly, 2 patients received radiation therapy for intrathoracic lesions prior to initiation of post-nivolumab chemotherapy and this radiation therapy may affect the response to subsequent chemotherapy. Thirdly, the smoking status, histology, and driver mutations could not be determined in 1 patient without post-nivolumab treatment, 1 patient with post-nivolumab treatment, and 1 patient with post-nivolumab treatment, respectively. Therefore, these patients were excluded from statistical analysis. Finally, this was a retrospective study with a small sample size. Further studies with larger sample size are warranted to verify the findings presented herein and ensure successful application to clinical practice.In conclusion, the median post-progression survival in patients with advanced NSCLC, treated with chemotherapy after cessation of nivolumab administration was approximately 1 year. These data on PPS suggest a possible survival benefit of cytotoxic chemotherapy in these patients.