Presence of metabolic syndrome (MetS) in patients with type 2 diabetes mellitus (type 2 DM) increases the risk of cardiovascular morbidity and mortality. Therefore, recognition of MetS in type 2 DM is important in initiating the appropriate preventive and therapeutic measures. The commonly used definitions have similarities and discrepancies. Aims of this study was to investigate the prevalence of MetS among patients with type 2DM using all three well known  definitions and to identify the concordance and the difference of these three definitions. This cross-sectional study included patients with type 2 DM who were followed up at the regional diabetes centre in Galle, Sri Lanka. A total of 2913 type 2 DM patients were recruited by convenient sampling method, and their clinical and biochemical data were collected. p < 0.001) and NCEP-ATP III  criteria were poor, they were average  between NCEP-ATP III and IDF criteria. The mean age (SD) of the sample was 49.9 (10.2) years and the mean duration of diabetes was 5.04 (5.71). Prevalence of MetS was highest by WHO (70%) followed by IDF (44%) and NCEP-ATP III (29%) definitions. The prevalence was significantly higher in women according to all three definitions, and the difference was most marked with NCEP-ATP III and IDF definitions. Around 25% were identified as having MetS by all three definitions whereas around 45% were recognized with MetS by two definitions. While concordances between WHO with IDF  whereas lowest was observed with NCEP-ATP III definition. Type 2 diabetes mellitus (type 2 DM) has become a global epidemic with significant disability, premature death, and enormous medical costs . Total nAlthough there is general agreement of the core components of the MetS such as insulin resistance/glucose intolerance, elevated blood pressure, obesity and dyslipidaemia, the diagnostic criteria put forward by various professional bodies differ based on the mandatory inclusion criteria . The firPrevalence of MetS ranges from <10% to as high as 84%, depending on factors such as the population studied, ethnicity, geographical region, urban or rural environment, gender, and the definition of MetS used , 13. OveMetS in patients with type 2 DM increases the risk of cardiovascular mortality and morbidity . Thus, eThis cross-sectional study included patients with type 2 DM who were followed up at the regional diabetes centre in Galle, Southern Sri Lanka, and this study was part of a large study on “cardiovascular risk assessment in patients with diabetes in Sri Lanka.” As described elsewhere , all preIndividuals with ages ≥ 20 years and clinically determined type 2 DM were qualified to participate in the study.Participants aged < 20 years, pregnant, and lactating mothers were excluded from the study. Also patients with other chronic illness including rheumatoid arthritis, severe osteoarthritis, symptomatic heart failure, type 1 DM, myocardial infarction within last 6 months, acromegaly, clinically apparent hypothyroidism, hypogonadism, chronic obstructive airway disease, nephrotic syndrome and chronic kidney disease (stage 3 or more), and chronic liver disease were also excluded. In addition, patients with malignancies and extreme body habitus (BMI >40), those on prolong steroid use, and those who were on active drug treatment for obesity were excluded from the study.2 (m2).A pretested interviewer-administered questionnaire was used to obtain demographic and medical information such as age, sex, ethnicity, social background, duration of diabetes, and family history of dyslipidaemia, and diabetes among first degree relatives. Anthropometric measurements including waist circumference (cm), weight (Kg), and height (m) were then measured. Waist circumference (WC) was recorded by placing a nonstretchable fibre-glass measuring tape around the waist midway between the last rib and iliac crest with the subject in the standing position. All anthropometric measurements were performed by trained nurses adhering to the WHO guidelines, using calibrated equipment. Blood pressure was measured using an electronic instrument , as the mean of two readings taken five minutes apart. BMI was calculated as weight (kg)/heightAll chemical analyses were performed in the laboratory attached to the Regional Diabetic Centre mentioned above and same method of biochemical analysis was used throughout the study period. Overnight fasting venous blood samples were collected to measure HDL-C and LDL-C, serum TG, and glucose. Cholesterol esterase oxidase peroxidase-aminopyrine method was used to assess serum cholesterol and for measurement of serum TG glycerol phosphate oxidase peroxidase-aminopyrine method was used. For HDL cholesterol, direct method poly-ethylene-glycol-pretreated enzymes were used.Ethical clearance for the present study was obtained under the study on “cardiovascular risk assessment in patients with type 2 diabetes in Sri Lanka,” from the Institutional Ethics Committee of the Faculty of Medicine, University of Ruhuna. Written informed consent was obtained from all study subjects in the local language.The metabolic syndrome (MetS) was defined according to the three well known  definitions , 10.According to the IDF definition, ethnicity specific cut-off value for central obesity should be present as an essential criterion together with two of the following four components to diagnose MetS: raised triglycerides ≥ 150 mg/dL (1.7 mmol/L) or specific treatment for this lipid abnormality; reduced HDL cholesterol < 40 mg/dL (1.03 mmol/L) in males, < 50 mg/dL (1.29 mmol/L) in females or specific treatment for this lipid abnormality; raised blood pressure (BP): systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg or treatment of previously diagnosed hypertension and; raised fasting plasma glucose (FPG) ≥ 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes. The cut-off values of WC ≥90 cm in men or ≥80 cm in women recommended for South Asians for central obesity were used in this study .According to NCEP- ATP III definition, an individual can be diagnosed with MetS when any of the three following components are present: WC ; plasma triglycerides (≥ 150 mg/dl); HDL cholesterol ; blood pressure (≥ 130/85 mm Hg), and fasting plasma glucose (≥110 mg/dl).According to the WHO definition , MetS ca t-test, the chi-square test or ANOVA. Univariate logistic regression analysis was used to identify the associations between individual components and the MetS according to the three definitions. Kappa (κ) statistics was used for finding the agreement between the three definitions. All the data were analyzed using SPSS 17.0.All numerical data were expressed as means and standard deviations and categorical data were expressed as frequencies and proportions. Statistical significance was assumed at a p value of < 0.05. The significance of the differences between means and proportions (%) was tested using Student'sp = 0.03). The mean BMI (SD) was 24.5 (4.3) and 37% and 57% had global and visceral obesity, respectively.The baseline characteristics of the study population are summarized in Tables Females had significantly higher duration of diabetes, blood pressure, total cholesterol, and LDL cholesterol. The mean values of various anthropometric, clinical, and biochemical variables measured are summarized in Tables Almost all subjects recognized as having MetS by NCEP-ATP III were also identified as having MetS by one of the other two definitions. However, close to 40% (763/2055) of MetS recognized by WHO were found to have no MetS by the other two definitions. Females had higher prevalence of MetS than male according to all three definitions, and the difference was most obvious with NCEP-ATP III and IDF definitions .p < 0.05) and diastolic blood pressure (p < 0.05), BMI (p < 0.05), and waist circumference (p < 0.05) compared to those with MetS based on WHO criteria. Similar observation was seen with NCEP-ATP 111 criteria as well; however, there was no significant difference of BMI and waist circumference between two groups. Individuals with MetS based on NCEP-ATP III criteria also had significantly higher BMI (p < 0.05), and waist circumference (p < 0.05), higher systolic (p < 0.05) and diastolic blood pressure (p < 0.05), and lower HDL cholesterol compared to those with MetS based on WHO. Age, duration of diabetes, and glycaemic control as indicated by HbA1c did not differ in individuals identified by the three criteria.As shown in p < 0.001) and 0.53 (p < 0.001), respectively, whereas the agreement between NCEP-ATP III and WHO criteria was 0.24 (p < 0.001).The agreement between the three criteria was assessed by the kappa index. The agreement between IDF with WHO and NCEP-ATP III criteria was 0.37  than with the two other definitions; the difference undoubtedly could be attributed to the study population having diabetes and the presence of microalbuminuria as a component of MetS. In our study, the overall prevalence of microalbuminuria was as high as 45% and it may explain the higher prevalence of WHO-defined MetS. The unexpectedly high prevalence of MetS with WHO definition in our study contrasts with that reported elsewhere , 28. It Of the participants, only around 25% were recognized as having MetS simultaneously by all three definitions, suggesting that the three definitions identify a diverse group of people. Particularly this is true with WHO definition, with roughly 40% (763/2055) being classified as having MetS when other two failed to do so. In contrast, nearly all MetS recognized by the NCEP-ATP III definition were identified as having MetS by one of the other two definitions. In our study, the concordance of individuals with MetS based on IDF criteria with that of WHO and NCEP-ATP III was 0.37 and 0.53, respectively, whereas it was 0.24 between NCEP-ATP III and WHO. In contrast, previous studies revealed comparatively higher concordance between the three definitions, particularly in nondiabetic individuals. A study conducted by Deepa et al. in India had shown that the IDF had a higher agreement (0.58) with WHO definition and similar agreement with NCEP-ATP III (0.58)  in compaIdentification of MetS among individuals with diabetes is important as it increase the future cardiovascular event. Bonora et al. reported fivefold increase in cardiovascular risk among individuals with type 2 diabetes having MetS compared no MetS . TherefoAs far as we are aware, our study is the first sufficiently large study to examine the prevalence of MetS in diabetic population in Sri Lanka. In addition, other strengths of the present study include its large sample size with close to 3000 individuals with diabetes and being the first ever Sri Lankan study to examine the performance of all commonly used definitions. However, there are few noteworthy limitations of our study. First, cross-sectional design of our study limits the inference of causal relationship between metabolic syndrome and cardiovascular events. Hence, performance of three definitions of MetS in our study is limited to the prevalence of MetS. Second, this study is a single centre study; therefore, generalization of our findings to the whole diabetic population in Sri Lanka may not be feasible.In conclusion, our study demonstrates that the prevalence of metabolic syndrome among diabetic patients can significantly be varied based on the definition used. The highest prevalence of MetS was observed with WHO (70.6%) whereas lowest was observed with NCEP-ATP III definition. Raised waist circumference is an important predictor of MetS defined by all three definitions.


Scelsi  n = 944 subjects from the Alzheimer’s Disease Neuroimaging Initiative database diagnosed as Alzheimer’s disease, mild cognitive impairment or healthy at the time of imaging. We identified a genome-wide significant locus implicating LCORL . The top variant rs6850306 was found to act as an expression quantitative trait locus for LCORL in brain tissue. The clinical role of rs6850306 in conversion from healthy ageing to mild cognitive impairment or Alzheimer’s disease was further validated in an independent cohort comprising healthy, older subjects from the National Alzheimer’s Coordinating Center database. Specifically, possession of a minor allele at rs6850306 was protective against conversion from mild cognitive impairment to Alzheimer’s disease in the National Alzheimer’s Coordinating Center cohort , in keeping with the negative direction of effect reported in the genome-wide association study (βdisease progression score = −0.07 ± 0.01). The implicated locus is linked to genes with known connections to Alzheimer’s disease pathophysiology and other neurodegenerative diseases. Using multimodal imaging phenotypes in association studies may assist in unveiling the genetic drivers of the onset and progression of complex diseases.Identifying genetic risk factors underpinning different aspects of Alzheimer’s disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide association studies of imaging-derived biomarkers in sporadic late-onset Alzheimer’s disease focused only on phenotypes derived from single imaging modalities. In contrast, we computed a novel multi-modal neuroimaging phenotype comprising cortical amyloid burden and bilateral hippocampal volume. Both imaging biomarkers were used as input to a disease progression modelling algorithm, which estimates the biomarkers’ long-term evolution curves from population-based longitudinal data. Among other parameters, the algorithm computes the shift in time required to optimally align a subjects’ biomarker trajectories with these population curves. This time shift serves as a disease progression score and it was used as a quantitative trait in a discovery genome-wide association study with  APOE4) is the strongest known common genetic risk factor for sporadic late-onset Alzheimer’s disease ] on a large cohort from the ADNI database . The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of the ADNI has been to test whether serial MRI, PET, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early Alzheimer’s disease. For up-to-date information, see www.adni-info.org.Data used in the preparation of this article were obtained from the ADNI database , the latest diagnosis available in ADNI was used . Furthermore, diagnosis at baseline florbetapir PET scan and latest diagnosis were compared to define clinical progression  for each subject.At the time of this study single nucleotide polymorphism (SNP) genotyping data were available for 1674 subjects across all ADNI phases. Genotyping was conducted using three different platforms: Human610-Quad, HumanOmniExpress and Omni 2.5M (Illumina) (http://www.well.ox.ac.uk/∼wrayner/tools/), to check SNPs for strand consistency, allele names, position, Ref/Alt assignments and minor allele frequency (MAF) differences with the reference panel. The Sanger Imputation Server (https://imputation.sanger.ac.uk/) was used with SHAPEIT for phasing (P < 5.7 × 10−7) were excluded. Finally, subjects missing 10% or more of the genotypes were removed.Following recommendations by  phasing  for impuSNPweights .P < 0.05 (Bonferroni corrected); exclusion of samples with >10% missing genotypes and high relatedness . At the time of manuscript preparation, the Sanger server did not support imputation of X chromosome variants. Thus, we applied an in-house imputation pipeline for this task, using the 1000 Genomes Project data as a reference panel (P < 0.05 (Bonferroni corrected).Variants on the X chromosome underwent recommended pre-imputation quality control provided with the X-wide analysis toolset (XWAS version 1.1) (ce panel . Pseudo-18F-florbetapir PET scans for 1089 subjects were available in the ADNI database (date accessed 24/03/2016). Preprocessing of florbetapir PET scans in ADNI has been described in detail elsewhere (3), and smoothed down to the lowest resolution available in ADNI .At the time of this study, 2034 preprocessed longitudinal 1-weighted magnetic resonance scans (voxel size 1 × 1 × 1.2 mm3) were downloaded for the same subjects. Details about the magnetic resonance preprocessing can be found in 1 registrations were visually assessed to ensure correct alignment.To compute the standardized uptake value ratio (SUVR), information from structural magnetic resonance scans was used. A total of 1931 preprocessed TSUVRs were computed as a measurement of cortical amyloid deposition for each subject and time point. The SUVs were computed as the weighted sum of the florbetapir PET signal intensities with weights corresponding to voxel-wise cerebral grey matter probability. The SUVR is then defined as the SUV in the cortical region divided by the SUV in the reference region. The probability-weighted sum to compute SUVs controls for partial volume effects. A composite reference region comprising white matter, whole cerebellum, brainstem and pons was used  is the value of biomarker j for subject i at time t, jg is assumed to be a monotone function, 0ijα and 1ijα are a random intercept and slope, respectively, allowed for each subject, ijɛ(t) is the fitting residual, and iγ is an unknown subject-specific parameter. For each subject iγ is estimated as the shift in time required to optimally align the subjects’ biomarker trajectories with the estimated population long-term progression curves. Once all subjects have been aligned, the population curves are re-estimated and a new set of iγ is computed with respect to the updated population curves. This process is iterated until convergence. We utilise the final iγ parameters as a continuous DPS. The DPS provides an estimate, based on the observed biomarker values, of how advanced in the disease process a subject is compared to the average of the cohort. The curves are all centred at t = 0, thus, individuals with negative time shift, i.e. residing on the left plateau of the sigmoid, are likely to be labelled as controls. Conversely, highly abnormal values for the biomarkers place a patient further in time on the standardized population trajectory, approaching the right plateau of the sigmoid , respectively. This Z-score-based measure ranks the different biomarkers according to disease severity with respect to healthy controls. The independent variable for the fitting procedure was time from study entry (in years) because, from a computational perspective, GRACE implementation requires the input independent variable to start from t = 0.Florbetapir SUVR and hippocampal volumes were used as input for GRACE, after being Z-normalized with respect to healthy controls in the cohort:d and 95% confidence intervals (CI), for three comparisons .Effect sizes for differentiating diagnostic categories of the single-modality biomarkers  and the DPS were computed as Cohen’s A one-way ANOVA and a Tukey’s range test were performed to quantitatively assess pairwise differences in the DPS distributions among the diagnostic groups at first PET scan and the clinical progression of healthy control and MCI subjects.We hypothesized that the DPS would be able to give a more integrated view of the disease status than the single-modality phenotypes separately. To test this hypothesis, we looked at the association between the three phenotypes used in our GWAS and a set of Alzheimer’s disease genetic risk score (GRS). A GRS represents a ‘genetic summary’ of an individual’s disease risk, combining the weighted contribution of risk alleles across the whole genome into a single metric.n = 990 study subjects. Briefly, we used 15 P-value thresholds in the range 0.95–10−5. SNPs in the extended APOE locus  were excluded from the GRS construction to enable investigations of genome-wide risk independent from APOE. For each of the P-value thresholds we selected the final set of SNPs for the score by using linkage disequilibrium (LD) clumping implemented in PLINK resulting in only the most significant SNP above the P-value threshold within an LD block to be selected for the score , conferring decreased risk to homozygous and heterozygous carriers of the minor allele A and confirming the negative direction of effect reported in the GWAS , confirming the protective role of rs6850306 revealed through GWAS and linking rs6850306 genotype, lower DPS values and decreased risk for conversion. Additionally, there is supporting evidence for the two top associated loci in the literature; linking one locus to age-related macular degeneration, which shares many genetic similarities with Alzheimer’s disease including d burden B did notIn summary, we performed the first successful genetic study of a progression score for Alzheimer’s disease derived from multiple imaging modalities. We believe that this integrative approach has great potential for identifying common genetic variation related to the multiple, interlinked pathogenic pathways involved in Alzheimer’s disease and other complex diseases.M.A.S. acknowledges financial support by the EPSRC-funded UCL Centre for Doctoral Training in Medical Imaging (EP/L016478/1). M.D.G. was supported by the NIH (P50 AG047366). J.M.S. acknowledges the support of the National Institute for Health Research Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, Wolfson Foundation, Engineering and Physical Sciences Research Council (EP/J020990/1), Medical Research Council (CSUB19166), Alzheimer's Research UK , Brain Research Trust (UCC14191) and European Union’s Horizon 2020 research and innovation programme (Grant 666992). S.O. receives funding from the EPSRC , the Medical Research Council (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), the National Institute for Health Research Biomedical Research Unit (Dementia) at UCL and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative- BW.mn.BRC10269). A.A. holds an Medical Research Council eMedLab Medical Bioinformatics Career Development Fellowship. This work was supported by the Medical Research Council [grant number MR/L016311/1].Brain online.www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI)  and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health  for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer's Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728.The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 , P30 AG013846 , P50 AG008702 , P50 AG025688 , P50 AG047266 , P30 AG010133 , P50 AG005146 , P50 AG005134 , P50 AG016574 , P50 AG005138 , P30 AG008051 , P30 AG013854 , P30 AG008017 , P30 AG010161 , P50 AG047366 , P30 AG010129 , P50 AG016573 , P50 AG005131 , P50 AG023501 , P30 AG035982 , P30 AG028383 , P30 AG053760 , P30 AG010124 , P50 AG005133 , P50 AG005142 , P30 AG012300 , P30 AG049638 , P50 AG005136 , P50 AG033514 , P50 AG005681 , P50 AG047270 .The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: the GTEx Portal on 08/05/2017 and dbGaP accession number phs000424.v6.p1 on 08/05/2017.Supplementary DataClick here for additional data file.


Statins and/or PCSK9 inhibitors cause the regression of coronary atheroma and reduce clinical events. However, it currently remains unclear whether these drugs modulate coronary atheroma calcification in vivo. Coronary artery calcium (CAC) scores  were estimated in 120 patients receiving coronary computed tomographic angiography (CCTA) . The CAC scores were compared among the three groups: (1) neither statin nor PCSK9 inhibitor therapy, (2) statin monotherapy, and (3) statin and PCSK9 inhibitor combination therapy in an unpaired cross-sectional study. Additionally, CCTA was performed twice at an interval in 15 patients undergoing statin monotherapy to compare the previous (baseline) and subsequent (follow-up) CAC scores in a paired longitudinal study. In addition, a PCSK9 inhibitor was administered to 16 patients undergoing statin therapy. Before and after that, CCTA was performed twice to compare the previous and subsequent CAC scores in a paired longitudinal study. The unpaired cross-sectional study and paired longitudinal study consist of completely different patients. Among 120 patients, 40 (33%) had a CAC score >100 AUs. The median CAC score increased in the following order: statin group, statin and PCSK9 group, and no-statin-no-PCSK9 group. Annual CAC score progression was 29.7% by statin monotherapy and 14.3% following the addition of the PCSK9 inhibitor to statin therapy. The annual rate of CAC with the combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. CAC may be prevented with PCSK9 Inhibitor. Today, rapid aging in society is making progress in developed countries. One of the most serious health problems in an aging society is atherosclerosis, of which final phase is coronary artery calcification (CAC). CAC could increase the risk of complications during coronary catheterization and coronary artery bypass surgery as well as ischemic heart disease (IHD). We, members in the aging society, would see much more patients with CAC in the near future. We, however, have no medications for CAC today. Moreover, statins that are used in the world have been known for CAC formation after long-term use. The team led by Yuichi Ikegami and Ikuo Inoue in Japan’s Saitama Medical University found that CAC in patients with atherosclerosis is improved by PCSK9 inhibitors compared to statins by using coronary computed tomographic angiography. This study shows us a hint that could lead us to new preventive therapies of IHD. Various image analysis methods are employed to identify patients at risk of coronary artery disease (CAD) events before their onset. Serial intravascular ultrasonography (IVUS), an invasive method for the detection of CAD events, revealed that PCSK9 inhibitor exerted favorable effects against the progression of coronary atherosclerosis.2 Moreover, coronary computed tomographic angiography (CCTA) has recently emerged as an accurate non-invasive method for the detection of coronary atherosclerosis and exclusion of obstructive CAD.3 Unlike IVUS, CCTA is a non-invasive method that is easy to use in outpatient clinics. It also permits the visualization of the coronary artery calcium (CAC) score beyond direct luminal diameter stenosis including graded measures of coronary plaque composition.Recent studies reported that protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy4 and is a risk factor for atherosclerotic complications.5 The statin therapy6 reduces CAD events by decreasing LDL levels. However, the findings of recent studies with large sample sizes suggested that statins promote coronary vascular calcification.8 In contrast, other studies demonstrated that statins protect against coronary vascular calcification.11 The extent of LDL-cholesterol (LDL-C)-lowering effects may modulate coronary vascular calcification.CAC score is a strong marker of coronary events12 Evolocumab , the other type of PCSK9 inhibitor and a human immunoglobulin G2 mAb, inhibits PCSK9 using the same mechanism as that of alirocumab.14 Moreover, the addition of evolocumab to the statin therapy achieved serum LDL-C levels of less than 30 mg/dL.15 The effects of PCSK9 inhibitors, which have potent LDL-lowering activities, on vascular calcification have been of attracting interest. However, it currently remains unclear whether PCSK9 inhibitors modulate coronary atheroma calcification in vivo in humans.As more powerful and novel medications, PCSK9 inhibitors have safely been administered to patients worldwide. Alirocumab , a type of PCSK9 inhibitor and a human immunoglobulin G1 monoclonal antibody (mAb), mediates the proteolytic degradation of hepatic LDL receptors (LDLR), resulting in the more efficient clearance of apolipoprotein B (ApoB)-containing lipoproteins.The aim of the present study was to retrospectively evaluate the relationship between statin and/or PCSK9 inhibitor therapy and CAC score in patients undergoing CCTA.n = 120).Univariate and multivariate analyses for CAC score in the unpaired cross-sectional study (P < 0.0001). No correlations were found between CAC score and several traditional risk factors for CAD such as hemoglobin A1c (A1c) levels, blood pressure, and lipid levels. The occurrence of CAC score significantly increased with age (P = 0.048), particularly when patients aged >60 years were compared with those aged between 35 and 50 years (data not shown). CAC score was also slightly more common in males than in females (P = 0.20), in patients using antihypertensive drugs than in those without (P = 0.07), and in patients using insulin than in those without (P = 0.0001).There were no adverse events during this clinical study. Forty-seven (47%) patients had a CAC score >0, 15 (12.5%) had severe coronary artery calcification (CAC score >400 AUs), while no patient had extensive coronary calcification with a CAC score >1000 AUs. The relationships between CAC score and each clinical variable were initially examined using Univariate and multivariate analyses  was significantly lower in the no-statin-no-PCSK9 group. There was no homozygous or compound heterozygous familial hypercholesterolemia in the three groups. CAC progression was also calculated as [log(CAC) at the follow-up]–[log(CAC) at the baseline]. Figure P < 0.05 and P < 0.01, respectively).Table P < 0.01)  at the follow up]-[log(CAC) at the baseline], and was then retransformed to depict the percentage change in CAC Fig. . Annual 01) Fig. .Fig. 3a,P value of the multivariate analyses for associations between the log-transformed annual CAC score progression rate and each data were: Triglyceride 0.7454, HDL-C 0.9476, LDL-C 0.8751, Lp(a) 0.5421, hemoglobin A1c 0.5831, fasting blood glucose 0.3679, systolic blood pressure 0.2665, and diastolic blood pressure 0.5685. In the case of statin monotherapy therapy, the P value of multivariate analyses for associations between the log-transformed annual CAC score progression rate and each data were: Triglyceride 0.5781, HDL-C 0.6427, LDL-C 0.8991, Lp(a) 0.8546, hemoglobin A1c 0.4456, fasting blood glucose 0.2240, systolic blood pressure 0.4687, and diastolic blood pressure 0.6697. Thus, the results of multivariate analysis indicated that there was a statistically significant difference in annual CAC score progression rate.Moreover, each clinical value was also calculated as [value at the follow-up]–[value at the baseline] and was then re-transformed to depict the percentage change in the value. A multivariate analysis was performed to identify the risk factors of annual CAC score progression rate. Potential confounding factors included in the model were: Triglyceride, HDL-C, LDL-C, Lp(a), hemoglobin A1c, fasting blood glucose, systolic blood pressure, and diastolic blood pressure retrieved. In the case of PCSK9 inhibitor added to the statin therapy, the We identified a strong relationship between statin and/or PCSK9 inhibitor therapy and CAC score. Annual CAC score progression was 29.7% by statin monotherapy and 14.3% by PCSK9 inhibitor added to statin therapy. Our results indicated that the annual increase induced in CAC scores by adding PCSK9 inhibitors to statin was smaller than that by statin monotherapy. Our data showed that CAC might be prevented with PCSK9 inhibitors.16 An annual increase in CAC >15% or in CAC >100 units is predictive of future myocardial events. Previous studies reported that CAC was associated with atherosclerotic complications. CAC is a strong marker of coronary events.4 The prevalence of CAC is dependent on age and gender, occurring in more than 90% of men and 67% of women older than 70 years of age.18 Additionally, individuals with a higher BMI, higher blood pressure, abnormal lipids (higher LDL-C or triglyceride (TG), lower high-density lipoprotein cholesterol (HDL-C), or use of lipid-lowering medication, glucose disorders , a familial history of CAC and chronic kidney disease (CKD), higher fibrinogen level, and higher C-reactive protein (CRP) level were found to be more susceptible to CAC.19Computed tomography (CT) for calcium scoring is a simple and convenient test for the identification of CAD and is widely used worldwide. Raggi et al. reported that an annual calcium score progression of >15% was associated with a worse prognosis for each standard calcium score category.P < 0.0001)  with plaque regression2 using serial IVUS imaging, suggesting the ability of PCSK9 therapy to affect coronary artery plaque composition. Grayscale IVUS imaging enables qualitative assessments of atherosclerotic plaques.22 Further studies need to focus on how to change coronary plaque composition assessed by greyscale IVUS, with PCSK9 inhibitor therapy.The findings of recent studies with larger sample sizes also suggest that statins promote vascular calcification.23 (1) CAC progression is an independent predictor of CAD events; (2) statins and/or PCSK9 inhibitors promote plaque regression; and (3) statins promote CAC progression  difficult to perform. Coronary calcification increases the risk of procedural complications such as dissection, thrombosis, and restenosis.31 Blood vessels with advanced calcification are less likely to respond successfully to bypass surgery. When statins were administered to patients with an annual increase in CAC of >15% or annual increase of CAC >100 units, repeat CCTA was considered every 6 months. Large doses of radiation may cause serious tissue damage and increase the risk of developing cancer. Although CT for calcium scoring involves exposure to radiation, the effective dose is very small (~1.0 mSv).23 However, it is necessary to evaluate the accumulated radiation exposure dose by other CT, PET scans, or any other imaging modalities.It is important to consider estimating CAC progression. Liu W et al.32 should be developed by elucidating the progression mechanisms of CAC for its recovery and repair for anti-aging. Further studies should investigate whether PCSK9 inhibitor is the anti-aging drug through this pleiotropic mechanism.Although add-on PCSK9 inhibitor to statin is one of the options to prevent CAC, medical and pharmaceutical advances are critical. Specifically, a new class of drug therapyThe present study had several limitations, because the differences in the dose and the products of statins have significant influence on the results, it will be necessary to evaluate the effect of each statin. The enrolled number of subjects was very small and this study had an open-label design. The markedly short study duration may also be a limitation. The treatment period may have been too short to obtain a complete therapeutic effect. Therefore, a long-term, larger-scale, and double-blinded study in which the drugs are administered to patients with high risk hyperlipidemia is needed in the future. Furthermore, a selection bias may be present. This study retrospectively evaluated the relationship between statin and/or PCSK9 inhibitor therapy and CAC score in patients undergoing CCTA. Thus, a prospective study is needed in future. Another limitation is that CCTA imaging cannot perform qualitative assessments of atherosclerotic plaques. Methods that provide information on the composition of plaques need to be considered. In addition, we excluded subjects with TG > 400 mg/dL because we calculated the LDL-C level using the Friedewald equation. Moreover, all participants were Japanese, therefore our results cannot be generalized to other races or ethnic groups.Our results indicated that the annual increase in CAC was smaller by add-on PCSK9 inhibitors than by statins. The progression of CAC scores by statin monotherapy was 29.7%, while that by combination therapy with a PCSK9 inhibitor and a statin was 14.3%. Our data showed that CAC might be prevented with PCSK9 inhibitors.n = 41), (2) statin monotherapy , and (3) combination therapy with a PCSK9 inhibitor and a statin . In the paired longitudinal study, CCTA was repeated and compared for the duration of statin therapy in 15 patients. CCTA was repeated and compared before and after the addition of a PCSK9 inhibitor to the ongoing statin therapy in 16 patients. We enrolled the completely different patients for an unpaired cross-sectional study and a paired longitudinal study. The participants were provided written informed consent to participate in the study. As the present study is retrospective, we didn’t obtain them from all participants.This study was parallel, retrospective in nature, and was divided into two parts; an unpaired cross-sectional study and paired longitudinal study. In the unpaired cross-sectional study, we enrolled 120 patients receiving CCTA and divided them into three groups: (1) neither statin nor PCSK9 inhibitor therapy  with CAD, (2) with HeFH according to the “2017 Guidelines for the Treatment of Dyslipidemia” by the Japan Atherosclerosis Society (JAS). Alirocumab was additionally administered at a dose of 75 or 150 mg once every 2 or 4 weeks. Evolocumab was additionally administered at a dose of 140 mg once every 2 or 4 weeks. All participants were treated with a stable dose of statins for at least one year prior to the investigation by CCTA. The LDL-C levels of the patients who received PCSK9 inhibitor, were higher than the target level recommended by the guidelines.In laboratory tests on serum lipids, blood was collected in early in the morning after fasting. Plasma total cholesterol levels (TC) and TG were measured by enzyme methods, while HDL-C was measured using a selective solubilization method at the facilities of Saitama Medical University. LDL-C levels were calculated by the method of Friedewald (F method), and patients with TG of 400 mg/dL or higher were excluded.Most patients have clinical symptoms such as chest pain and the ischemic change in electrocardiogram, which are suspecting symptoms of coronary arteriosclerosis. Thus, CCTA, an accurate non-invasive approach, was carried out twice to diagnose whether fatty deposits or calcium deposits were present in the coronary arteries. CAC was assessed by CT performed on a 64-channel detector scanner  in the cine and straight mode. Scans were assessed by the electrocardiogram (ECG)-gated method, and a standard non-contrast protocol was used with a tube voltage of 120 kV, tube current of 50–80 mA, rotation time of 280 ms, slice thickness of 3 mm, and display field of view (DFOV) of 20 × 20 cm. CAC data were processed and analyzed using SYNAPSE VINCENT (FUJIFILM). These CAC data were blinded and evaluated by a single radiologist. SMARTSCORE 4.0  was used to assess the CAC scores. Plaque measurement software automatically recognized the plaques and lumens, and vessel walls and plaque edges were then manually modified where needed in order to define both ends of the plaques.2 and peak intensity >130 Hounsfield Units (HUs)33 based on the Agatston method previously described in detail and expressed in Agatston units (AUs).34 The total CAC score was calculated as the sum of the CAC scores in the left main artery (LM), the left anterior descending artery (LAD), the left circumflex artery (LCX), and the right coronary artery (RCA). Since a CAC score >100 AUs is associated with an increased risk of myocardial ischemia and coronary heart disease (CHD)-related events,35 we used this threshold to identify patients with a definite to extensive plaque burden. It has been reported that CAC score >400 AUs were related to heart failure.33CAC was quantified as a lesion with an area >1 mm15 that we describe in detail. Major exclusion criteria were as follows: (1) patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists, (2) CKD (eGFR < 45 mL/min), (3) fasting TG greater than or equal to 400 mg/dL, (4) blood pressure >180/110 mmHg, (5) A1c that changed by more than 2% within 3 months, (6) severe ketosis, diabetic coma or precoma, peripheral artery disease, abdominal aortic aneurysm, carotid artery occlusion >50% without symptoms, carotid endarterectomy, carotid artery stent procedure, renal artery stenosis, or renal artery stent procedure, (7) severe infection before and after surgery, patients determined to be ineligible for the trial by the investigator or a doctor and those suffering from serious trauma, (8) pregnant or breast-feeding women, (9) women of childbearing potential with no effective contraceptive method, (10) participants not previously instructed on a cholesterol-lowering diet in the first visit who were being treated with a stable dose of statins for at least 6 weeks prior to screening.We used our previous criteriaThis study was conducted in accordance with the Good Clinical Practice (GCP), International Conference on Harmonization Guidelines (ICH), and applicable laws and regulations. The study protocol was approved by the Ethics Committee of Saitama Medical Hospita (Approved No. 17–041). Our study was a retrospective study, which was simply look back in time and collect the data. It was posted on the official website of Saitama Medical University Hospital as a widely well-known method of research contents. If there was an offer that the patient did not want to participate in the study, we removed the relevant information. We collected the information that has been recorded from April 1, 2011 to January 13, 2018.U-test with significance levels of 5%. In addition, the multivariate analysis was conducted to prove the significant different of the annual CAC score progression rate.Measurement values were expressed as means ± SD or medians (range of the 10th–90th percentile). Statistical analyses were performed using JMP® ver.7.0 . Univariate and multivariate analyses were performed on clinical variables to CAC scores. CAC scores were compared by a one-way analysis of variance with significance levels of 5% in three groups. CAC scores of the baseline and follow-up of statin and/or PCSK9 inhibitor therapy were compared with the non-parametric Wilcoxon signed-rank test with significance levels of 5%. Annual CAC score progression rate by statin monotherapy and by PCSK9 inhibitor added to statin therapy was compared with the non-parametric Mann–Whitney https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000007750. And the trial number is UMIN000018818, and the registry URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000021766.The data are available with an appropriate material transfer agreement. All relevant data are available from the authors. The trial number is UMIN000006539, and the registry URL:


The supercapsular percutaneously-assisted total hip arthroplasty (SuperPath) was proposed to be minimally invasive and tissue sparing with possible superior postoperative outcomes to traditional approaches of total hip arthroplasty (THA). Here, we compared the short-term outcomes of staged THA with the SuperPath or through posterolateral approach (PLA) for bilateral osteonecrosis of the femoral head (ONFH).Patients with bilateral late-stage ONFH were prospectively recruited from our department from March 2017 to March 2018. Staged bilateral THAs with one side SuperPath and the other side PLA were performed consecutively in the same patients with right and left hips alternating within approaches. The average time interval between the staged THAs was 3 months. Perioperative status  and postoperative function  were recorded and compared between the SuperPath and PLA approaches within 12-month postoperatively.Four male patients  with bilateral alcohol-induced ONFH (Ficat III/IV) were followed up over 12 months postoperatively. Compared with the PLA, the SuperPath yielded shorter incision length (7.62 vs. 11.12 cm), longer operation time (103.25 vs. 66.50 min), more blood loss (1108.50 vs. 843.50 ml), deficient abduction angle of the acetabular cup (38.75° vs. 44.50°), and inferior early-term hip function  at 12-month postoperatively. Soft tissue damage, length of hospital stay, postoperative pain, postoperative range of motion, and 12-month patient satisfaction were comparable between both approaches.The SuperPath may be a minimally invasive technique but the present study shows less favorable short-term outcomes than PLA for total hip arthroplasty in osteonecrosis of the femoral head. More investigations are required to provide convincing favorable evidences of the SuperPath over other traditional THA approaches.https://www.researchregistry.com (No. Researchregistry4993) on July 04, 2019. The first participant was enrolled on March 13, 2017.The trial was retrospectively registered in  Osteonecrosis of the femoral head (ONFH), a devastating morbidity mainly in mid-aged population, usually progresses to femoral head collapse and requires a total hip arthroplasty (THA) . In AsiaTo minimize the overall surgical aggression, the supercapsular percutaneously-assisted total hip arthroplasty (SuperPath) was proposed as an emerging minimally invasive and tissue sparing surgical technique . This poThe present pilot study is aimed to compare the short-term outcomes of staged THA with the SuperPath and PLA for bilateral ONFH patients. We hypothesized that the SuperPath would yield superior outcomes over the PLA in terms of both the perioperative status  and postoperative function .This research was approved by the Medical Ethics Committee of the West China Hospital, Sichuan University, Sichuan, China. Patients with bilateral ONFH was recruited from our department from March 2017 to March 2018. Subjects included were: (1) adult surgical candidates of bilateral THA for ONFH, (2) signed consent for implanting, and (3) ability to complete scheduled postoperative 12 months follow-ups. Subject excluded were: those with non-inflammatory degenerative joint diseases (e.g. osteoarthritis and posttraumatic arthritis), inflammatory joint diseases , inadequate neuromuscular status , and overt infections or distant foci of infections.Operations were performed by a senior surgeon specialized in traumatology and lower limb reconstruction with over 15-year experience performing primary and revision THAs with the posterior approach . The surgeon also has accomplished more than 50 SuperPath cases. Each patient underwent bilateral staged THA with one side SuperPath and the other side PLA with an average interval of 3 months, allowing for a compensation of the possible impact of the first operation on the second one (and vice versa). Both approaches were randomizedly selected for the first operation, using a shuffled deck of cards  and performed in either right or left hip. Double-blindness was undertaken in the present study in which the specific approach type was unknown to both the patients and examiners  assessing patients’ outcomes. The SuperPath was performed with specific prostheses  as described by Chow et al. , and thePreoperative data were collected for each subject, including the age, gender, etiology, age of pain onset, history of hip injury/surgery, BMI, occupation category , AmericaStandardized patient care was provided including infection prophylaxis, venous thromboembolism prevention, nausea and vomiting management, wound care, and functional rehabilitation.Identical rehabilitation program was undertaken for all patients after both SuperPath and PLA. Briefly, Immediate hip flexion, pneumatic compression with foot pumps, and deep breathing exercise were emphasized to minimize thromboembolic and pulmonary complications. After obtaining approvals from the physical therapists, patients began indoor walking independently using crutches with tolerated weight-bearing. Self-care and home-based rehabilitation were educated before discharge, in which patients were instructed to daily walk and gradually increase the walking distance towards a goal of 2 km. All patients were generally discharged and allowed for walking with a cane on the postoperative day 3.Perioperative total blood loss was indirectly calculated from the change in the hematocrit (Hct) according to the Gross formula :pre - Hctpost) / Hctave.Total blood loss = PBV ×  was estimated according to the Nadler formula :PBV = k1 × height (m) + k2 × weight (kg) + k3.where k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for males; and k1 = 0.3561, k2 = 0.03308, and k3 = 0.1833 for females.Serum markers are widely used to evaluate soft tissue damage in the hip arthroplasty –27 and mStandardized anteroposterior pelvic radiographs were acquired on the postoperative day 1. Inclination and anteversion angles were measured with a computer-assisted measurement system . Concisely, an ellipse was fitted to the rim of the acetabular shell on radiographs. Inclination angle was defined as the angle between the longitudinal axis of the body and the acetabular axis . AnteverThe patient reported pain was measured with a visual analogue scale from 0 (no pain) to 10 (worst imaginable pain) at the day of hospital admission, postoperative day 1, day 3, day 14, 3 months, 6 months, and 12 months, respectively . The ROMValues are expressed as mean ± standard deviation. One-way ANOVA was performed to compare the VAS and HHS between the different assessment timepoints.2   male patients was included with a mean BMI 21.49 kg/mThe incision length in the SuperPath approach (7.62 ± 0.97 cm) was shorter than the PLA approach (11.12 ± 1.21 cm)  than in the PLA approach (44.50°)  for total hip arthroplasty. Rachbauer and colleagues defined “a minimal invasive surgery” with the following characteristics: a short skin incision, preventing muscle splitting and/or detachment, and preserving the joint capsule . PreviouAcetabular cup positioning impacts wear rates and long-term stability of the prostheses –44. BiedInterestingly, the pain VAS following the SuperPath approach improved slower than that following the PLA approach, and both approaches reached the comparable levels between 3 months and 12 months postoperatively, as well as the equivalent range of motion at 12 months postoperatively. These data also contradict with previous encouraging outcomes from the above-mentioned clinical trial from Xie and colleagues . NoteworRemarkably, the HHS demonstrated relatively impaired early-term hip function in the SuperPath approach than in the PLA approach. The improvement of hip function after the SuperPath approach is slower than that after the PLA approach, and the HHS was 15-point (at the postoperative day 14) and 11-point (at the postoperative 3 months) lower in the SuperPath approach compared with the PLA approach and gradually approached comparable levels after 6 months postoperatively. One possible explanation of such impaired early-term hip function in the SuperPath approach might be the longer operation time and more total blood loss, which were previously reported as major factors influencing the functional recovery and quality of life of patients , 49.Moreover, the learning curve of new technically demanding techniques should not be underestimated, which is defined as the number of times an approach must be repeated before reaching a steady plateau. Compared with other approaches, the SuperPath is more subtle with changes in implant and instrument design and requires surgeons to augment performances via the fine-tuning with the learning curve . The onlA standardized multidisciplinary teamwork of physicians, surgeons, physical therapists, and physiologists, and patient family (caregivers) is critical to ensure an effective performance of the implanted hip prosthesis, which is generally applied to all THA patients treated in our clinic . This miSeveral limitations exist in the present study. Firstly, the sample size of the current study is greatly limited and the postoperative follow-up is relatively short, which might not allow us to draw a definitive conclusion of both approaches. Secondly, different hip implants were utilized in both approaches, which might influence the final postoperative outcomes. However, the staged bilateral hip arthroplasty in identical individuals with a comprehensive self-comparison between the SuperPath and PLA and the significant differences of both preoperative status and short-term postoperative function opens up new questions for further comparisons of the SuperPath with other traditional THA approaches.In summary, the SuperPath technique may be a minimally invasive technique but our data show less favorable outcomes than PLA for total hip arthroplasty in osteonecrosis of the femoral head. More randomized controlled trials are required to define the learning curve of the SuperPath technique, in terms of postoperative outcomes, and to provide convincing evidence of its clinical benefits over other traditional THA approaches.Additional file 1: Table S1. Perioperative changes of serum markers. Table S2. Range of motion. Table S3. Comparisons of the range of motion, pain VAS, HHS at the day before surgery and postoperative 12 months. Table S4. Comparisons of the pain VAS and HHS between each time point.


Only few descriptions of intraoperative carcinoid syndrome (ioCS) have been reported. The primary objective of this study was to describe ioCS. A second aim was to identify risk factors of ioCS. We retrospectively analysed patients operated for small-bowel neuroendocrine tumour in our institution between 2007 and 2015, and receiving our preventive local regimen of octreotide continuous administration. ioCS was defined as highly probable in case of rapid (<5 min) arterial blood pressure changes ≥40%, not explained by surgical/anaesthetic management and regressive ≥20% after octreotide bolus injection. Probable cases were ioCS which did not meet all criteria of highly-probable ioCS. Suspected ioCS were detected on the anaesthesia record by an injection of octreotide due to a manifestation which did not meet the criteria for highly-probable or probable ioCS. A total of 81 patients  were included; 139 ioCS occurred in 45 patients: 45 highly probable, 67 probable and 27 suspected. ioCs was hypertensive (91%) and/or hypotensive (29%). There was no factor, including the use of vasopressors, significantly associated with the occurrence of an ioCS. All surgeries were completed and one patient died from cardiac failure 4 days after surgery. After preoperative octreotide continuous infusion, ioCS were mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. No intraoperative carcinoid crisis occurred, suggesting the clinical relevance of a standardized octreotide prophylaxis protocol. Small-bowel neuroendocrine tumours (SB-NETs) are rare secreting neoplasms. Hormones  released into the systemic circulation can lead to a carcinoid syndrome (CS), which occurs in 10–20% of SB-NET patients. CS is characterized by isolated or associated symptoms such as cutaneous flushing (90%), diarrhoea 80%), abdominal pain 35%), bronchospasm (15%) and/or cardiovascular changes ) 5%, bronc. Up to 40%, abdomExpert groups recommend primary SB-NETs open surgical removal with partial bowel resection and lymphadenectomy even in the metastatic stages (>50% of cases at diagnosis) to prevent local complications and decrease tumour mass , 10. TheThe perioperative period is at high risk of intraoperative carcinoid syndrome (ioCS) as many triggering factors are present . HormoneHowever, only few studies reporting on the clinical presentation of ioCS have been published , 20, 21.After approval by the ethics committee of our institution , we retrospectively analysed a series of consecutive patients who underwent resection of SB-NET in our institution between January 2007 and December 2015. This study was approved by the national data protection commission  on 6 November 2015 (n°15-111). Consents have been obtained from patients after full explanation of the purpose and nature of data used. All patients receiving our local regimen of preoperative continuous octreotide were included. Patients operated for other neuroendocrine tumour location, hepatic metastases only or not receiving our octreotide administration regimen were not included.Octreotide was administered 12–48 h prior to surgery by intravenous continuous infusion at a dose of 40 µg/h or 80 µg/h if patient had prior CS, hepatic metastases or carcinoid heart disease. Octreotide was continued during the intraoperative and postoperative periods at the same doses. IoCS were treated by additional intraoperative octreotide boluses (0.5–2 µg/kg) and surgical break.Highly probable ioCS was defined as rapid (onset period ≤5 min) hemodynamic changes (heart rate (HR) or blood pressure (BP)) ≥40%, not explained by surgical or anaesthetic management and regressive ≥20% within 5 min after the octreotide bolus injection; probable ioCS was defined as cases for which manifestations did not meet all criteria of highly probable ioCS (onset period of 5–10 min and/or hemodynamic changes of 20–40% and/or no octreotide bolus and/or no reversibility of ≥20% after octreotide injection and/or confounding factors related to anaesthetic management). Suspected ioCS was detected on the anaesthesia record by an injection of octreotide for a manifestation which did not meet the criteria of highly-probable or probable ioCS.Median variations of BP and HR from basal state to maximum and then during regression for each type of ioCS were collected. Carcinoid crisis was defined as a life-threatening ioCS refractory to octreotide boluses. Carcinoid crisis includes cardiogenic shock, severe cardiac dysrhythmias, cardiac arrest or bronchospasm refractory to bronchodilators and compromising mechanical ventilation.e TO, Atys medical, Soucieu-en-Jarrest, France) and Bispectral index (BIS) . Warming blankets were always used . Hypotensive episodes were treated by octreotide boluses and, if necessary, by ephedrine (0.10–0.15 mg/kg) or phenylephrine (1–2 µg/kg) boluses and then by norepinephrine intravenous continuous infusion starting at dose at 0.05 µg/kg/h.All patients had preoperative assessment, including a transthoracic echocardiography at least 48 h prior to surgery. The day before surgery, premedication with antihistamines or gabapentin was prescribed if anxiety was 6 or more on a 10-point verbal numeric scale. After standard monitoring installation, anaesthesia was induced intravenously with propofol or etomidate, remifentanil and cisatracrium. Anaesthesia was maintained with desflurane delivered by control mode mechanical ventilation  and with a continuous infusion of remifentanil. Adequate muscle relaxation was obtained by intravenous cisatracrium boluses according to train-of-four monitoring. Two 16 or 18-G peripheral venous catheters and a triple lumen central venous line were inserted. An arterial catheter was inserted at the discretion of the attending anaesthetist as were transoesophageal Doppler , prior CS , prior carcinoid heart disease, hepatic and extra-abdominal metastases, elevated urinary 5-hydroxyindoleacetic acid (5-HIAA), and the prior use of long-acting somatostatin analogues. Anaesthesia management with use of premedication, anaesthetic agents, and vasoactive drugs, as well as the timing of occurrence of ioCS during the surgical procedure, hemodynamic changes during ioCS, the type of surgical procedure and number of SB-NETs on histologic examination were recorded, as was death following carcinoid crisis.s.d.) and compared with the Student t-test, whereas continuous variables with a non-Gaussian distribution were reported as median and interquartile range (IQR) and compared using the Mann–Whitney test. Univariate analyses of potential ioCS risk factors were performed. Categorical variables were compared using a χ2 or Fisher exact test. A P value ≤0.05 was considered as statistically significant.Continuous variables with a Gaussian distribution were reported as mean with standard deviation (s.d.) age was 59  underwent SB-NET surgery during the study period and were included. The mean (e was 59  years. Ts.d.) operative time was 300 (92) min. All tumours were confirmed to be SB-NET. Characteristics of intraoperative anaesthetic management are shown in All patients underwent bowel resection, 79 with ileocolic anastomosis and 78 with lymphadenectomy. The median (IQR) number of tumours removed was 1 , 3, 4. Hs.d.) number of ioCS episodes per patient was 3 , incision  and anaesthetic induction . No triggering factor of ioCS was identified for 11 (1/4) patients. Patients received a mean (s.d.) of 3  occurred in 45 patients. The mean s.d.) numd.) of 3 . BP chanAmong probable ioCS, missing criteria to classify them as highly probable ioCS were, for hypertensive and hypotensive episodes respectively, hemodynamic changes ≤40% (57% and 73%), onset period between 5 and 10 min (14 and 9%), no octreotide injection (48 and 0%), reversibility ≤20% after octreotide injection (4 and 0%) and confounding factors with anaesthetic management (16 and 18%).There was no factor, including the use of vasopressors, significantly associated with the occurrence of ioCS . The anaNo intraoperative carcinoid crisis occurred during the study period. All surgeries were completed. One patient died postoperatively, 4 days after surgery, developing a carcinoid crisis with a refractory cardiac failure and a cardiac arrest. He was a 74-year-old man who had a highly secreting tumour with a severe clinical presentation, an asymptomatic carcinoid heart disease, and hepatic metastases.After preoperative continuous octreotide infusion, ioCS were mostly hypertensive and no ioCS risk factor was identified. To our knowledge, this is the first study that pre-defined ioCS in order to describe the occurrence and the risk factors of this complication.et al. underlined the heterogeneity in the definition of ioCS and carcinoid crisis , measurement interval and method (noninvasive vs invasive) and minimal episode duration   , 19, 21.pisodes) , 21. DifFew patients needed several injections (up to three boluses) to control ioCS suggesting the efficiency of low dose of octreotide. No intraoperative carcinoid crisis occurred and all surgeries were completed. Although continuous octreotide infusion is insufficient to prevent all ioCS, our local protocol seems to be effective to prevent carcinoid crisis, the most feared complication.No factor was statistically associated with occurrence of ioCS. In 1/4 of cases, no triggering factor was found suggesting that ioCS can occur at any time and that anaesthetists should be constantly ready to treat hemodynamic instability. The small sample size is likely to be a major limitation for the identification of predictive factors. However, another explanation could be related to the protocol used that includes a double dose of octreotide in case of preoperative CS, hepatic metastases, or carcinoid heart disease, which may have reduced the risk of ioCS in such patients to that of other patients. Some reports suggest that vasopressor use can trigger ioCS and recommend to avoid this medication , 13, 17.et al. reported was not feasible (The study has some limitations. First, it was a single-centre study, but this design allowed for homogeneous surgical procedure and anaesthetic management. These results are related to our local protocol of octreotide and they could be different with other octreotide administration protocols. Second, our definition of ioCS was developed by an experienced anaesthetist team, but it can be discussed. We did not include duration of each ioCS. The analysis of hypertensive episodes reveals an increase of BP ≥50% during highly probable ioCS. This threshold for diagnosis of ioCS could be decreased considering ioCS classified as probable because of a variation of BP lower than 40%. Thus, a better definition of ioCS is needed but requires validation in a prospective multicentric study. Third, the retrospective nature of this study did not allow for a deep assessment of postoperative complications. Thus, the impact of ioCS on outcomes, as Condron and Massimino feasible , 21. In In conclusion, when a preoperative continuous octreotide infusion is administered to patients, ioCS are mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. A standardized octreotide prophylaxis protocol seems to be clinically relevant to manage ioCS and to prevent occurrence of carcinoid crisis.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.Contributed to the design of the work, acquisition of data: M F, Y B, M-C L, J P, F M, P S, F C, D H S, A P, G P , T W, T R. Conducted the analysis and interpretation of data: M F, Y B, T W. Drafted the manuscript: M F, Y B. Revised the work for important intellectual content: M-C L, F M, D H S, F C, J P, P S, T W, A P, G P, T R. All authors approved the submitted version of the manuscript.


In the second multivariate analysis, administration of proton-pump inhibitor, administration of antibiotics in the preceding 90 days, ICU admission, blood lymphocyte count less than 0.8 × 109/L, elevated BUN/ALB level, and presence of MDR pathogens were still associated with 30-day mortality. The area under the receiver operating characteristic curves in the BUN/ALB predicting 30-day mortality due to HAP was 0.685. A high BUN/ALB was significantly associated with a worse survival than a low BUN/ALB (P < 0.001). Therefore, an elevated BUN/ALB level is a risk factor for mortality on patients with HAP.This study aimed to evaluate the factors that affect 30-day mortality of patients with HAP. The data used in this study were collected from all HAP occurred in our hospital between January 2014 and December 2017. A total of 1158 cases were included. 150 (13.0%) of whom died within 30 days. This reported mortality identified by the univariate Cox regression analysis is found to have been affected by the following factors: age greater than 70 years, presence of diabetes mellitus and chronic obstructive pulmonary disease, gastric tube intubation, administration of proton-pump inhibitor, blood albumin level less than 30 g/l, elevated neutrophil-to-lymphocyte ratio, antibiotics therapy in the preceding 90 days, intensive care unit (ICU) admission, blood lymphocyte count less than 0.8 × 10 Nosocomial or hospital-acquired pneumonia (HAP) is a common infection associated with a prolonged hospital length of stay and high patient mortality, generally with symptom onset at 48 h or more after admission to the hospital, or within 14 days of discharge from the hospital . HAP is 4 colony-forming units/ml, fever (>37.8°C) or hypothermia (<35.6°C), leukocytosis, left shift, or leucopenia based on local normal values. Cases of ventilator-associated pneumonia and acquired immunodeficiency syndrome and those with missing key data were excluded.Data related to all incidence of HAP that occurred in the third affiliated hospital of Sun Yat-sen University, Guangdong, China, between January 2014 and December 2017 were collected. Variables of interest included age, gender, comorbidity, central venous catheter use, prior treatment, laboratory data, and 30-day mortality. All patients included were aged at least 18 years. The criteria for a diagnosis of HAP [Pathogenic bacteria isolated from the clinical specimens were further characterized by conventional biochemical tests to identify the specific strain by using standard microbiologic methods . Pathogeα of 0.05, and all P values were based on two-sided tests. Statistical analysis was performed using IBM SPSS Statistics, version 20 .The 30-day survival was the main endpoint of this study. Survival was defined as the time interval between HAP diagnosis and death or the last follow-up. Multivariate analysis using a stepwise Cox proportional hazards model was used to test for independent significance of baseline characteristics and explanatory variables. The performance of relevant parameters was assessed by using the Kaplan–Meier method, and differences in survival between groups were compared by using the log-rank test. In addition, the receiver operating characteristic (ROC) curves of BUN/ALB for predicting 30-day mortality with HAP were plotted. Sensitivity of a score less than the cutoff point indicated 30-day mortality, while specificity of that greater than the cutoff point indicated survival beyond 30 days, both of which could be evaluated for each possible cutoff point. The cutoff point representing the highest Youden index (specificity + specificity − 1) was selected as the optimal threshold value. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to measure the effects of relevant parameters on prognosis. An HR greater than 1 indicated a worse prognosis in patients with a relevant parameter, while a HR less than 1 indicated a better prognosis. The criterion for statistical significance was set at an 9/L and blood urea nitrogen/albumin (BUN/ALB) level of 0.21 ± 0.17, and 193 (16.7%) patients had MDR pathogens in their system  cases of HAP were recorded. 314 of which were excluded because of missing key data or presence of repeated infection; finally, only a total of 1158 cases were included . Within r system .9/L, elevated BUN/ALB levels, and presence of MDR pathogens. Multivariable analysis revealed that administration of proton-pump inhibitor , antibiotic therapy in the preceding 90 days , ICU admission , blood lymphocyte count less than 0.8 × 109/L , elevated BUN/ALB  levels, and presence of MDR pathogens  were still associated with 30-day mortality. ROC analysis presented similar results with Cox regression and revealed that the BUN/ALB was a significant predictor of 30-day survival. The area under the ROC curves in the BUN/ALB predicting 30-day mortality with HAP was 0.685 (P < 0.001)  .9/L, elevated BUN/ALB levels, and presence of MDR pathogens.We revealed that the mean mortality rate in this study was 13.0%, consistent with the HAP mortality reported by other researchers , 14. In 9/L was also an independent risk factor for 30-day mortality in this study. It was similar to a previous study [As HAP is often associated with peptic disease and nonsteroidal drugs are usually used to allay patients' fever, the administration of proton-pump inhibitor was common in HAP patients. In the current study, we found that the administration of proton-pump inhibitor had a negative effect on HAP patients' 30-day mortality, consistent with the literature report . Whetherus study . The BUNus study . An elevus study . It is ius study . Our curThere are several limitations of our study that may decrease the impact of the results presented. First, as a single-center retrospective study, the assessment of HAP may contain bias. Second, there was no microbiologic documentation in half of the patients. It can be argued that some patients without etiologic diagnosis may not actually have had HAP. However, this is the usual situation in clinical practice, and our rate of etiologic diagnosis was similar to the ancillary reports in this field.The purpose of the current study is to evaluate the factors that affect 30-day mortality of patients with HAP which have been highlighted in the findings. The results indicate that the mortality rates of HAP were different in each department and that peripheral blood BUN/ALB level is a simple but independent predictor of 30-day mortality with HAP. With solid statistics, the findings of this research are consistent with those of similar studies of prognostic factors of 30-day mortality with HAP.


In the Central and Eastern European region, the British EQ-5D-3L value set is used commonly in quality of life (QoL) studies. Only Poland and Slovenia have country-specific weights. Our study aimed to investigate the impact of value set choice on the evaluation of 18 chronic conditions in Hungary.Patients’ EQ-5D-3L index scores were calculated using the VAS-based Slovenian and European and the time-trade-off-based Polish and British value sets. We performed pairwise comparisons of mean index values by dimensions, diagnoses and age groups. We evaluated disease burden by comparing index values matched by age and gender in each condition with those of the general population of the CEE region in all four value sets.Altogether, 2421 patients  were included in our sample with the average age of 55.87 years (SD = 17.75). The average Slovenian, European, Polish and British EQ-5D-3L scores were 0.598 (SD = 0.279), 0.661 (SD = 0.257), 0.770 (SD = 0.261) and 0.644 (SD = 0.279), respectively. We found highly significant differences in most diagnoses, with the greatest difference between the Polish and Slovenian index values in Parkinson’s disease (0.265). Systematic pairwise comparison across all conditions and value sets revealed greatest differences between the time-trade-off (TTO) and VAS-based value sets as well as varying sensitivity of the disease burden evaluations of chronic disease conditions to the choice of value sets.Our results suggest that the choice of value set largely influences the health state utility results in chronic diseases, and might have a significant impact on health policy decisions. The burden of chronic diseases is ever increasing as these conditions are the main causes of poor health, disability, and account for most the health care expenditures nowadays . ChronicEvidence on patient’s health-related quality of life can be obtained using patient-reported outcome measures, some of which are generic, meaning they cover a more general spectrum of health problems and are designed to be applicable for various health conditions . The EQ-For the valuation of the EQ-5D-3L health profiles, different value sets are applicable. However, not all countries have their own value set: in the Central and Eastern European (CEE) regions, only Slovenia and Poland have country-specific value sets. In health economic analyses as well as the assessment of the health status of the general population, in other countries of the CEE region, usually, the British TTO value set is used . The EurPrevious studies indicate that differences are present between results calculated with different value sets and that it may be attributed to societal and cultural differences. The relative importance of the problems reported in the five EQ-5D dimensions differs by value sets , and cerWe aimed to compare the Slovenian, Polish, British and European EQ-5D-3L value sets, which are most commonly used or are potentially applicable for health economic evaluations in the CEE region. Our study was based on the comparative analysis of patient-level data from cross-sectional surveys conducted in Hungary among patient populations in 18 different chronic conditions. We explored the differences of the EQ-5D-3L index scores calculated with the four value sets by diagnosis, age group and disease severity. Furthermore, we analysed the potential impact of the choice of value sets on health priority setting by comparing the disease burden evaluations across different conditions using different value sets.The EQ-5D-3L questionnaire is a health status measure that consists of two parts, a descriptive system and the EQ VAS. The descriptive system focuses on five dimensions of health: mobility (MO), self-care (SC), usual activities (UA), pain/discomfort (PD) and anxiety/depression (AD). In each dimension, there are three response categories  representing: no problems—1, moderate problems —2; severe problems —3. Respondents are asked to indicate for each dimension the level of problem that best describes their current health status . The resEQ-5D-3L value sets have been developed in various countries based on preferences of the general population using direct methods such as time-trade-off (TTO) and EQ-5D visual analogue scale  or both . In the In our study, we compared four value sets. The British valuation study was conducted in 1993. From 6080 randomly selected addresses, 2997 respondents provided complete data for evaluation. The value set was determined by the valuation of 42 health states in a face-to-face TTO exercise in addition to “full health” (11111) and “death”. Each respondent valued 13 health states. –28. The This current study is a secondary analysis of 18 previous surveys conducted by the Department of Health Economics of the Corvinus University of Budapest in the past 14 years –48. We sN = 61, max: N = 249), analytical weights were constructed to make the pooled dataset a balanced sample of the 18 diseases. The sum of weights was set to 100 by each condition. We calculated weighted mean and percentage values when reporting characteristics of the pooled sample totals. We compared the four value sets by (1) EQ-5D-3L dimensions, (2) by diagnosis, (3) by respondents’ subjective health assessment (EQ VAS) and (4) by age group, according to the following. (1) When comparing value sets by EQ-5D-3L dimensions, we graphically represented indices of health states with moderate and severe levels of isolated problems in each dimension , as well as the combinations of moderate and severe problems  against full health (11111). This comparison allows us to take into account the full disutility arising from the severity of problems and the dimension-specific preferences [t tests [We applied descriptive methods and graphical representation of key findings. As sample sizes varied substantially across the datasets (min: n = 6926), by calibrating to the 2011 European population census by age, gender and education [Finally, for each value set, we calculated disease burden (DB) scores and the sensitivity of DB evaluations to the choice of value set. DB was defined as the difference between the average health status of the patient group and health state of the general population comparable by age and gender. For DB score calculations, we used the population norm values estimated from a joint database of Polish, Slovenian and Hungarian population studies (ducation . We expri condition was compared to the other 17 j conditions (i ≠ j). In each comparison with value set k , the difference between DBi and DBj (ΔDBijk) could be significantly positive (+), non-significant (0) or significantly negative (−). Second, we evaluated how consistent ΔDBij1···ΔDBijk were across the k value sets. In case of consistent difference, the pattern was identical for all four value sets . In case of inconsistent difference, the outcome was diverse . When comparing value set pairs, then the pattern of difference was assessed on two ΔDBij pairs (k = 2). The pattern of consistent difference was ++, 00 or −−, while examples of inconsistent difference were 0 + , −0 or +−, etc. Finally, the sensitivity index was expressed as the proportion of diverse outcomes among all pairwise comparisons. We calculated sensitivity indices by comparing the four value sets for each diagnosis as well as for the total sample. These sensitivity indices can be interpreted as a general measure of how sensitive the DB evaluations are to the choice of a value set. For each diagnosis, the general sensitivity index calculation was based on 17 diagnosis pairs and four value sets . For the sample total, the general sensitivity index calculation was based on 153 diagnosis pairs and four value sets . The pairwise sensitivity indices express for each diagnosis how sensitive the DB evaluations are to the choice between two particular value sets , as well as how sensitive the sample total is to the choice between two particular value sets . Table From the 18 samples, we modelled the effect of the choice of the value set on DB evaluations. We calculated a sensitivity index according to the following procedure. First, we performed all pairwise DB comparisons for each condition using the four value sets. Each n = 1356, 58.6%) and it is worthy of note that some studies involved exclusively female  or male (BPH) patients. The mean disease duration in our sample was 8.75 (SD = 8.95) years, with outstandingly high average disease duration in patients with psoriasis and epilepsy  groups. The total sample included 2421 patients with psoriatic arthritis (PsA) , age-relIn our sample, 519 patients (20.7%) did not report any problem in any of the five EQ-5D-3L dimensions, while 420 (16.1%) reported problems (of any level) in all the five dimensions. Severe problems in at least one dimension were reported by 419 patients (17.6%), while 2002 patients (82.4%) did not report the severe problem in any of the five dimensions.The distribution of patients by problem levels and diagnoses across the five EQ-5D-3L dimensions are presented in Fig. The percentage of patients reporting any problems in mobility, self-care, usual activities, pain/discomfort and anxiety/depression was greatest in PAOD (89.3%), RA (56.2%), RA (20.9%), RA (8.4%) and SCZ (76.9%), respectively. Patients with dementia reported severe problems most frequently in the mobility 11.3%), self-care (19.7%), usual activities (36.1%) and anxiety/depression (30.2%) dimensions, while PAOD patients reported most frequently severe problems in the pain/discomfort dimension (31.1%) . Patients with endometriosis had the highest, while dementia patients had the lowest mean EQ-5D-3L scores in all four value sets. The most significant difference between any two value sets was found in PD: the difference between the Slovenian and Polish index values was 0.265. The pairwise comparisons of the four value sets by two-sided t tests showed highly significant differences in most diagnoses. In SCZ, the British value set did not differ significantly from the Slovenian and European value sets. In other diagnoses, five or six pairwise value set comparisons were significantly different. The British and European value sets did not differ significantly in 10, and the British and Slovenian in 2 out of the 18 diagnoses. All other value set comparisons showed significant differences in all diagnoses  with all the four value sets for each diagnosis. The weighted mean EQ-5D-3L index scores in our total sample were, respectively, 0.598 SD = 0.279), 0.661 (SD = 0.257), 0.770 (SD = 0.261) and 0.644 (SD = 0.334) with the Slovenian, European, Polish and British value sets. All pairwise value set comparisons were significant . In this range, the Slovenian index values were lowest, while the European and British value sets provided nearly identical index values. Differences were the smallest in the EQ VAS range between 80 and 100 , and the pattern of value sets changed below EQ VAS levels of 40 , where the Slovenian, European and Polish value sets converged, and the British value set provided the lowest index values.We explored how disease severity influenced the differences between value sets. As a proxy for disease severity, we used subjective health assessments by the EQ VAS. We observed three distinct EQ VAS regions based on the pattern of value set differences Fig. . Across n = 275), 26.7% to the middle (n = 609) and 56.6% (n = 1525) to the oldest age group.We aimed to analyse whether the EQ-5D-3L index scores calculated with the four value sets differed depending on the patients’ age. Three age groups were created: 18–34, 35–54 and 55+ years old. From the 2421 patients 16.3% belonged to the youngest , endometriosis (64.6%) and epilepsy (54.2%). In certain diseases that typically affect the elderly, most of the patients were over 55 years old. In AMD 100%, in dementia 96.5%, in BPH 95.8%, in PAOD 95.2% and in OP 93.7% of the patients belonged to the oldest age group.p ≤ 0.001). In all age groups, index values were lowest when measured with the Slovenian, followed by the European and the British value sets, while the Polish index values were highest. The difference between index values of the youngest and eldest age groups was biggest when using the Slovenian (0.217), followed by the British (0.206), the European (0.171) and the Polish (0.150) value sets. All age group comparisons were significant (p < 0.001).The Slovenian, European, Polish and British index values were 0.765 (SD = 0.214), 0.793 (SD = 0.190), 0.886 (SD = 0.140) and 0.804 (SD = 0.213) in the 18–34 age group, 0.601 (SD = 0.277), 0.662 (SD = 0.255), 0. 773 (SD = 0.251) and 0.644 (SD = 0.329) in the 35–54 age group, and 0.548 (SD = 0.277), 0.622 (SD = 0.262), 0.735 (SD = 0.281) and 0.598 (SD = 0.350) in the 55+ age group, respectively. All value set comparisons differed significantly , 22.9% provided diverse outcomes. Most of the diverse outcomes were combinations of non-significant differences and significant differences in one direction. Mainly due to the modest sample sizes of the disease subsamples, there were no pairwise comparisons where alternative value sets provided statistically significant reverse DB rankings.  The sensitivity index suggested that the disease conditions are not identically sensitive to the choice of the value set. The outcome of DB comparisons including conditions such as dementia, MS or PAOD depended strongly on the value set, while DB comparisons of other diseases, such as BPH and BC, were hardly affected. The sensitivity index also provided information about how the choice between two value sets influenced DB evaluation results across the 18 conditions. Overall, the Slovenian and Polish value sets provided the most divergent DB comparisons: in 21.2% of the DB comparisons, the choice between the Slovenian and Polish value sets provided a divergent outcome. At the other extreme, the choice between the European and Slovenian value sets hardly affected the outcome of DB comparisons, just as the choice between the Polish and the British value sets.As a general measure of sensitivity to the choice of the value set, we introduced the sensitivity index Table . AltogetWe analysed the systematic differences between four value sets and their potential impact on health priority setting across 18 chronic conditions –48. We cWe found remarkable differences across diagnoses, age groups or patients with different disease severity. For example, the mean EQ-5D-3L index difference was as high as 0.265 in PD and 0.187 in the 55 + age group. The systematic pairwise comparison of DB evaluations between all disease conditions revealed inconsistent results between value sets determined via the VAS and TTO valuation methodology. The proportion of discrepant DB evaluations was 21.9% when comparing the Slovenian VAS and Polish TTO value sets. However, value sets determined via the same methodology provided rather consistent results. Only 2.9% of DB evaluations were discrepant when comparing the VAS-based Slovenian and European value sets, and 5.6% when comparing the TTO-based Polish and British value sets, despite the apparent cultural or economic differences between the populations whose preferences were valued. Our results confirm the findings of previous studies highlighting the methodology-driven differences between EQ-5D-3L value sets , 54.The differences between EQ-5D-3L value sets can lead to significant differences in health gains in EQ-5D-3L-based cost-utility analyses. Taking the extremes, for example, if the health status of a patient is improved from ‘22222’  to ‘11111’  over a year with a new treatment, the QALY gain will be 0.685 with the Slovenian, but only 0.284 with the Polish value set. Improvement from the worst possible health state (‘33333’) to a moderate health state (‘22222’) would result in 1.239 QALY gain with the Polish, but only 0.555 with the European value set. Results of the DB evaluations and the examples for the potential QALY-gain differences pinpoint that the value set chosen to calculate health state utilities in chronic diseases might significantly influence the results as well as the health policy and financing decisions. These findings deserve careful consideration in health economic analyses in the CEE, where local data are sparse, and economic analyses frequently need to rely on a variety of external sources. .There is increasing interest in developing country-specific value sets. Local value sets could reflect better the health preferences of a given population  than value sets derived in a foreign country . By feedThe differences of the value sets might at least partly explain the differences between Poland and Hungary in terms of access to highly effective but costly biological drugs in chronic immune-mediated diseases. Several studies were conducted involving these two countries in CEE to evaluate access to biologicals in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis and psoriasis. , 61–63. Variations of reimbursement policy may be one of the factors explaining the differences to a certain extent in Bulgaria, Latvia, Lithuania, and Poland, but the association with other possible.Determinants  were not proven. We assumed, nevertheless, in these papers that health deterioration linked to these diseases might be valued differently against other systemic inflammatory conditions in distinct countries and which may contribute to the immense diversity in the utilisation of biological drugs for immune-mediated chronic diseases. However, comparison of Hungary and Poland which have very similar total health expenditure refutes this assumption since in Hungary the exposure to biologicals used to be approximately ten times higher compared to Poland in inflammatory bowel diseases , despiteIn addition to the availability of patient-level data from 18 conditions, a unique strength of our study is that we could calculate disease burden scores with the four value sets using population norm database involving patient-level data of 6926 respondents. Our database contained 997 individuals in the 65+ age group, allowing for potentially more reliable DB estimates in older populations than the available local population norm values , 5. HoweAs a conclusion, based on the analysis of a wide range of chronic conditions and a variety of value sets in terms of the population and method of valuation, our study highlights the potential impact of value set choice on health policy decisions.