Although, in-part through an impact on left ventricular mass (LVM), resistin (an adipokine) may contribute to heart failure, whether this is explained by the adverse effects of resistin on aortic stiffness and renal function is unknown.inappr]) (echocardiography) were determined in 647 randomly selected community participants, and in regression analysis, the extent to which these relations could be explained by aortic pulse wave velocity (PWV) or estimated glomerular filtration rate (eGFR) was evaluated.Relationships between circulating resistin concentrations and LVM index (LVMI), and LVM beyond that predicted by stroke work , PWV and eGFR. Furthermore, independent of confounders, LVMI, LVMinappr and LVH were independently associated with PWV and eGFR. However, adjustments for either PWV or eGFR failed to modify the relationships between resistin concentrations and LVMI, LVMinappr or LVH. Moreover, in multivariate regression analysis neither PWV nor eGFR significantly modified the contribution of resistin to LVMinappr or LVMI.Independent of confounders, resistin concentrations were independently associated with LVMI, LVMIndependent relationships between circulating concentrations of the adipocytokine resistin and LVM are not explained by the impact of resistin on ventricular-vascular coupling or renal dysfunction. Resistin’s effects on LVM are therefore likely to be through direct actions on the myocardium. Obesity is recognized as one of the major drivers of the increasing prevalence of cardiovascular disease worldwide. Importantly, obesity, independent of conventional risk factors and myocardial infarction, is a risk factor for several cardiovascular events including the progression to heart failure –3. InsulRecently, we reported the presence of strong, independent relations between circulating resistin concentrations and left ventricular mass (LVM) in a large community-based sample . As LVM The protocol for the present study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand . Informed, written consent was given by all participants and the study was carried out in accordance with the principles outlined in the Helsinki declaration. The design of the current study has been described previously , 23, 24.A standardized questionnaire was used to obtain demographic and clinical data , 24. MeaSerum creatinine concentrations were measured using the Advia Chemistry systems (Siemens) with calibration traceable to isotope dilution mass spectrometry (IDMS). The 4-varible CKD-EPI equation was employed to estimate glomerular filtration rate (GFR) . Blood s2.7. Left ventricular hypertrophy was defined as an LVMI> 47 g/m2.7 in women and LVMI> 50 g/m2.7 in men [inappr). The extent of LVMinappr was established from predicted LVM as previously described [Echocardiography was performed as described previously , 24, 26.7 in men . Using tescribed , 26. RelAortic stiffness was assessed using carotid-femoral (aortic) pulse wave velocity (PWV) as previously described , 21, as 2-statistic, respectively. Log transformation of resistin concentrations was performed as data were non-normally distributed and transformation improved distribution [SAS software, version 9.4  was used for database management and statistical analyses. Continuous data are represented as mean ± SD. Comparisons of unadjusted means and proportions were made using the large-sample z-test and the χribution . For conribution .A high proportion of participants was overweight or obese and had central  obesity Table . In addir = 0.03, p = 0.40) and WC  were not independently associated with resistin concentrations. Similarly, no independent associations between adiposity indexes and resistin concentrations were noted in those not receiving antihypertensive therapy . No independent relationships were noted between resistin concentrations and HOMA-IR .On bivariate analysis resistin was related to BMI and WC, but not to HOMA-IR . With the same adjustments, circulating resistin concentrations were also independently associated with aortic PWV  and with CRP .On bivariate analysis resistin was related to eGFR, PWV and CRP . With the same adjustments, aortic PWV was similarly independently associated with LVMI (Table p < 0.02), but not with LVMinappr (Table inappr (Table p = 0.44).With adjustments for age, sex, body weight, regular smoking, regular alcohol intake, treatment for hypertension, systolic blood pressure, the presence of diabetes mellitus or an HbA1c > 6.5%, eGFR was independently associated with LVMpr Table , LVMI , LVMinappr (p < 0.0001) and relative wall thickness (p < 0.02), but not left atrial volume index (p = 0.09). In stepwise regression models BMI, WC, HOMA-IR, and resistin concentrations were all directly and independently associated with LVMinappr (Tables p = 0.14) or left atrial volume index (p = 0.26). The relationships with LVMI and LVMinappr were not affected by the inclusion of either eGFR, aortic PWV or CRP in the models . The contribution of resistin to LVMI was not modified by the inclusion of PWV or CRP in the model , and only marginally modified by the inclusion of eGFR in the model . In the models including waist circumference , and only marginally modified by the inclusion of PWV in the model . The contribution of resistin to LVMI was not modified by the inclusion of PWV or CRP in the model , and only marginally modified by the inclusion of eGFR in the model .In multivariate regression analyses, resistin concentration was second to BMI as a determinant of LVMpr Table . For LVMpr Table . The incinappr was negligible (0.37 ± 0.09 g/m2.7 and − 0.06 ± 0.23% respectively). Similarly, the contribution of eGFR to resistin-related increases in LVM and LVMinappr was negligible (0.93 ± 0.09 g/m2.7 and 3.28 ± 0.23% respectively. When waist circumference (instead of body weight or BMI) was included in the multivariate model, the contributions of PWV or eGFR to resistin-related increases in LVM and LVMinappr were also negligible .In mediation analysis, the contribution of PWV to resistin-related increases in LVM and LVMinapp, and LVH, as well as with both eGFR and aortic stiffness . In this regard, consistent with the well recognized impact of ventricular-vascular coupling and renal dysfunction on LVM, both eGFR and PWV were also independently associated with LVM and LVH. However, in multivariate regression, neither eGFR nor aortic PWV could account for independent relationships between circulating resistin concentrations and LVM or LVH. In addition, in multivariate regression analysis neither PWV nor eGFR significantly modified the contribution of resistin to LVMinappr or LVMI.The main findings of the current study are as follows: In a large, randomly selected, community-based sample, circulating resistin concentrations were independently associated with indexes of structural changes in the LV including LVMI, LVMThe mechanisms that may explain the ability of circulating resistin concentrations to predict the progression to heart failure and its prognosis –12 are uinappr or LVMI. Thus, together with the fact that resistin concentrations are not independently associated with brachial, central aortic or ambulatory BP [Increases in aortic stiffness are strongly associated with LVM , 29 and atory BP , indepeninappr and only had a marginal impact on the contribution of resistin to LVMI. Thus, in risk-prediction, the assessment of eGFR, a simple and cost-effective assessment of cardiovascular risk, will not adequately identify the adverse effects of resistin on the LV.Through renal dysfunction, well before the onset of renal failure, reductions in estimated glomerular filtration rate are strongly associated with LVM and these effects are not attributed to an impact of hemodynamic factors . As resiResistin is induced in response to various pro-inflammatory stimuli such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β –6. FurthThe relationships between circulating resistin concentrations and LVM beyond indices of obesity (BMI or waist circumference) despite the high proportion of participants with obesity in the current study, suggest that the adverse effects of resistin on LVM are through effects beyond adipose tissue. However, unlike mice, resistin in humans is often undetectable in adipocytes, and the major source of circulating resistin is likely to be peripheral blood mononuclear cells . Indeed,There are several limitations to the current study that require consideration. In this regard, the present study was cross-sectional in design and hence no conclusions regarding causality can be drawn. However, as previously emphasized , the preIn the current study performed in a large sample of community participants in whom a high proportion had obesity, we show that despite striking relations noted between circulating resistin concentrations and both aortic stiffness and glomerular function, these effects do not account for the independent relationships between circulating resistin concentrations and LVM or LVH. Thus, neither ventricular-vascular coupling nor renal dysfunction is likely to explain the relationships between circulating resistin concentrations and LV hypertrophy. Circulating resistin concentrations may therefore be a biomarker of direct rather than indirect actions of resistin on the myocardium which may ultimately predict the progression to heart failure.Additional file 1: Figure S1. Impact of adjustments for aortic pulse wave velocity (PWV), estimated glomerular filtration rate (eGFR) or C-reactive protein (CRP) on multivariate adjusted left ventricular mass (LVM) beyond that predicted by stroke work (inappropriate LVM or LVMinappr) across octiles (Oct) of log resistin concentrations. Figure S2. Impact of adjustments for aortic pulse wave velocity (PWV), estimated glomerular filtration rate (eGFR) or C-reactive protein (CRP) on multivariate adjusted relations between log circulating resistin concentrations and left ventricular hypertrophy (LVH) in a community sample (n = 170 with LVH). Table S1. Bivariate relationships between circulating resistin concentrations and other factors in a community sample (n = 647). Table S2. Impact of adjustments for estimated glomerular filtration rate (eGFR), pulse wave velocity (PWV) or C-reactive protein (CRP) on the relative contribution of circulating resistin concentrations to variations in inappropriate left ventricular mass (LVMinappr) in a community sample (n = 647). Table S3. Impact of adjustments for estimated glomerular filtration rate (eGFR), aortic pulse wave velocity (PWV) or C-reactive protein (CRP) on the relative contribution of circulating resistin concentrations to variations in left ventricular mass index (LVMI) in a community sample (n = 647). Table S4. Circulating resistin concentrations as a determinant of inappropriate left ventricular mass (LVMinappr) or left ventricular mass (LVMI) in a community sample (n = 647).


The purpose of this study was to investigate whether age has an effect on short and long-term outcome in patients who undergo simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy.n = 97, 76.1 ± 3.9 years) and patients below 70 years .From 2005 to 2017, 186 consecutive elective patients underwent CABG and synchronous endarterectomy at our institution. Patients were retrospectively classified according to age into 2 groups: patients above 70 years (elderly group: p < 0.001) and Society of Thoracic Surgeons (STS) score  were significantly higher in the elderly group. Otherwise, there was no difference between the two groups concerning important preoperative risk factors or the intraoperative data. Postoperatively, the incidence of temporary dialysis was significantly higher in the elderly group . The rate of tracheotomy , of re-intubation  and drainage loss  was significantly higher in this elderly group. Neurological complications and 30-day mortality were comparable. Long-term survival was satisfactory for both groups. Nevertheless, 5-year survival rates (63% vs. 85%) were significantly lower in the elderly group (p = 0.003). Logistic regression analysis identified chronic obstructive pulmonary disease (COPD) and arrhythmia as significant risk factors for 30-day-mortality, but not age.The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, 4.4% vs. 2.5%; CABG in combination with synchronous endarterectomy can also be performed with satisfactory results in elderly patients.The online version of this article (10.1186/s13019-019-0928-5) contains supplementary material, which is available to authorized users. Coronary artery disease (CAD) is the most common type of heart disease and cause of mortality in the developed countries . AccordiThe purpose of this study was to investigate whether age has an effect on outcome in patients who undergo simultaneous coronary artery bypass grafting and carotid endarterectomy.In our center, 186 consecutive elective adult patients had a simultaneous CABG and CAE between January 2005 and December 2017. Patients were divided into two groups: younger than and equal to or older than 70 years. The younger group consisted of 89 patients (63.2 ± 4.8 years) and the elderly group of 97 patients (76.1 ± 3.9 years).In framework of our standard clinical concept, the extracranial cardotid arteries of each patient is examined first using ultrasound, before a CABG operation. If there is a suspicious of carotid artery stenosis, the patient is additionally examined using computed tomography (CT) or magnetic resonance imaging (MRI). After the confirmation of the indication, the patient will prepared for the simoultanous surgical procedure.The study population included all patients who underwent elective isolated CABG surgery with CAE. Exclusion criteria for this study were combined procedures or off-pump surgery.All clinical data were collected prospectively on admission and during the in-hospital stay. We retrieved the data retrospectively by reviewing the hospital records. Primary end points were intraoperative and 30-day mortality, as well as long-term survival. Secondary end points were postoperative course . Patients were followed up directly in our out-patient clinic, seen by their general practitioner, or contacted directly by telephone or e mail.Detailed information about the used surgical technique and statistical analysis in this work are available in the Additional file p < 0.001). The logistic EuroScore II  and STS score  were significantly higher in the elderly group. The median creatinine value in the elderly group was significantly higher . There was no difference between the two groups concerning the preoperative risk factors or clinical presentation.Relevant demographics and preoperative data of patients are given in Table p = 0.018). The intraoperatively administered number of red blood cell (RBC) units was higher in the elderly group, although this difference was not statistically significant . Otherwise no significant differences were noted between the two groups with regard to intraoperative data. The number of distal anastomoses, the extracorporeal circulation time and the cross-clamp time were similar in both groups . However, the postoperatively administered number of RBC units was similar in both groups. Pulmonary infections occurred more frequently in the elderly group . Consequently, the incidence rate of re-intubation  and tracheotomy  were significantly higher in the elderly group. Other factors determining ICU stay, such as postoperative neurological complications  or sternal wound infection , were comparable.The incidence of postoperative temporary dialysis was significantly higher in the elderly group . There was no difference between the two groups concerning 30-day major adverse cardiac and cerebrovascular events .The 30-day mortality in the elderly group in Table p = 0.003) , 3-year (75% vs. 87%) and 5-year (63% vs. 85%) survival rates were significantly lower in the elderly group (03) Fig. . The Log03) Fig. .Fig. 1ThIn our single-center study, the effect of age on outcome in 186 patients who underwent simultaneous CABG and CAE was investigated. The patients were divided into two groups of younger than 70 and equal to or older than 70 years. The two groups were compared concerning their demographic, pre-, intra-, and postoperative data. There were no significant differences between the two patient groups concerning their pre- and intraoperative data, or their 30-day mortality and short-term major adverse cardiac and cerebrovascular events.The optimal surgical approach (simultaneous or staged) for the treatment of patients with concomitant severe carotid and coronary stenosis is still the subject of controversial debate. In addition, with increasing age of the population, it is clinically relevant to clarify whether the postoperative risk of stroke and death in patients of an advanced age is higher than in younger patients.In a larger analysis, Brott et al. .  evaluateFeldman and colleagues  comparedp = 0.27), postoperative stroke (p = 0.07), combined early mortality or stroke (p = 0.11), and combined endpoint of myocardial infarction or stroke (p = 0.2) between the two approaches.Sharma et al.  performeThe results of Brott et al., Feldman and Colleagues and Sharma et al. concerning the risk of periprocedural stroke, myocardial infarction are in line with our presented results.p < 0.001). The 30-day, 1-year and 5-year mortalities for octogenarians were 3.7, 10.8 and 29.0%, respectively. The octogenarians had higher adjusted 30-day (p = 0.018) and 1-year mortality (p < 0.001) compared to the younger group. Octogenarians had longer post-operative stays in ICU and hospital, and higher rates of ICU readmission (p < 0.001). After multi-variable adjustment, an age of older than or equal to 80 years was an independent predictor of death at 30 days and 1 year. In contrast to Wang et al., we did not find any differences between our patient groups concerning the post-operative stays in ICU and hospital, and also 30-day mortalities. But the one-year, 3-year and 5-year survival rates were significantly lower in our elderly group.In a retrospective single-center study, Wang et al.  reviewedAlexander et al.  examinedp = 0.001), and not age and preoperative myocardial infarction. The 10-year estimated rates free from cardiac death and cardiac events were not significantly different among the groups. In multivariate Cox models, independent risk factors predicting cardiac events were the NYHA classification, and ejection fraction, but not age. Ohira et al. reported that neither short- nor long-term cardiac outcomes after off-pump CABG are influenced by age at surgery.Ohira et al.  investigIn our study, CABG in combination with synchronous endarterectomy can be performed with satisfactory results, especially in the specific high-risk subgroup of patients of advanced age. The multivariate logistic regression analysis of clinically relevant parameters indicated that there is no significant effect of age on outcome in patients who undergo simultaneous CABG and CAE with single anesthesia. Based on our current results, we would recommend this surgical approach. However, further prospective, multi-center, and randomized clinical studies with a larger group of patients are required to investigate in detail the effect of age on patient outcome.The presented data were retrospective from a single center, and the sample size remains small.Additional file 1:Extended material and methods section. (DOCX 25 kb)


HIV-positive children had higher arachidonic acid than uninfected children (p = 0.003). Total omega-6 FAs were significantly associated with HAZ regardless of HIV status (p = 0.035). Mean total omega-3 FAs (2.90%) were low in this population compared to other cohorts in Africa. These results provide reference serum FA values for 6–10-year-old children in Uganda and may be used to inform lipid supplementation programs to promote child growth. Future studies should investigate the relationships between child growth trajectories in relation to HIV status and serum FAs.Fatty acids (FAs) are crucial in child growth and development. In Uganda, antiretroviral therapy (ART) has drastically reduced perinatal human immunodeficiency virus (HIV) infection of infants, however, the interplay of FAs, ART, and HIV in relation to child growth is not well understood. To investigate this, serum was collected from 240 children between 6–10 years old in Uganda and analyzed for FAs using gas-chromatography mass-spectrometry. HIV status and anthropometric measurements were taken, and relationships with FAs were assessed. No significant differences in growth parameters or serum FAs were found between HIV uninfected children with and without exposure to ART. HIV positive children had significantly lower height-for-age- Fatty acids are a major source of energy and are involved in a variety of bodily functions ranging from cellular signaling  to the dDietary intake plays an important role in determining the FA status of individuals. In Uganda, the diet consists mainly of foods high in carbohydrates such as cereals, sweet potatoes, and cassava. Despite access to freshwater sources, the consumption of fish, a good source of n-3 FAs, is uncommon . This maIn Uganda, an estimated 1.3 million individuals were still living with HIV as of 2017, though the rate of new HIV infections has been decreasing since 2009 due, in part, to the implementation of antiretroviral therapies . StandarThis study aimed to identify differences in FAs and growth based on HIV status in children between the ages of 6–10 years old in Kampala, Uganda. It was expected that HIV positive and ART exposed children would have an altered serum FA profile than uninfected, unexposed children which could have adversely affected their growth. These results establish reference serum FA values and may be used to develop future lipid-based interventions to support healthy growth in adolescent Ugandan children regardless of HIV status.Participants were enrolled from the Kawempe Division of Kampala, Uganda—a region with the highest prevalence of HIV (11%), compared to national prevalence of 7.3% . Particin = 102), perinatally HIV exposed but uninfected  and HIV unexposed uninfected  community control children were enrolled from the same hospital. Some HEU children were also exposed to ART peripartum, while PHIV children continue ART treatment postpartum.Ugandan children between 6 and 10 years old and their adult primary caregivers were enrolled between March 15, 2018 and September 15, 2018 as part of a larger study of determinants of functional survival in HIV-infected/uninfected children. All measurements and sample collections were performed at enrollment. Of the 305 children in the parent study, blood samples for laboratory assessment for fatty acid measures was available in 240 that form the study base for the current analysis. Current adult caregivers were enrolled regardless of their HIV status. By design, approximately equal numbers of children with perinatally acquired HIV infection , Makerere University College of Health Sciences, School of Medicine (Protocol REC REF# 2017-017) and the Uganda National Council for Science and Technology (Protocol #: SS 4378). All caregivers gave written informed consent and children provided assent for study participation.z-score (HAZ), weight-for-age z-score (WAZ), and BMI-for-age z-score (BAZ) calculated using WHO AnthroPlus  [Anthropometric measurements were performed by trained health care professionals. Height and weight measurements were taken in triplicate and recorded as the mean of three measures. Height was measured with children directly looking forward and in contact with a flat wall. Specifically, children were not wearing shoes and the back of their feet, calves, bottom, upper back and back of head was in contact with the wall. Each child’s height is determined in centimeters by measuring the distance from the ground to a mark against the wall is made directly from the top of children’s head. Weight was measured in kilograms on a calibrated beam balance scale . For analytic purposes, growth parameters are analyzed as continuous outcome variables with height-for-age zerland) .Hemoglobin in grams per deciliter was assessed as part of complete blood count. Absolute T-cell lymphocyte count in cells/micro liter was measured using a fluorescence-activated cell sorting (FACS) Calibur flow cytometer . Child perinatal HIV status was defined on the basis of HIV mother-to-child transmission as PHIV, HEU and HUU. PHIV and HEU status were objectively determined prior to the 18th month of life on the basis of a positive and negative DNA-polymerase chain reaction, respectively. For both HEU and HUU, HIV-status at enrolment was confirmed on the basis of a negative HIV-rapid diagnostic test ,27.v/v) solution of freshly prepared methanol (0.01% (w/v) butylated-hydroxy-toluene):acetyl chloride containing C18d35 internal standard  were mixed in a test tube with 400 uL hexane and heated at 100 °C for 1 h. The mixture was cooled to room temperature and neutralized with 2 mL of 5% (w/v) sodium bicarbonate. Fatty acid methyl esters (FAMEs) were extracted to a new tube using 2 × 2 mL portions of hexane and dried under nitrogen. FAMEs were resuspended in isooctane and stored in capped GC vials at −20 °C until GC/MS analysis. All reagents used were HPLC-grade or higher and purchased from Sigma-Aldrich unless otherwise specified. Fatty acid values are presented as percent of total FAs.At the time of enrollment, venous blood was collected. Serum fractions were separated from venous blood after collection and stored at −80 °C. Serum samples was shipped on dry ice to the US for fatty acid analysis. Fatty acids were extracted and methylated from serum as described by Masood et al. (2005) . BrieflyFor analytic purposes, fatty acid measures were operationally defined as: (a) a continuous covariate and (b) as a categorical covariate. First, as a continuous variable, each FA was normalized by the sample wide standard deviation in order to estimate differences in growth per standard deviation increase in a given FA. Of note, continuous variables assume a linear functional form in relationship to growth measures which may not hold in throughout the range of fatty acid values. Hence, to relax linear functional form assumption for continuous measures, FA was also analyzed FA as categorical covariate. Four categories of approximately equal size were defined based on the quartiles of respective fatty acids in our sample and differences in growth outcomes were calculated for three lower quartiles compared to the highest quartile.A Clarus 600/680 gas chromatograph/mass spectrometer  (GC/MS) was used for FAME analysis. The GC was equipped with a DB-23  column  and used helium as carrier gas. The GC temperature profile was as follows: 100 °C, ramp 8 °C/min to 200 °C, ramp 2.5 °C/min to 220 °C, ramp 10 °C/min to 240 °C, hold for 1 min. Selective ion monitoring was used to improve FA resolution. The Supelco 37 component FAME mix (Sigma-Aldrich) was used to create standard curves for all FAMEs except palmitelaidic, mead, n-6 docosatetraenoic (DTA), n-6 docosapentaenoic (DPA n-6), and n-3 docosapentaenoic (DPA n-3) acid methyl esters, which are not present in the Supelco mix and had to be purchased separately from Cayman Chemical . TargetLynx version 4.0.1  was used for all GC/MS data analysis. Χ2 test was used for comparison of all categorical variables. Multivariable linear regression for each growth measure was implemented in relationship to FAs with adjustment for child HIV status, child hemoglobin, the caregiver’s sex, the caregiver’s education, and the caregiver’s quality scale as covariates. Mean differences and associations were considered statistically significant if p < 0.05. Statistical analyses of data were performed using R version 3.4.3 .As part of descriptive analyses, mean and standard deviations of continuous variables and number and proportion for categorical variables are presented in the overall sample and by HIV status to describe growth measures, fatty acid levels and socio-demographic characteristics. The mean and standard error of the mean (SEM) were reported for all FAs and ANOVA with Tukey’s post-hoc test was used to assess differences based on HIV status for all continuous variables. The p-value for the interaction term was <=0.10, the effect of FAs on growth was explored within each HIV stratum. All regression analyses of FAs as categorical covariates was implemented in Statistical Analysis Software (SAS) version 9.4 .To evaluate the potential for heterogeneity in relationship of FA to growth measures by HIV status, an interaction term between HIV status and FA (HIV*FA) quartile was introduced in multivariable models including respective individual measures. Wherever Information on the mean ± sd of population demographics with a breakdown based on HIV status is presented in p = 0.524). A similar number of male (52.5%) and female (47.5%) participants were enrolled. The mean height, weight, and hemoglobin level was 124 cm, 23.4 kg and 13.1 g/dL, respectively. The CD4 count of PHIV children was 1340 cells per microliter. The average age of the children was 8.06 ± 1.53 years and did not differ among children in different HIV groups . Oleic acid, the most abundant monounsaturated FA (MUFA), made up 3.39 ± 0.050% of total FAs and also did not differ due to HIV status (p = 0.148). Though total n-6 FAs (49.5 ± 0.328%) did not differ between HIV groups (p = 0.446), the essential FA linoleic acid was significantly higher in HEU (37.7 ± 0.584%) than the PHIV (35.4 ± 0.591%) group (Tukey’s p = 0.016). In contrast, the n-6 FA arachidonic acid (AA) was significantly higher in PHIV children (12.5 ± 0.262%) than HEU  and HUU children . n-3 FAs did not differ significantly between HIV groups. HIV related differences in growth outcomes of the children are presented in p = 0.002) and HEU  groups. There were no differences in any growth measure for HEU compared to HUU  accounted for 41.9 ± 0.300% of the total FAs and did not differ due to HIV status (p = 0.027), with a 0.16 z-score decrease in HAZ per standard deviation increase in total SFAs. In contrast, total n-6 FAs were positively associated with HAZ (p = 0.035). The R2 adjusted value for HAZ regressions were between 4–7%. Total MUFAs were inversely associated with WAZ (p = 0.033), and palmitelaidic acid was inversely related to BAZ (p = 0.021). The R2 adjusted values for WAZ and BAZ regressions were between −4% and 3%.Mean differences in growth parameters- HAZ, WAZ, and BAZ, per standard deviation increase in respective FA measures are presented in p = 0.029) and LA  had a lower WAZ relative to their peers in the highest quartile of the respective FAs. Likewise, being in the lowest quartile for DHA , total n-3 , and LA  relative to being in the highest quartile for the respective FAs was associated with significantly lower HAZ. On the other hand, children in the lower two quartiles of the n-6 FA eicosadienoic acid  had a higher BAZ score than peers in the highest quartile. Additionally, being in quartiles 2–3 vs. the highest quartile for oleic acid was associated with higher HAZ .Mean differences in growth measures for the three lower FA quartiles relative to the highest FA quartile are presented in p = 0.100 for both WAZ and BAZ regressions and almost significant for the HAZ regression (p = 0.101), hence differences in growth between HIV groups was explored in relation to oleic acid quartiles in p < 0.05) relationships between oleic acid quartiles and all three growth parameters was present for HIV positive and negative children, but not for exposed children. Additionally, all significant relationships were positive, indicating that HIV positive and negative children not in the highest quartile for oleic acid had better growth outcomes than children in the highest oleic acid quartile.The interaction term between HIV status and oleic acid in quartile regressions  was loweIn this study, the serum FA profiles of 240 children from the Kawempe Division of Kampala, Uganda were characterized and related to anthropometric growth measurements. Total n-6 FAs was positively associated with linear growth, measured by HAZ. This is in agreement with a previous report of children six years old and under from Tanzania ,30,31. Op = 0.033). This was largely driven by oleic acid, the most abundant MUFA. The middle two quartiles of oleic acid were associated with higher HAZ and BAZ, and all oleic quartiles were associated with higher WAZ when compared to the highest quartile of oleic acid. This was unexpected because oleic acid is recognized as being important in brain development, especially during myelination [Interestingly, EFA deficiency was not detected in this population. EFA deficiency is determined by the triene-to-tetraene ratio, or mead acid/AA, and a ratio of 0.02 is a clinical marker of EFA deficiency . The laclination , and inclination ,7. It isTotal n-3 FAs were low in the Ugandan population when compared to that of 7–9-year-olds in Zimbabwe . This may be due to low consumption of foods rich in n-3 FAs as the diet is an important determinant of n-3 status, however no conclusion can be made due to lack of information on the children’s diet. The highly unsaturated FA (HUFA) ratio was higher in the Zimbabwean than Ugandan population  . The HUFIn this study, no differences in total SFAs, MUFAs or PUFAs were observed between PHIV and HUU children, the SFA stearic acid was higher in PHIV children and, as previously discussed, AA was higher and LA lower in PHIV vs. HUU children. This agrees with previous reports. In fact, the overall FA profile of HIV positive individuals is altered compared to uninfected individuals, resulting in higher SFAs and lower MUFAs and PUFAs . TreatmeThe authors acknowledge there are limitations to this study. Information on the diet of the children is unavailable, hence dietary effects on child FA composition could not be discussed. This population is from an urban area and the results may not be representative of other adolescent populations in rural Uganda due to dietary and lifestyle differences. Participants were recruited in the context of primary care, however acutely ill children were given appointments to return for study-related evaluation when the child was well. Because HIV-infected children are systematically linked to the clinic for HIV-care and were less likely to be acutely ill, this element of design may have resulted in muted contrasts for HIV-uninfected relative to HIV-infected children on nutritional measures. In addition, the cross-sectional design of this study limits our ability to infer that relationships between fatty acid deficiency and growth outcomes are causal. There are many strengths including the large sample size, which allowed for meaningful evaluation of anthropometric growth parameters in relation to several factors. In this study, we systematically characterized the serum FA related differences in growth Ugandan children with and without perinatal HIV exposure/infection during early school-age years , while also controlling for sociodemographic confounders such as child caregiver education. Few studies have focused on growth of children between the ages of 6–10 years in sub-Saharan Africa. The data reported here may serve as reference values for future researchers. Furthermore, this study provides valuable information for comparison of not only HIV infected and uninfected individuals, but also of perinatally exposed, uninfected children. The information presented here may be used to tailor nutrient supplementation programs to the population in order to improve child growth, development, and health outcomes.The growth and serum FA profile of 6-to-10-year old Ugandan children that were PHIV, HEU, or HUU was assessed. No differences in growth or FA profile was observed between HEU and HUU children, therefore perinatal exposure to ART may not affect long-term growth and development. However, HAZ was lower in PHIV vs. HEU and HUU children, indicating perinatal HIV infection may cause a reduction in growth over time. PHIV children had lower LA and higher AA and stearic acid compared to HEU and HUU. Total n-3s were low across the entire population when compared to other African cohorts. Total n-6 FAs were positively associated with HAZ. This was consistent with previous reports. Surprisingly, higher MUFAs was inversely associated with HAZ, WAZ, and BAZ. This was an unexpected finding and warrants further investigation. These results may be used as reference values for future studies on lipid supplementation to support growth in the population. Additionally, future studies should focus on FA differences and child growth trajectories in relation to perinatal HIV status as literature on the topic is limited.


The association between dietary saturated fatty acids (SFA) intake and type 2 diabetes (T2D) remains unclear. This study aimed at investigating the association between SFA intake and T2D risk based on (1) individual SFA (differing in carbon chain length), (2) food sources of SFA and (3) the substituting macronutrients.37,421 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort were included in this study. Baseline dietary intake was assessed by a validated food frequency questionnaire. T2D risks were estimated by Cox regression models adjusted for non-dietary and dietary covariates.893 incident T2D cases were documented during 10.1-year follow-up. We observed no association between total SFA and T2D risk. Marginally inverse associations were found for lauric acid , myristic acid , margaric acid , odd-chain SFA , and cheese derived SFA . Soft and liquid fats derived SFA was found related to higher T2D risk . When substituting SFA by proteins, carbohydrates and polyunsaturated fatty acids, significantly higher risks of T2D were observed (HRs per 1 energy% ranging from 1.05 to 1.15).trans fatty acids or limited intake variation in polyunsaturated fatty acids and vegetable protein.In this Dutch population, total SFA does not relate to T2D risk. Rather, the association may depend on the types and food sources of SFA. Cheese-derived SFA and individual SFA that are commonly found in cheese, were significantly related to lower T2D risks. We cannot exclude the higher T2D risks found for soft and liquid fats derived SFA and for substituting SFA with other macronutrients are influenced by residual confounding by The online version of this article (10.1007/s00394-018-1630-4) contains supplementary material, which is available to authorized users. Dietary guidelines recommend that intake of total saturated fatty acids (SFA) should not exceed 10% of energy per day . DietaryFirst, individual SFA that differ in carbon chain length may have different associations with T2D risk. So far, only three studies have addressed the associations between intakes of individual SFA through self-reported dietary measurements and T2D , 9, 10. Second, the association between SFA and T2D risk can be modulated by its food sources. As far as we know, no study has investigated SFA derived from different food sources in relation to T2D risk. However, a recent cross-sectional study found that SFA from meat was positively associated with more insulin resistance and less insulin secretion, whereas SFA from dairy and plant sources were beneficially related to these markers . In addiThird, the association may also depend on macronutrients that substitute SFA in the diet. The Nurses’ Health Study and Iowa’s Women Study found that replacing energy from SFA with polyunsaturated fatty acids (PUFA) was related to lower T2D risk , 15. HowThe aim of this study was to investigate the associations between intake of SFA and risk of incident T2D in a Dutch population based on (1) individual SFA (differing in carbon chain length), (2) the food sources of SFA and (3) the macronutrients that substitute SFA.The European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort consists of the MORGEN (Monitoring Project on Risk Factors for Chronic Diseases) and the Prospect cohorts. The design and rationale of EPIC-NL were described in detail elsewhere . Brieflyn = 1046); prevalent diabetes cases at baseline (n = 679); participants with missing information of dietary intake (n = 180) and other co-variables, such as education information and physical activity level, (n = 339); participants with implausible energy intake based on the ratio of reported energy intake to estimated basal metabolic rate, i.e., the top or bottom 0.5% of the ratio (n = 346); leaving a total of 37,421 men and women for analyses.For this study, participants were excluded when one of the following criteria was fulfilled: participants who withheld permission for linkage with disease registries (Food intake was assessed by a self-administered Food Frequency Questionnaire (FFQ) on the usual consumption frequency of 79 main food categories during the year preceding enrolment. The FFQ was described in detail elsewhere . The FFQThe intakes for all micronutrients and macronutrients except individual SFA were calculated based on the Dutch food composition table 1996 . The intIntake of total SFA was calculated as the sum of SFA derived from the predefined food groups mentioned above. Considering relative low intakes of single individual SFA, two additional groups were made to add efficiency of the study: short- and medium-chain SFA  and odd-chain SFA (pentadecylic plus margaric acids).Energy reporting status of participants was estimated by comparison between self-reported energy intake and BMR . AccordAlcohol consumption was categorized as follows: 0, 0.1–6.0, 6.1–12.0, 12.1–24.0, and > 24.0 g/day for women and 0, 0.1–6.0, 6.1–12.0, 12.1–24.0, 24.1–60.0, and > 60.0 g/day for men. Glycaemic index (GI) of foods, a measure of the extent to which foods raise the blood glucose level, was obtained from international table complied by Foster-Powell et al. . To adjuThree sources of ascertaining incidence T2D were included in this study: self-report, hospital discharge diagnoses and urinary glucose strip tests . Verification of potential diabetes cases detected by any of these methods was carried out with information from participants’ general practitioner or pharmacist. Verification information was available for 89% of the potential diabetes cases, and 72% of these cases were verified as T2D and subsequently used for the analysis. The process of ascertainment and verification of incident and prevalent diabetes cases is described in detail elsewhere .At baseline, information on demographic characteristics, lifestyle characteristics, the presence of chronic diseases, and risk factors of chronic diseases was obtained with general questionnaires. Smoking status was categorized as current, past or never smoked. Family history of diabetes was defined as at least one parent with diabetes. Education was classified as low, middle and high education. Physical activity was measured with a validated questionnaire, from which the Cambridge Physical Activity Index was calculated and categorized as inactive, moderately inactive, moderately active and active .2). Systolic and diastolic blood pressures were obtained as the mean of two measurements in the supine position on the left arm using a random zero sphygmomanometer (MORGEN), or on the right arm using a BOSO Oscillomat  (Prospect). Hypertension was defined when one or more of the following criteria were fulfilled: diastolic blood pressure > 90 mmHg, systolic blood pressure > 140 mmHg, self-reported presence of hypertension or use of hypertensive medication. Hyperlipidaemia was defined through self-reported diagnosis and/or use of medication.A baseline physical examination was performed according to standard operating procedures. Body weight, height, waist circumference and blood pressure were measured. BMI was calculated as weight divided by height squared  and median (interquartile range) for continuous variables, or percentage for categorical variables. Correlations between dietary intakes of total SFA, individual SFA and SFA from different food sources, as well as correlations between intakes of SFA from different food sources, total fatty acids from that food source and the food source itself, were calculated using Pearson correlations coefficients.Person-years were calculated as the time between the date of the study entry and the dates of diabetes diagnosis, death, loss to follow-up or end of follow-up (1 January 2006), whichever came first. The endpoint of analysis was incident T2D.trans fatty acids, protein , dietary cholesterol, vitamin E and fibre. Model 5 was additionally adjusted for BMI (continuous) and waist circumference (continuous). Similar models were used for intake of SFA in grams per day. Intakes of individual SFA or SFA from specific food sources were separately evaluated per 1 SD of intake and entered into Cox models as continuous variables. We used the same adjustment models as described above, except that we additionally adjusted for the sum of all other consumed SFA.Cox proportional hazard regression models were used to calculate HRs with 95% CIs for the association between SFA intake and risk of T2D. Total SFA intake was evaluated per 1% of energy and entered as a continuous variable into Cox regression models. In addition to a crude model which was adjusted for total energy intake (Model 1), four models were constructed to adjust for potential confounding. Model 2 was adjusted for sex (men or women) and age at baseline (continuous). Model 3 was additionally adjusted for lifestyle and demographic factors: alcohol consumption level (six categories), smoking (three categories), physical activity (four categories), and education level (three categories). Model 4 was additionally adjusted for dietary factors (continuous): energy-adjusted intake of trans fatty acids, total carbohydrates, animal protein, and vegetable protein) [Cox models were converted into substitution models to estimate the risk of T2D when energy intake from total SFA was substituted with an equal amount of energy from each of the other macronutrients , protein) . We choo2), family history of T2D (without family history and with family history), energy reporting status  and sex (men and women) were estimated using a likelihood ratio test and by including continuous interaction terms in the multivariable adjusted model (model 5). The analysis was repeated in the same population after excluding the first 2 years of follow-up to minimize the possibility of reverse causation. The analysis was also performed in the population after excluding prevalent cases of cancer or cardiovascular disease or hypertension or hyperlipidaemia and participants who had a stroke or myocardial infarction, due to their possible dietary changes caused by the illness. Furthermore, in additional analyses, we estimated the associations between non-SFA fatty acids derived from different food sources (per 1 SD of intake) and T2D risk, to see whether we can actually tease SFA apart from other fatty acids derived from the same food source in relation with T2D.The proportional hazards assumption was tested by calculating Schoenfeld residuals and visual inspection of log–log plots, no deviation was detected. Interactions of total SFA intake (en%) with BMI categories , and P-values < 0.05 (2-sided) was considered as statistically significant.trans fatty acids, animal protein, cholesterol, vitamin E, vitamin D and calcium, and lower intakes of vegetable protein, carbohydrates, fibre and alcohol. Dietary GI and intake of PUFA were similar across SFA intake levels.In this study population , participants with a relatively high SFA intake were on average older women with a lower education level and were more likely to be a smoker and less devoted to physical activity. They also tended to have a higher BMI and waist circumference, a higher blood pressure, but were less likely to have hyperlipidaemia Table . Furtherr = 0.92), myristic and pentadecylic acids (r = 0.92), myristic and margaric acids (r = 0.85), pentadecylic and margaric acids (r = 0.88) . SFA from specific food source was highly correlated with total fatty acids from that food source, as well as the intake of the food source itself .The mean ± SD baseline intake of total SFA in the study population was 14.0 ± 2.6 percentage of energy. More than 95% of the population surpassed the upper intake limit of 10% of energy per day recommended by the Health Council of the Netherlands. The long-chain SFA palmitic acid (51.1%) and stearic acid (25.2%) represented most of the SFA intake . Cheese (17.0%), meat (16.9%), milk and milk products (15.8%) were the main food sources of SFA . High Pearson’s correlations were observed between palmitic and stearic acids . This result was similar when intake of SFA was modelled in grams per day  , no significant association between intake of energy from total SFA with risk of T2D was observed , myristic acid , margaric acid  and odd-chain SFA . No significant associations were observed for intakes of short- and medium-chain SFA (butyric through capric), palmitic, pentadecylic and stearic acids.Table per SD increase: 0.90; 95%I 0.83, 0.98) after multivariable adjustment (model 5), but not for milk and milk products derived SFA . Higher intake of soft and liquid fats derived SFA was associated with a higher risk of T2D . No significant associations were observed for intake of SFA from other food sources  or carbohydrates  was associated with a significantly higher risk of developing T2D. Surprisingly, we also observed an increased T2D risk when substituting SFA with vegetable protein  or PUFA . Substituting SFA with carbohydrates differing in GI values resulted in differences in T2D risk: substitution with high GI carbohydrates associated with a higher risk of T2D , whereas substitution with low- or medium GI carbohydrates did not relate to T2D risk. No significant association was observed with substitution of SFA with MUFA.Table P values: 0.13–0.99) and energy reporting status  was found. Moreover, no meaningful effect modifications by baseline BMI and sex were observed for the relations of SFA and T2D , but interactions existed between sex and substituting SFA with animal protein and PUFA . Stratification for sex in substitution models indicated a significant higher risk of T2D in women when substituting SFA with animal protein or PUFA, whereas this association was not present in men . Our results did not materially change after excluding the first 2 years of follow-up , or restricting analyses by including only baseline healthy participants . Associations between non-SFA fatty acids from specific food sources and T2D risk were fairly similar to associations between SFA from that food sources and T2D risk .No significant effect modification of family history , it is difficult to conclude whether the observed inverse association of cheese derived SFA is due to (particular) SFA, cheese as a whole product, or other constituents present in cheese such as calcium [per SD increase: 1.10; 95% CI 1.02, 1.19) is also in line with existing evidence [per SD increase: 1.03; 95% CI 0.95, 1.11).The associations we observed for individual SFA correspond to our findings for SFA derived from different food sources. To our knowledge, this is the first observational study that investigated SFA from different food sources in relation to incident T2D. We observed that dietary SFA derived from cheese was inversely related to T2D risk. This finding is supported by previous studies that found intake of cheese to be associated with lower T2D risk , 32, alt calcium . Moreove calcium . Additio calcium . Additio calcium , 35. Ourevidence , 36. Whetrans fatty acids at the beginning of the study. During the mid-1990s, there was a notable reduction of trans fatty acids content in margarines. This may have led to residual confounding by underestimated trans fatty acids intake, consequently affecting the observed association of substituting SFA with PUFA. This may also explain why we found higher T2D risk with SFA from soft and liquid fats. Furthermore, compared to the Nurses’ Health Study , the intake range of PUFA is relatively small in our study . As we only found adverse association for substituting SFA with animal protein or PUFA in women in the gender-stratified analysis, the result could be largely driven by the large proportion of women in our study. Altogether, the increased T2D risks when substituting SFA by proteins, carbohydrates, and especially PUFA, needs to be interpreted with caution.As far as we know, no previous studies have investigated substitutions of SFA with protein, carbohydrate nor MUFA in relation to T2D risk. We found substituting SFA with carbohydrate, animal protein, vegetable protein or PUFA was associated with higher T2D risk, but not with MUFA. Previous studies suggest that animal protein is related to a higher T2D risk –39, whictrans fatty acid intake. Further investigation is still warranted, especially in populations with other dietary patterns contributing to SFA intake, and with more variation in intake of PUFA, to draw further conclusions of the relations of SFA with T2D risk.In conclusion, our findings emphasize the importance of distinguishing between the types and food sources of SFA in relation to T2D risk. Our study suggests that individual SFA that exist to a large extent in cheese, and SFA derived from cheese, relate to a lower T2D risk. Regarding substitution of SFA with other macronutrients, we cannot exclude the possibility that our results reflect inverse associations of dairy-derived fatty acids with T2D and/or residual confounding by Below is the link to the electronic supplementary material.Supplementary material 1 (DOCX 255 KB)


Cue-approach training (CAT) is a novel paradigm that has been shown to induce preference changes towards items without external reinforcements. In the task, the mere association of a neutral cue and a speeded button response has been shown to induce a behavioral choice preference change lasting for months. This paradigm includes several phases: after the training of individual items, behavior change is manifested in binary choices of items with similar initial values. Neuroimaging data have implicated the ventromedial prefrontal cortex (vmPFC) in the choice phase of this task. However, the neural mechanisms underlying the preference changes induced by training remain unclear. Here, we asked whether the ventromedial frontal lobe (VMF) is critical for the non-reinforced preference change induced by CAT. For this purpose, 11 participants with focal lesions involving the VMF and 30 healthy age-matched controls performed the CAT. The VMF group was similar to the healthy age-matched control group in the ranking and training phases. As a group, the healthy age-matched controls exhibited a training-induced behavior change, while the VMF group did not. However, on an individual level analysis we found that some of the VMF participants showed a significant preference shift. Thus, we find mixed evidence for the role of VMF in this paradigm. This is another step towards defining the mechanisms underlying the novel form of behavioral change that occurs with CAT. •We tested participants with focal lesions involving ventromedial frontal lobe (VMF).•Participants performed a behavioral change task without external reinforcements.•The VMF group did not exhibit behavior change but some individuals in it did.•We find mixed evidence for the role of VMF in this paradigm. This knThe CAT procedure includes several phases. First, participants rank the stimuli to indicate their subjective preference. Based on the initial ratings, items are chosen to be associated with the button press and the cue in the subsequent training phase. During training, the entire stimulus set is presented on the screen several times with some of the items consistently associated with the cue and the button press (“Go” items). Then, preference change is probed in a binary choice phase where pairs of items of similar initial rankings are pitted against each other. If training did not influence preference, participants are expected to be indifferent between the two items (i.e. at chance). While prior behavioral studies in healthy young people have shown that CAT produces a replicable group effect of about 60–65% preference of the trained Go items, the cognitive and neural mechanisms underlying this effect remain unclear. Eye-gaze data during the probe phase showed greater gaze towards Go items even when they were not chosen, compared to No-Go items. This suggests that the induced shift of preference in the CAT relies on attentional mechanisms to transform the low level visual, auditory and motor features of the training into an updated value of the associated items. Functional magnetic resonance imaging (fMRI) studies of CAT have implicated the ventromedial prefrontal cortex (vmPFC) in the probe phase of the task, with greater activations in vmPFC for choices of Go items compared to choices of No-Go items modulated by the preference for individual items . In the VmPFC and adjacent medial orbitofrontal cortex  have been implicated in representation and dynamic updating of value both in animals and humans . In humaActivation within vmPFC during choice in the fMRI studies of CAT suggests that this region might be necessary for the value update that underpins preference change in CAT. Alternatively, other structures (e.g. the visuomotor network) encode the value update and vmPFC is merely active during the choice of the preferred item, reflecting the updated value rather than making a causal contribution to the preference change. These two models propose different roles for vmPFC in CAT ; in the 22.1N = 11, mean age = 59.4 [39–78] years, 5 males), were recruited from the Cognitive Neuroscience Research Registry at McGill University. All had fixed, circumscribed lesions of at least 6-months duration (mean duration = 9.3 [5.4–16.5] years). Lesions were due to ischemic stroke, tumor resection, or aneurysm rupture. Thirty age-matched healthy control participants were recruited through local advertisements in Montréal. They were free of neurological or psychiatric disease and were not taking any psychoactive drugs. One control participant was excluded from the analysis due to extremely inconsistent choices . For the 29 included in this group, the mean age was 60.5 [44–79] y and 15 were females. All participants provided written, informed consent in accordance with the Declaration of Helsinki and were paid a nominal fee for their time. The study protocol was approved by the local Research Ethics Board. Table 1Participants with focal lesions involving the orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (vmPFC), together referred to here as ventromedial frontal: VMF (2.2www.mccauslandcenter.sc.edu/mricro/) by a neurologist experienced in imaging analysis and blind to task performance. MRIcron (www.nitrc.org/projects/mricron) was used to generate lesion overlap images  brain using MRIcro software  and 20 low-value items (ranked 39–58) were displayed once during each run. Twelve items from the subset  were consistently associated with a Go auditory-cue B. Partic2.3.3Preference change following CAT was evaluated in a probe phase. On each probe trial, two items appeared to the right and left of a central fixation cross and participants were asked to select their preferred stimulus. In each pair, both items were of similar initial value , but only one item was a Go item, i.e. associated with a cue during training. For each pair, participants had 1500-ms to select their preferred stimulus, followed by a 500-ms choice confirmation and a fixation cross for a jittered duration with an average of 3000-ms . The second assessed whether participants remembered which images were associated with the cue (Go/No-Go).2.4Binary choice outcomes were analyzed using a mixed-model logistic-regression (R package lme4 v1.1–13). Group means were compared by a two-sample permutation test (R package Deducer v0.7–9), and 95% confidence intervals were estimated using data bootstrapping.https://www.mccauslandcenter.sc.edu/mricrogl/home).Voxel level lesion analysis was used to test for associations between lesion location and CAT effect. For every voxel in which at least three VMF participants had damage, a permutation test was used to calculate the statistical significance of the difference in Go item choice ratio in the probe phase between VMF participants that had damage within that voxel and those who did not. Images of the results of this analysis were created using the software MRIcroGL  = −0.08, p = 0.96, 95% CI ; (30.1) = 0.70, p = 0.47, 95% CI ).For each participant, we estimated choice consistency as the prediction accuracy of a “leave one out” model. For each of the 300 binary choices, we applied the Colley-matrix algorithm to the remaining 299 choices, which yielded the ranks of the 2 competing items in this trial. For each participant, we defined the choice consistency index as the proportion of trials in which the highest ranked item was chosen (% correct choice predictions). We did not find a difference in choice consistency between the groups  = 1.26, p = 0.29, 95% CI ).We next examined the relationship between choice-difficulty (items’ rank difference) and reaction time. In both groups, there was a negative correlation between the rank difference of a given pair of items and choice reaction time, such that the larger the rank difference between the two items, the faster the choice was made. This correlation was similar in control and VMF groups (r3.2(15.3) = 1.26, p = 0.29, 95% CI ). Similarly, there were no differences between the groups in commission error rate (t(19.3) = −0.17, p = 0.82, 95% CI ) or omission error rate (t(34.3) = 1.35, p = 0.19, 95% CI ) during training.There were no differences between the groups in the button-press reaction time to the tone cue  during training .(control-VMF) mean proportion = 8.89%, OR = 0.652, 95% CI , p = 0.11).Following cue-approach training, the control group showed increased preference for the Go items over the No-Go items during probe (mean proportion = 59.28% (13.6), odds ratio (OR) = 1.58, 95% CI , p = 0.002; 3.3.2random choice probability= 0. 5, For each participant, we calculated the individual probability of obtaining a preference shift. We defined the threshold of individual learning based on the binomial distribution compared to chance: P3.3.3We found two distinct clusters in which Go vs. No-Go choice proportion was different between VMF participants. Participants with damage that included a region within vmPFC chose the Go items less than VMF participants with that sub-region spared. In contrast, those in whom damage affected the right posterior-central OFC chose the Go items more than VMF participants with that region intact. Caution is needed in interpreting these results, as the sample size is small for a voxel-based analysis, the power to detect effects is limited and not homogeneous across VMF and results are not corrected for multiple comparisons.3.3.4(20.7) = −2.79, p = 0.011, 95% CI ). In the control group the choice time of the Go items was faster than choice time of the No-Go items (t(28) = -2.88, p = 0.008, 95%, CI ). In the VMF group there was no difference in choice time of the Go and No-Go items (t(10) = −1.28, p = 0.23, CI ; We found a difference between the control group and VMF group in choice reaction time during the probe phase with longer RTs for the VMF group (t3.3.5(36.2) = −1.35, p = 0.28, 95% CI ).There were no differences between the groups in preference consistency  during probe between the groups (t3.4(37.3) = −1.48, 95%, p = 0.28, CI ). We did not find a difference in the recognition ratio of the experiment items’ training condition between groups (t(15.3) = 3.92, p = 0.29, 95% CI ). There was no difference between the control and VMF in the reaction time to recognition of the experiment items (t(38) = 1.47, p = 0.29, 95% CI ), and no difference between the control and VMF in the reaction time to recognition of the experiment items’ training condition (t(22.8) = 1.15, p = 0.38, 95% CI ).At the end of the experiment, we tested participants’ memory of the items  and of the training condition for the items . We did not find a difference in the proportion of items recognized between the control and VMF groups  both in the binary ranking phase and in the probe phase compared to the control group. While both groups showed a systematic relationship between RT and choice difficulty , as we have seen in other preference paradigms , only the control group was faster to select Go items than No-Go items. There are conflicting reports regarding choice reaction-times and VMF damage. A recent study showed that allowing participants extra time to make a choice eliminated the CAT effect . When weBeyond our main aim to shed light on the neural mechanism of CAT, this study is novel in several additional aspects. First, we show for the first time that a sample of healthy elderly participants (mean age 60.5) express a CAT effect (at the group level), similar to that observed in previous samples of young healthy adults (mean age 24;


Globally, Gestational Diabetes Mellitus (GDM) is rising, but it is a neglected health threat to mothers and their children in low resource countries. Although, GDM is known in Ethiopia, information regarding it remains scarce by recent diagnostic criteria. Therefore, this study aimed to determine the prevalence of GDM and associated factors among women attending antenatal care at Gondar town public health facilities, Northwest Ethiopia.A cross-sectional study was conducted among 1027 pregnant women selected by the systematic random sampling technique. The universal one-step screening and diagnostic strategy was done using a two-hour 75 g oral glucose tolerance test. GDM was diagnosed using updated diagnostic criteria (2017 American Diabetes Association (ADA) or 2013 World Health Organization (WHO) or modified International Association of the Diabetes and Pregnancy Study Groups diagnostic criteria (IADPSG)). Binary logistic regression model was used to identify factors associated with GDM.Of the total 1027 pregnant women, 12.8% (95% CI: 10.8–14.8) were diagnosed with GDM. Overweight and/or obesity (MUAC ≥28 cm) , previous history of GDM , family history of diabetes , low physical activity , inadequate dietary diversity , and antenatal depression  were significantly associated with GDM.The prevalence of GDM among women attending antenatal care at Gondar town public health facilities was high. Previous history of GDM, antenatal depression, family history of diabetes, low physical activity, overweight and/or obesity and inadequate dietary diversity were significantly associated with GDM. Routine screening of pregnant women and healthy lifestyle are strongly recommended. The World Health Organization (WHO) defined “Gestational Diabetes Mellitus (GDM) as glucose intolerance first detected during pregnancy” . VariousGlobally, GDM affects an estimated 15% of the pregnant women, 87.6% of the hyperglycemia were in low and middle-income countries. It is one of the challenging health problems of sub-Saharan African countries .A review indicated that the occurrence of GDM in sub-Saharan Africa was 14%  and MiddAccording several studies, the increasing occurrence of GDM was related to advanced age, family history of diabetes, inactive physical activity, obesity, and risky behaviors –15. StudGestational diabetes mellitus commonly identified during the second or third trimester of pregnancy as a result of the placental hormone plays an important role in the adverse effect on glucose metabolism . As pregAfter the pre-existing diabetes (overt diabetes) is ruled out at the first antenatal visit, the recommended oral glucose tolerance test (OGTT) has to be performed at 24–28 weeks of pregnancy , 22. HowRecognizing GDM offers an opportunity to reduce adverse pregnancy outcomes and improve the lifestyle to prevent the occurrence of diabetes in the future , 24. MorThe study was conducted at selected Gondar town public health facilities. It included one tertiary facility called University of Gondar Comprehensive Specialized Hospital (UOGCSH) and four health centers namely, Azezo, Gondar polyclinic, Woleka, and Maraki. Gondar town is located in the Northwestern part of Ethiopia, 747 km from Addis Ababa , and 170 km from Bahirdar . It has 12 sub-cities with 12 urban and 10 rural kebeles . Based on the 2014 population projection and census of the Central Statistical Agency (CSA) of Ethiopia , the totA cross-sectional study was conducted among a cohort of pregnant women receiving antenatal care at selected public health facilities from March 30, 2018 to January 4, 2019. The required sample size was determined using the single population proportion formula with the following statistical assumptions: a survey conducted by Management Sciences for Health (MSF) reported the prevalence of GDM among urban women in Tigray, Northern Ethiopia as 13% , a 95% cWhere, n = the sample size, Z = the desired level of the confidence interval, P = proportion of GDM, and d = margin of error. The minimum required sample size for significant result was 965, however we have added 15% by considered the non-response and attrition rates throughout the study period.Therefore a total of 1110 were recruited for the study. A two-stage sampling technique used to invite pregnant mothers and include them in the cohort. On the first stage, one hospital and four health centers were selected by the simple random sample; on the second stage, pregnant women who fulfilled the inclusion criteria were chosen using the systematic random sampling technique.+ 6 weeks of gestational age and singleton pregnancy. But pregnant women who had pre-existing diabetes mellitus or overt DM, chronic diseases, medications that may affect glucose metabolism such as steroids, β-adrenergic agonists, anti-psychotic drugs [During the study, 1110 new antenatal care attendants were invited and screened to participate in the study. Women were enrolled if they were aged 18 years or more with 20–23ic drugs , 27 were2, MUAC ≥28 cm, age ≥ 35 years, previous macrosomia, glycosuria, history of GDM, family history of diabetes, previous poor pregnancy outcome or developed pregnancy-related complications) were advised to repeat the test at 32–36 weeks even if their OGTT results were negative at regular tests and GDM diagnosis ascertained by the second test.Screening at first visit was carried out according to the recommendations of the International Diabetes Federation (IDF) , ADA 2828, and WA structured and pretested questionnaire was developed and interviewer-administered to all study participants The questionnaire was prepared in English and then translated to Amharic  and then translated back to English by language experts to check its consistency , marital status, religion, ethnicity, level of education, occupational status, average monthly income, family history of diabetes, previous history of GDM and birth weight of the previous child, behavioral and lifestyle characteristics, such as current exposure to alcohol, coffee, antenatal depressive symptoms, physical activity, and dietary diversity. Gestational age estimations were based on a reliable LNMP combined with first-trimester ultrasonography (if available). Additionally, socio-demographic information , obstetric history, medical history, hemoglobin) were retrieved from ANC cards.The short form International Physical Activity Questionnaire (IPAQ) was used to assessed the physical activities that women do as part of their everyday lives . The IPADietary diversity was assessed using a 24-h food recall method by the Food and Nutrition Technical Assistance (FANTA) 2016 version woman’s minimum dietary diversity measurement tool . It contA mother was asked, “How often have you drunk coffee since your pregnancy?” If the answer was “daily” or “sometimes in a week” the mother was categorized as exposed to coffee. She was also asked, “How often have you drunk alcohol since your pregnancy?” If the answer was “daily” or “sometimes in a week” the mother was labelled as exposed to alcohol.The mid-upper arm circumference (MUAC) was measured on the left arm using a non-stretchable measuring tape. As the result of most of the pregnant women could not recall their weight before conception, it was difficult to determine BMI. MUAC was as reliable measure due to quite stable during the course of pregnancy and highly correlated to the BMI before conception , 33. PreFor measuring blood pressure (BP), the pregnant women were asked to take rest for at least 5 min in sitting positions if they were exerted. Then, the pressure was measured on the right arm using normal cuffs fitted for adults with a standard sphygmomanometer placing the stethoscope bell lightly over the brachial artery. The average systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded in mmHg after two readings were taken with an intermission of 5–10 min. Hypertension was considered to be present if the systolic and diastolic blood pressures were greater than or equal to 140 mmHg and 90 mmHg, respectively.Antenatal depression symptoms were measured by using the Edinburgh Postnatal Depression Scale (EPDS) screening tool developed  and vali+ . . Multicollinearity was checked by using the variance inflation factor (VIF). Adjusted Odds Ratio (AOR) with a 95% confidence level was estimated to show the strength of association, and a P-Value < 0.05 was used to declare statistical significance in the multivariate analysis.All data were entered into Epi Info™ 7 software, then exported to statistical package for the social sciences (SPSS) version 22.0  for analysis. Descriptive statistics, like frequency, percentage, and mean, SD, and the range were used for the presentation of variables. Tables and figure were also used for data presentation. Categorical variables were expressed as proportions and chi-square analysis was performed to compare proportions. Student t-test was used to compare means for normally distributed variables. Binary logistic regression model was used to identify factors associated with GDM. Variables with P = 0.835), maternal age (P = 0.0691), parity (P = 0.544), gravidity (P = 0.109), marital status (P = 0.734), MUAC (P = 0.08), employment status (P = 0.056). However women with complete data were on average attended secondary educational level and above and had higher income level than those who were excluded in the analysis.Out of the 1110 pregnant women invited to participate in the study, 83 mothers  were excluded. The characteristics of pregnant women who of included and excluded in the final analysis were similar in terms of key socio demographic variables such as residence  years. Most of the participants (91%) lived in urban areas, 92% were married, and 60.5% unemployed. Five hundred and ninety-eight (58.2%) of women had secondary education and above. The mean of the MUAC was 24.77 (SD ± 3.08) cm, systolic blood pressure was 112.07 (SD ± 11.91) mmHg, and diastolic blood pressure was 71.91 (SD ± 10.22) mmHg. The mean hemoglobin level of the pregnant women with GDM and normal glucose level was 12.39 (SD ± 1.80) g/dl and 12.64 (SD ± 1.74) g/dl, respectively. Nearly half, 504 (49.1%) of the women were nulliparous. Sixty-two (6%) had a family history of DM (Table P = 0.476 and P = 0.311 respectively. Eighty-nine (8.7%) of the pregnant women had antenatal depression symptoms  and adequate dietary diversity 51.5% vs 27.5%) than women with GDM. Concerning exposure to drinking alcohol and coffee, no statistically significant difference was observed among women with normal glucose profile and GDM at 7.5% thanOf the total of 588 pregnant women who had prior pregnancy history, 71(12.1%) had macrocosmic babies, 166 (28.2%) history of abortion, 38 (6.5%) history of stillbirth, 42 (7.1%) history of preterm labor, 97(16.5%) history of caesarean delivery, and 54 (9.2%) previous GDM (Table p < 0.001). Pregnant women with GDM had the mean fasting, one-hour and two-hour glucose level of 100.81 (SD ±15.88) mg/dl, 163.82 (SD ± 28.42) mg/dl, and 138.76 (SD ±23.40) mg/dl, respectively. Whereas, women with normal glucose profiles had the mean fasting, one-hour and two-hour glucose levels of 78.3 (SD ± 9.55) mg/dl, 137.31 (SD ±22) mg/dl, and 116.22 (SD ±17.4) mg/dl, respectively ; 118 (90%) of them were diagnosed at regular OGTT and the rest 13 (10%) at late OGTT. At regular OGTT test (24–28 weeks), the mean fasting, 1 h, and 2-h glucose levels of the pregnant women were 81.17 (SD ± 12.96) mg/dl, 140.69 (SD ±24.55) mg/dl, and 119.10 (SD ± 19.75) mg/dl, respectively. The plasma glucose levels taken at the three time points of the OGTT were significantly different for women with GDM and normal glucose level , level of physical activity, dietary diversity, and antenatal depression were associated with GDM. However, on multivariate logistic regression, variables GDM was independently associated with being overweight and/or obese women (MUAC ≥28 cm) AOR = 2.25; 95% CI: 1.18–4.26), previous history of GDM , family history of diabetes , low physical activity , inadequate dietary diversity , and antenatal depression  were significantly associated with GDM . The result was consistent with the Management Sciences for Health (MSF) reported the prevalence of GDM among urban women in Tigray, Northern Ethiopia (13%), but the study used only a fasting blood glucose test which means it did not consider internationally recommended diagnostic criteria , Egypt (.8–14.8. Women with the mid-upper arm circumference of ≥28 cm were two times more likely to develop GDM than women with MUAC < 28 cm. This finding agreed with findings from Tanzania by Mwanri et al.  and NjetPregnant women with a previous history of GDM had six fold more increased odds of developing of the problem during the pregnancy at the moment. This finding was in line with those of studies in Egypt , NigeriaLow physical activity increases the likelihood of developing GDM at least three times compared to a high level of physical activity during pregnancy. This finding was in line with a study conducted in Vietnam , a meta-Pregnant women with inadequate dietary diversity had two times higher GDM than their counterparts. Healthy eating habits and the consumption of food from a variety of dietary groups during pregnancy contributes to the prevention of pregnancy-related complications . DespiteWomen with antenatal depression had four times higher GDM compared to women with non-depressive symptoms. The finding is supported studies by Morrison et al.  showed aThis study has strengths and limitation. The strength of the study was that it employed recent and universal screening tool to detect GDM and it has been done for all pregnant women at 24–28 weeks gestation. They underwent a two-hour 75 g OGTT, and updated standard reference cutoff values were considered. Besides, for pregnant women who had risk factors for GDM and whose OGTT results were negative at the regular test were tested again at late gestational age. WHO recommends that in settings where laboratories or proper storages and transport of blood samples is not guaranteed, which is the case in resource limited countries like Ethiopia, the use of point of care tests may influence the result . HoweverIn conclusion, the overall prevalence of GDM was found to be high and a major public health concern among pregnant women in Gondar town, Northwest Ethiopia. Previous history of GDM, antenatal depression, family history of diabetes, low physical activity, overweight and/or obese women and inadequate dietary diversity were significantly associated with GDM. Given the imminent burden of obesity, unhealthy eating, and physical inactivity, a substantial threat of GDM is anticipated in Ethiopia. This may be an appropriate time to think about considering the need for routine screening of GDM to reduce the impact of the diseases in the country. In this regard, our study may serve as a baseline for larger studies and background evidence for policy debates for universal GDM screening in the existing health care system. Integrating healthy lifestyle choices into ANC services, such as reduced obesity, healthy eating, improvement in physical activities and effective strategies for coping with depression are strongly recommended.Additional file 1. English version consent form and questionnaire for GDM survey among women attending ANC at Gondar town public health facilities, Northwest Ethiopia.Additional file 2. The specifications of the HemoCue Glucose B-201+ glucometer.


Routine cine cardiovascular magnetic resonance (CMR) allows for the measurement of left atrial (LA) volumes. Normal reference values for LA volumes have been published based on a group of European individuals without known cardiovascular disease (CVD) but not on one of similar United States (US) based volunteers. Furthermore, the association between grades of LA dilatation by CMR and outcomes has not been established. We aimed to assess the relationship between grades of LA dilatation measured on CMR based on US volunteers without known CVD and all-cause mortality in a large, multicenter cohort of patients referred for a clinically indicated CMR scan.n = 11,613) were obtained. Data analysis was performed on a cloud-based system for consecutive CMR exams performed at three geographically distinct US medical centers from August 2008 through August 2017. We identified 10,890 eligible cases. We categorized patients into 4 groups based on LAVi partitions derived from US normal reference values: Normal (21–52 ml/m2), Mild (52–62 ml/m2), Moderate (63–73 ml/m2) and Severe (> 73 ml/m2). Mortality data were ascertained for the patient group using electronic health records and social security death index. Cox proportional hazard risk models were used to derive hazard ratios for measuring association of LA enlargement and all-cause mortality.We identified 85 healthy US subjects to determine normal reference LA volumes using the biplane area-length method and indexed for body surface area (LAVi). Clinical CMR reports of patients with LA volume measures  months. On univariate analyses, mild [Hazard Ratio (HR) 1.35 ] and severe LA enlargement [HR 2.14 (95% CI 1.81 to 2.53)] were significant predictors of death. After adjustment for significant covariates, moderate [HR 1.45 (95% CI 1.1 to 1.89)] and severe LA enlargement [HR 1.64 (95% CI 1.29 to 2.08)] remained independent predictors of death.The distribution of LAVi from healthy subjects without known CVD was 36.3 ± 7.8 mL/mLAVi determined on routine cine-CMR is independently associated with all-cause mortality in patients undergoing a clinically indicated CMR. Left atrial (LA) dilation is associated with various cardiac disorders, such as valvular heart diseases , 2, leftCardiovascular magnetic resonance imaging (CMR) is the gold standard for measuring cardiac chamber volumes due to its superior accuracy and precision compared to other imaging modalities –18. AlthOur first objective was to define normal LA volumes for healthy US subjects by CMR based upon routinely acquired cardiac imaging planes using the biplane area-length method. In our second objective, we explored the association of LA size with all-cause mortality in a large cohort of patients referred for clinical CMR. We further assessed for the persistence of such an association after adjusting for clinically relevant variables, bi-ventricular ejection fraction (EF), and LV myocardial scar.n = 85) without any known CVD were recruited from Houston Methodist between October 2008–July 2017 to undergo CMR for assessment of LA volumes. LA volumes were calculated using the biplane area-length method. Height, weight, blood pressure and heart rate were obtained from each subject at the time of the scan. Body surface area (BSA) was calculated using the Mosteller formula  and Bias: 1.84 , Site 1 [n = 30] ICC: 0.95  and Bias: 2.6 , Site 2 [n = 30] ICC: 0.94  and Bias: 5.2 , and Site 3 [n = 30] ICC: 0.92  and Bias: -2.3 ).In our healthy cohort we derived a mean LAVi of 36.3 (standard deviation [SD] 7.8) mL/m2Normal – 21 to 52 mL/m2Mild – 52 to 62 mL/m2Moderate – 63 to 73 mL/m2Severe – greater than 73 mL/mWe categorized our clinical patients into four groups based on their LAVi cutoff values:P < 0.001), Blacks  (WRS Asians and Black P = 0.014) or other races  (WRS Asians and Others P < 0.001).Compared with healthy volunteer subjects, the clinical patient cohort was older and had a slightly higher BSA. Baseline characteristics of the patient population are described Table . We founP < 0.001).There were 835 (7.7%) all-cause mortality events in the total cohort. There was a significant increase in the prevalence of mortality with increasing severity of LAVi enlargement  (P = 0.003), moderate  and severe  LA enlargement were robust predictors of mortality  and severe LA enlargement  remained significant predictors of mortality (Table P = 0.08), history of hypertension  and LV mass  did not show significance on the multivariate analysis (Model 3). Severe LA enlargement remained an independent predictor of mortality in various subgroup analyses  and multivariate analysis .On univariate analysis, older age, BMI, lower systolic and diastolic blood pressure, faster heart rate, lower eGFR, inpatient hospitalization status, history of hypertension, history of diabetes mellitus, history of dyslipidemia, prior myocardial infarction, decreased indexed LV stroke volume, decreased LV EF, increased LV mass, larger LV scar and decreased RV EF were significant predictors of mortality. Mild  , 27–29. The numerous mechanisms and pathways of LA enlargement have not been completely understood. Some of the most common causes of an enlarged LA are mitral and aortic valve disorders , 2, hypeOur study had limitations. The patient population selected for the study had at least 1 clinical indication for CMR. This introduces a selection bias of having a relatively symptomatic group of people as the study cohort, in comparison to a general population. The data we gathered through CloudCMR may not have included all clinically relevant variables. Hence not all significant variables, such as biomarkers of increased mechanical load and wall stretch, were available on all patients. However, such biomarkers are not routinely assessed in the outpatient setting. LA volumes measured in the patient cohort was derived at the time of clinical reporting by board certified physicians from 3 geographically distinct institutes. This could potentially be a source of discrepancy and bias in LAVi measurement. LA volumes were measured using the biplane area-length method, which is not the gold-standard method of measuring LA volume. There is the potential for foreshortening which could have affected the LA volume calculation. However, we feel that the cost of accuracy is compensated for by practicality, as this method can be performed on essentially all clinical cine-CMR studies. Approximately 9% of the patient population had atrial fibrillation at the time of our scan, in which case prospective triggering was commonly utilized to acquire cine images. Although cine image quality can be affected in patients with arrhythmias, the ventricular end systolic phase was always captured and hence may not affect the measurement of maximum LA volume significantly. Our database was constructed from patients from 3 different sites, with each site having multiple CMR technologists and board-certified level 3 physician readers, which could introduce heterogeneity in measuring techniques of LA volumes. Nevertheless, this aspect of our study supports the external validity and generalizability of our findings. The number of death events recorded in CloudCMR was reliant on the electronic health records and SSDI. This could slightly underreport the actual number of deaths in the cohort due to an absence of direct patient contact and status verification. Lastly, the CloudCMR database did not have the capability to capture clinical outcomes other than death at the time of our query. Therefore, we were unable to investigate the association of LA size with heart failure events or other cardiovascular endpoints.CMR is considered a gold standard technique at measuring cardiac chamber volumes. We showed LA enlargement measured by routinely performed 4- and 2- chamber cine-CMR images demonstrates a strong independent association with all-cause mortality. We also established LA enlargement classification by standard deviation method correlated precisely with risk of mortality. Further studies are needed to supplement the classification of LA enlargement severity using CMR, based off of data observing mortality, heart failure admissions, and other cardiovascular events.


Possible cardiotoxicity of sofosbuvir in humans has not been demonstrated yet. Also, since HCV can exert deleterious effects on hearth function, it is of interest to know whether HCV eradication provides any benefits using global longitudinal strain (GLS), a measure of left ventricular function more reliable than ejection fraction (EF).Patients eligible for treatment with the combination therapy for HCV were invited to perform a transthoracic cardiac ultrasound at four different time points: before starting treatment, after one month, at the end of treatment and, after six month. Left ventricular function was measured with both EF and GLS.From March 2015 to December 2016, 82 patients were enrolled. Fifty-six percent patients were males. Mean age was 66.12 (SD: 9.25) years. About 20% patients did not present any cardiovascular risk factors or comorbidities. A worsening trend of GLS was observed. Variations were not found to be statistically significant when EF was studied along the follow-up. However, when GLS was studied, its variations were found to be statistically significant indicating a worsening effect, albeit with different trends in patients who underwent treatment for three months compared to six months. Worsening of GLS was found to be statistically significant even after adjusting for body mass index and liver fibrosis, independently from treatment duration.Our results showed unexpected worsening of left ventricular function when measured through GLS after HCV treatment response induced by DAAs including sofosbuvir. Although this result is not proven to be clinically significant, the safety profile of sofosbuvir-based regimens needs to be studied further.The online version of this article (10.1186/s12879-018-3426-9) contains supplementary material, which is available to authorized users. Extra-hepatic manifestations  occur in about 70% of patients infected by hepatitis C virus (HCV) –3. AmongAnimal studies reported death for cardiac causes after administration of a sofosbuvir metabolite at blood concentrations much higher than the therapeutic index used in humans . CurrentLeft ventricular function (LVF) is routinely evaluated through the ejection fraction (EF), calculated by means of the modified Simpson method in current clinical practice, with the use of trans-thoracic echocardiography . Trans-tMore recently, the global longitudinal strain (GLS) was developed as a more reliable index to measure left ventricular function . Indeed,In the present study, we aimed at measuring possible changes of cardiovascular function in patients with chronic HCV infection before and after sofosbuvir-based regimens, using both left ventricular EF and GLS. The latter was chosen as advanced biomarker to measure the effect.Mater Domini” teaching hospital in Catanzaro , according to the criteria set by the Italian Medicinal Agency (AIFA) .Patients were assessed at four time points: baseline , after one month, at the end of the treatment course (either month 3 or month 6), and after 6 months from the end of treatment (off treatment follow-up).Cardiac ultrasound was performed at baseline and at each follow-up using trans-thoracic Vivid E9 ultrasound. Speckle tracking echocardiography analysis was performed from apical views. Standard grayscale 2D images were obtained at a frame rate of 70–90 frames/s during three cardiac cycles and software package  was used for offline analysis. Two expert cardiologists (L.G.D.A. and J.S.) performed cardiac ultrasound blinded of previous examinations, type and length of prescribed treatments.2), normal (BMI = 18.5–24.9 Kg/m2), over-weighted (BMI = 25–29.9 Kg/m2) or obese (BMI ≥ 30 Kg/m2) [At baseline, risk factors for CVD , and heart diseases were carefully investigated. Patients were considered to be underweighted (BMI ≤ 18.4 Kg/m0 Kg/m2) .Complete blood count, AST, ALT, total and fractioned bilirubin, and HCV RNA were recorded at enrolment and each follow-up points. Indirect indices of fibrosis, such as Fibrosis 4 index (FIB-4) and AST to platelets ratio (APRI) score were calculated at baseline and at month 6 after the end of treatment –23. At tDrug interactions with other co-medications were carefully evaluated using the application HEP Drug Interaction . Drugs wMater Domini” teaching hospital in Catanzaro  and was conducted in accordance with the guidelines of the Declaration of Helsinki and the principles of Good Clinical Practice [This study was coordinated by the Infectious and Tropical Diseases Unit in collaboration with the Cardiology Unit of “Practice –27. The To adjust the analysis for treatment duration, the enrolled patients were ranked into two groups: group A, i.e. patients with indication for a 3 month treatment, and group B, i.e. patients with indication for a 6 month treatment with DAAs. Study parameters were expressed as means  or proportions as appropriate. FIB-4, APRI score, alpha-fetoprotein, creatinine, cholesterol, glucose, haemoglobin, and triglycerides values at baseline were compared with those at last follow-up using Student’s t-test for paired data. We evaluated the temporal trends of AST, ALT, platelet count, total bilirubin, EF and GLS using univariate mixed models for repeated measures. We also assessed the temporal trend of GLS using a multivariate mixed model adjusting for BMI, fibrosis and duration of treatment (3 or 6 months). Moreover, although in the analysis hypertension was not a confounder by definition, since it could have been associated with the outcome (GLS) but not with the exposure, we tested whether hypertension was a effect modifier.Lastly we explored whether ribavirin could have a role on the change of GLS over time using a mixed model with an interaction term between ribavirin and time.All statistical tests were two-sided, assuming a level of significance of 0.05 and were performed using Stata software version 12.0 .Among 109 patients who started a DAA treatment during the study period, 87 subjects were eligible and 82 were enrolled . Amongst these patients, 71/82 (86.6%) continued follow-up until the end of the study  patients met AIFA criterion 1 or 4. Nine patients had extra-hepatic manifestations (AIFA criterion 3), and one patient had a HCV RNA relapse after liver transplantation (AIFA criterion 2). Fifty-seven (69.5%) patients were prescribed a treatment lasting for three months, while 25 (30.5%) were prescribed a treatment for six months. The baseline characteristics of patients are described in Table Prescribed treatments and related outcomes are described in Table At baseline, mean EF and GLS were 56.7% and − 20.9%, respectively. Hence, 20/82 24.1%) patients had abnormal EF (< 55%), while 3/82 (3.6%) had abnormal GLS (> − 16.5%) according to litereature standards , 29. Com% patientp = 0.031)    Fig. . By cont97) Fig. . The risp = 0.388). We also tested whether ribavirin could have a role on the change of GLS over time and in a mixed model with an interaction term between ribavirin and time but ribavirin exposure did not exert a statistically significant effect on GLS  or a statistically significant role as effect modifier was not demonstrated .Lastly, we explored whether hypertension was a effect modifier but we did not found any significant evidences  was stopped after a safety signal of cardiotoxicity . In thisHowever, the clinical significance and the long-term effects of the GLS variations in our patients are unknown. Correlations with other biomarkers of heart dysfunction  –34 and lSince we did not find any significant correlations between GLS and ribavirin or anaemia (data not shown), we may hypothesize that these factors were not implicated. However, we have to take into account that the small sample size reduced the power to detect a smaller effect of ribavirin, significantly. Indeed, the evidence of a prolonged worsening of GLS after stopping treatment is more consistent with an effect of ribavirin  than with an effect of sofosbuvir . For the same reason, the trend in GLS is more consistent with an immune-mediated phenomenon occurring after viral eradication, so consideration of immune markers could provide better insights on the phenomenon. With regard to hypertension, we did not find any significant evidences of a possible role at interaction model independently from time, but a complete assessment in a multivariable model would require grater numbers and a time-dependent consideration of hypertension as a variable in future studies.In patients treated for three months, we noted an initial improvement of GLS, followed by a progressive worsening. The first phase of improvement could be due to a beneficial reduction of HCV RNA  while apThe associations between worse GLS and smoking or high BMI at baseline was not unexpected, suggesting the importance to quit negative behaviours, such as smoking and unhealthy diet in patients chronically infected by HCV. This is even more relevant if one considers that cardiac function may worsen after treatment, concomitantly with an increase of cholesterol occurring after HCV eradication as demonstrated in our study and confirmed by others . ApproprIn conclusions, if confirmed by datasets from independent cohorts to replicate the data, our results are important because demonstrated for the first time the possible cardiotoxicity of DAA treatments. The same study protocol for patients who are eligible for DAAs treatment with sofosbuvir-free regimens should be applied, in order to evaluate whether worsening of GLS is a specific drug-related or a class effect. While these results should be confirmed in more powerful studies and pathogenic hypotheses should be tested in translational studies, in the meantime a cautious approach should include assessment of cardiac function during DAA treatment, particularly for the most fragile patients, who may benefit from interventions to reduce the risk of cardiovascular diseases both before and after treatment.Additional file 1:Table S1. AIFA  criteria for prescription of a DAA treatment. Table S2. Association between global longitudinal strain (dichotomized on median) and demographical and clinical features at baseline. Table S3. Multivariate mixed model, effect of time, BMI, presence of significant liver fibrosis and duration of treatment on global longitudinal strain. (DOCX 24 kb)