Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes.1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527.In this multicentre, open-label, randomised controlled trial, we recruited women aged 18–40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin . Pregnant CGM users spent more time in target  and less time hyperglycaemic  than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic . Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age , fewer neonatal intensive care admissions lasting more than 24 h , fewer incidences of neonatal hypoglycaemia , and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial  and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy).Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women  to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbAUse of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use.Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research. Type 1 diabetes increases the risk of adverse pregnancy outcomes, including higher rates of pre-eclampsia and caesarean section in mothers, and of congenital anomaly, preterm delivery, perinatal mortality, large for gestational age, and neonatal intensive care admission in infants.9Evidence before this study1c) and macrosomia; however, it used an intermittent, masked continuous glucose monitoring (CGM) device so that patients did not see the glucose values in real time. Another study used intermittent real-time CGM and found no difference in glycaemic control or perinatal outcomes. However, only five women in this study used real-time CGM continuously. Together, these two studies included 225 women of whom 165 had type 1 diabetes. A third small pilot study compared continuous and intermittent CGM in 25 women with type 1 diabetes, and found no difference in glycaemic control or neonatal outcomes; however, the study was not powered for these outcomes. A 2017 Cochrane review of self-blood glucose monitoring among pregnant women with pre-existing diabetes concluded that the evidence is weak regarding the efficacy of continuous glucose monitoring and that additional evidence from well designed, large randomised trials is needed to inform choices of glucose monitoring.We searched PubMed for articles published before June 30, 2017, without restriction on language or start date. We included the search terms (“Diabetes Mellitus” OR “Diabetes”), AND “pregnancy”, OR “pregnancy in diabetics”, AND “continuous glucose monitoring”, AND . We identified three randomised trials that used continuous glucose monitoring in women with pre-existing diabetes during pregnancy, which found conflicting results. Two of the three studies included women with both type 1 and type 2 diabetes. One study found a reduction in glycated haemoglobin  levels during early pregnancy and that despite intensive support , only 40% of women with type 1 diabetes achieve target HbA1c levels after 24 weeks' gestation.Thus, clinical care guidelines recommend that women with type 1 diabetes strive for optimal glycaemic control before and during pregnancy.Continuous glucose monitoring (CGM) provides detailed data on the direction and rate of change of glucose levels.This open-label, multicentre, multinational, randomised, controlled study included two parallel trials: a pregnancy trial and a planning pregnancy trial. Participants were recruited from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA.The clinical study protocol was approved by the Health Research Authority, East of England Research Ethics Committee (12/EE/0310) for all UK sites and at each individual centre for all other sites. All participants provided written informed consent. Full details of the clinical study protocol have been previously published.1c between 6·5–10·0% (48–86 mmol/mol). Women planning for pregnancy were eligible if they had an HbA1c level between 7·0–10·0% (53–86 mmol/mol).We recruited women aged 18–40 years with type 1 diabetes for a minimum of 12 months, receiving intensive insulin therapy via multiple daily injections or an insulin pump, who were pregnant or planning pregnancy. Pregnant women were eligible if they had a live singleton fetus confirmed by ultrasound, were at 13 weeks and 6 days' gestation or less, and had HbARegular CGM users and women with severe nephropathy or medical conditions such as psychiatric illness requiring hospitalisation that could prevent them from completing the trial were excluded. Women using automatic insulin delivery options, such as low glucose suspend pumps, were not excluded.1c . The randomisation schedule was created by a programming manager, encrypted, and maintained in a secure database to which the trial coordinating team and investigators had no access.After enrolment, participants had to complete a run-in phase with a masked CGM device  before they were eligible for randomisation. In the run-in period, glucose values were recorded but were not visible to the user or clinical team. Eligibility required that participants wear the sensor for 6 days, provide at least 96 h of glucose values including a minimum of 24 h overnight, and obtain at least four capillary glucose tests daily. Participants meeting these criteria were randomised to receive either CGM in addition to capillary glucose monitoring (intervention) or capillary glucose monitoring alone (control). Treatments were allocated in a 1:1 ratio via a web-based system that used a computer-generated randomisation list with permuted block sizes and stratification by method of insulin delivery (pump or multiple injections), and baseline HbA1c levels of no higher than 6·5% (48 mmol/mol) during pregnancy and no higher than 7·0% (53 mmol/mol) if planning pregnancy.Participants in the CGM group were provided with a CGM system . They were trained to use the study devices and were instructed to use them daily by their local diabetes or antenatal clinical teams. CGM users were advised to verify the accuracy of CGM measurements using their capillary glucose meter before insulin dose adjustment, as per the regulatory labelling instructions. Participants in the control group continued their usual method of capillary glucose monitoring. Participants in both groups were advised to test capillary glucose levels at least seven times daily  and given written instructions for how to use capillary or CGM measures for insulin dose adjustment, customised for method of insulin delivery. The detailed treatment algorithms have been published previously.In the pregnancy trial, study visits were scheduled at randomisation (≤13 weeks and 6 days' gestation), and at 8, 12, 16, 20, 24, 28, 32, 34, and 36 weeks' gestation. In the planning pregnancy trial, study visits were scheduled at 4, 8, 12, 16, 20, and 24 weeks after randomisation. Women who conceived during the trial continued in their same randomised group and followed the pregnancy study visit schedule. Participants' weights, blood pressure, insulin dose, adverse events, and episodes of severe hypoglycaemia (defined as an event requiring third party assistance) were recorded at each visit. Additional clinic visits or telephone or email contacts would occur if they were part of the centres' usual care protocols or if indicated by clinical need. All scheduled and unscheduled (telephone or email) contacts were documented in the electronic clinical report forms.1c measures were taken at randomisation, 24 weeks' gestation, and 34 weeks' gestation in the pregnancy trial, and at randomisation, 12 weeks, and 24 weeks in the planning pregnancy trial; if a participant conceived before 24 weeks, their final HbA1c measure was taken following confirmation of a positive pregnancy test. All HbA1c measurements were done using the turbidimetric inhibition immunoassay for haemolysed whole blood on the Cobas Integra 700 platform  at a central laboratory . The samples were shipped at the end of the planning pregnancy trial or after delivery of the neonate and collection of the cord blood and were unavailable to participants and health-care teams during the trial. After the visits at 24 and 34 weeks' gestation in the pregnancy trial, and 12 and 24 weeks or following confirmation of a positive pregnancy test in the planning pregnancy trial, CGM measures were obtained using real-time sensors in the CGM group and a masked sensor in the control group. These were repeated, as required, if fewer than 96 h of glucose values were obtained.HbA1c from randomisation to 34 weeks' gestation in the pregnancy trial and to 24 weeks or conception in the planning pregnancy trial.The primary outcome was difference in change in HbAPrespecified secondary glycaemic outcomes for all groups were percentage of time spent in, above, and below the recommended glucose control target range (3·5–7·8 mmol/L); area under the curve for glucose levels; episodes of hypoglycaemia; and glucose variability measures derived from CGM measures. For pregnant women, prespecified health outcomes were gestational weight gain, gestational hypertension, pre-eclampsia, mode of delivery, length of hospital stay, insulin dose, and questionnaires relating to fear of hypoglycaemia, coping with diabetes, quality of life, and satisfaction with monitoring device. Prespecified neonatal health outcomes included preterm delivery, neonatal hypoglycaemia requiring intravenous dextrose, neonatal intensive care unit admission requiring a duration of at least 24 h, cord blood gas pH, total length of hospital stay, birthweight, and macrosomia (birthweight ≥4 kg). Because of differences in gestational age at delivery, we prespecified use of customised birthweight percentiles  that adjust for infant sex and gestational age as well as maternal height, weight, parity, and ethnicity to calculate the birthweight percentile and proportion of infants large or small for gestational age (birthweight percentile >90th or <tenth).We included the following outcomes both as individual and as a composite neonatal measure: pregnancy loss , birth injury, shoulder dystocia, neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress syndrome, or neonatal intensive care admission. To capture clinically important adverse outcomes, neonatal hypoglycaemia was defined as requiring treatment with intravenous dextrose and neonatal intensive care unit admission as requiring a duration of at least 24 h. We measured fetal hyperinsulinaemia and infant adiposity with cord blood C-peptide, anthropometric measurements, sum of skin-folds, and neonatal fat mass.At baseline and trial completion, participants completed the following questionnaires: Blood Glucose Monitoring System Rating Questionnaire (BGMSRQ),Adverse events were captured throughout the study. Reportable adverse events included all serious adverse events other than prespecified protocol exceptions. Maternal death was considered a serious adverse event regardless of whether or not it was caused by severe hypoglycaemia.1c of 0·5%. We assumed a correlation of 0·4 between baseline and follow-up HbA1c, with an SD of 1·1 and up to 20% loss to follow-up during pregnancy; and an SD of 0·8 and 15% loss to follow-up before pregnancy.To achieve 90% power at a two-sided 5% significance level, we planned a sample size of 214 pregnant participants and 110 participants planning pregnancy to detect a between-group difference in HbA1c and insulin therapy (pump or multiple daily injections). We included all randomised women who had a baseline assessment, with multiple imputation of missing HbA1c values using the mice package in R.vs control) and group × time interaction effects. To avoid potential baseline imbalances, we did not include the obstetric and neonatal outcomes of women in the planning pregnancy trial who conceived with those of the pregnancy trial. Analyses of secondary outcomes used all available data without imputation. We used a two-sided significance level of 5% for primary and secondary outcomes without adjustment for multiple comparisons.The primary analysis used ANCOVA to compare treatment arms with adjustment for baseline HbA1c group and method of insulin delivery as covariates.We used logistic regression analyses to estimate the odds of occurrence of an adverse event with 95% CIs by intervention versus control group. We used Poisson regression to calculate the rate of occurrence 95% CIs over the study period (randomisation until delivery). p values are from these models, with baseline HbAClinicalTrials.gov. number NCT01788527.The trial was overseen by a trial steering committee and an independent data safety monitoring board. An interim safety review  was done when 50% of neonates were delivered. This trial is registered with The funders had no role in the trial design, data collection, data analysis, or data interpretation. Medtronic  provided discounted-price insulin pumps and CGM devices. They also had no role in trial design, collection, handling, analysis, or interpretation of data, or the decision to publish. The National Institute for Health Research and Juvenile Diabetes Research Foundation reviewed the manuscript prior to submission but did not play a part in manuscript preparation or revision. DSF and HRM oversaw the conduct of the trial, had full access to all the data, and take full responsibility for the decision to submit for publication.1c levels at randomisation were lower in the pregnant women , whereas we found no between-group differences in participants planning pregnancy. Pregnant participants using CGM also had more unscheduled contacts  and to sensor-related diabetes management issues . We found no difference in contacts for general diabetes management or contacts for other reasons. We noted similar findings among CGM users in the planning pregnancy trial  and participants planning pregnancy (6·2 days per week [IQR 5·2–6·9]). Sensor compliance was generally high with 70% of pregnant participants and 77% of participants planning pregnancy using CGM for more than 75% of the time. Sensor use was highest in later gestation (median 6·5 days [IQR 3·9–7·0] at 25–34 weeks) in pregnant women and earlier (median 6·7 days [IQR 5·3–6·9] at 1–12 weeks after randomisation) in women planning pregnancy .1c from baseline to 34 weeks' gestation, favouring CGM  owing to withdrawals, lost samples, or participants being unavailable (admissions or preterm delivery). For the primary outcome, the patterns of change were similar between analyses of imputed and available HbA1c data  in the infants of mothers randomly assigned to CGM , table 4Infants of mothers randomised to CGM experienced fewer neonatal intensive care admissions lasting more than 24 h , fewer incidences of neonatal hypoglycaemia requiring treatment with intravenous dextrose , and a reduced total length of hospital stay (p=0·0091) than did infants of control participants , table 4The obstetric and neonatal outcomes of the 34 women who conceived during the planning pregnancy trial are shown separately . Their sWe found no between-group differences in any of the patient-reported outcome measures . SignifiMore participants in the CGM groups experienced adverse events than in the control groups, with recognised CGM frustrations affecting more than 80% of women . The mosFew serious adverse events occurred (15 in the pregnancy group and three in the planning pregnancy group), with no between-group differences in either the pregnancy or planning pregnancy trial . The mos1c  and with lower  prevalence. The clinically small improvement in HbA1c levels, but with wide confidence intervals, either due to smaller sample size or more variation in the treatment effect. The motivation of participants planning pregnancy for optimising glucose control might have also been more variable than the motivation of pregnant participants, although 50% of CGM participants and 40% of control group participants in the planning pregnancy trial did achieve their glycaemic control target.In the authors' clinical experience, women are uncomfortable changing treatment modality during early pregnancy, and thus starting CGM in women planning pregnancy seemed logical. The direct CGM measures suggest a lower mean glucose and 5% higher time in target (1·2 h/day) but these were not significant . Longer 1c. Furthermore, contact for non-sensor related issues did not differ between groups.During pregnancy, CGM users had slightly more frequent scheduled and notably more unscheduled contacts. Problems encountered with CGM use were commonplace, with more than 80% of women reporting frustrations of CGM use, such as connectivity issues, alarms, and calibration errors, and almost 50% experiencing skin reactions, such as bleeding, erythema, and discomfort. The increased contacts for sensor-related diabetes management issues might also reflect the heightened anxiety of pregnant women seeing the 288 daily glucose values in real time, and the initial support required to incorporate CGM data into their diabetes routines. The increased rate of change of glucose concentrations most likely reflects CGM users' actions taken in response to out-of-range glucose levels. Post-hoc analysis showed that adjusting for additional contacts did not affect treatment effect and was unrelated to changes in HbA1c levels, but with less effect on large for gestational age. The direct CGM measures suggested that although women achieved lower mean HbA1c (5·8% or 40 mmol/mol), they spent only 56% of time in target, 33% above target, and 13% below target.1c and glucose control to the UK study .It is difficult to make direct comparison with the smaller previous studies that included pregnant women with both type 1 and type 2 diabetes. We found a greater effect on neonatal outcomes, which is probably due to our larger sample size  compared with previous studies, with approximately 10% or 2·4 h/day less hypoglycaemia. Of note, 19 (16%) of 119 Danish women had 59 severe hypoglycaemia episodes1c levels compared with women using insulin pump therapy. The finding that the treatment effect of CGM is comparable between pump and injection users is very important for widening access to technology. This result is consistent with recent CGM studies outside of pregnancy which focused specifically on multiple injection users.Compared with the landmark Juvenile Diabetes Research Foundation study1c levels in early and late pregnancy and fewer women achieving target HbA1c levels (40% compared with 66% of pregnant CGM users).We note that even with the improvement obtained with CGM use, pregnancy outcomes remained suboptimal, with a high proportion of infants large for gestational age and high levels of neonatal morbidity. The UK pregnancy in diabetes audit, which used the same customised birthweight charts, reported a lower proportion of infants large for gestational age (46%) despite higher maternal HbA1c assays, and direct CGM measures of glycaemia. Third, it has high external validity, including 31 antenatal clinics with variable diabetes technology experience and providing results that are applicable to pregnant women using insulin pumps or multiple daily injections. The data for maternal and neonatal health outcomes are more than 99% complete.Our trial has several strengths. First, the sample size for the pregnancy trial was large enough to provide statistical power for a range of clinically relevant maternal and neonatal outcomes. Second, our trial has a robust randomised controlled design with prior publication of the clinical study protocol, CGM treatment algorithms, prespecified statistical analyses, central laboratory HbA1c and CGM datasets, this was not achieved because of missing or lost samples, withdrawals, and pregnancy losses or delivery before 34 weeks. However, the percentage of missing data (∼20%) fell within the prespecified power calculation assumptions and the patterns of change were similar in analyses of imputed and of available HbA1c data. Women entering the trial had to demonstrate willingness to use CGM before randomisation. Unfortunately, we do not have data on the frequency of capillary glucose monitoring and its relationship to glucose control or on the use of insulin suspension. We observed more unscheduled contacts for women in the CGM group than in the control group. We also acknowledge that there are potential differences between the CGM data collected using real-time sensors in the CGM group and masked sensors in the control group, and a large number of statistical tests were conducted without adjustment for multiple testing.However, our trial also has some limitations. The planning pregnancy trial did not have sufficient power to detect the magnitude of differences that were significant in the pregnancy trial. Although every effort was made to ensure complete HbATo our knowledge, this study is the first to show an effect of continuous glucose monitoring on health outcomes other than glycaemic outcomes, and with substantial reductions in neonatal complications attributed to maternal hyperglycaemia. The results were consistent across 31 international study sites and comparable for women using insulin pumps or multiple daily injections, regardless of baseline glucose control. Our data indicate a role for offering CGM to all pregnant women with type 1 diabetes using intensive insulin therapy in the first trimester.This online publication has been corrected. The corrected version first appeared at thelancet.com on October 20, 2017


The prescription dose was 21 Gy, and a dose covering 95% of the planning target volume (PTV) in three fractions was administered. The PTV was 4,790 mm3. Follow-up magnetic resonance imaging conducted 3 and 12 months after the SRT demonstrated a remarkable and gradual reduction of the recurrent lymph node metastasis in the right parapharyngeal space and no evidence of recurrence. For multidisciplinary therapy of unresectable and/or RIT unresponsive locoregional lymph node metastases and recurrences of DTC, SRT using the CyberKnife system should be considered. A woman in her 60s presented with a recurrent lymph node metastasis from a papillary thyroid carcinoma in the right parapharyngeal space. She had already undergone total thyroidectomy, five resections for cervical lymph node metastases, and right carotid rebuilding. Surgical resection of the current metastasis was impossible.  The application of external beam radiotherapy (EBRT) as postoperative treatment for differentiated thyroid cancer (DTC) has been controversial in the field of head and neck surgery, as well as in radiation oncology –3. We pr18F-fluorodeoxyglucose (FDG) uptake was detected in the right parapharyngeal space, which was diagnosed as a recurrent lymph node metastasis , which comprised of 3.7 GBq of the 131I . Therefo3 (A prescription dose of 21 Gy and a dose covering 95% of the planning target volume (PTV) (and the maximum dose of 26.3 Gy) were administered in three fractions at Osaka Medical College Mishima-Minami Hospital CyberKnife Center. The PTV was 4,790 mm3 . The totFollow-up magnetic resonance imaging performed 3 and 12 months Figures  after thGenerally, postsurgical treatment of DTC patients with metastases involves RIT , 3, and In our case, surgical resection of the lymph node metastasis in the right parapharyngeal space was impossible. Therapeutic effectiveness of RIT could not be expected. Therefore, we administered SRT using the CyberKnife system, which allowed for a reduction in the lymph node metastasis. A year after the SRT, no recurrence has been detected.SRT using the CyberKnife system demonstrated good therapeutic performance in our case. The prescribed dose in our case was 21 Gy. Yamazaki et al. reported the prescribed dose to head and neck tumor lesions, including cervical lymph node metastases, ranged from 13 Gy to 39 Gy, with a median of 30 Gy . TherefoIn 2015, the American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer (the ATA guideline) considers using EBRT delivered via modern techniques such as stereotactic radiation for locoregional recurrence that is not surgically resectable. However, as far as we know, no previous report of treating DTC with SRT by using a CyberKnife system has been published.For multidisciplinary therapy of unresectable and/or RIT ineffective locoregional lymph node metastases and DTC recurrence, SRT delivered via the CyberKnife system should be considered.


Anatomic variations, calcified, tortuous, angulated lesions, and lack of support to increase the complexity of transradial intervention (TRI). Guidezilla is a mother-and-child catheter enabling increased support during complex interventions. As there are few published reports of its use, we describe our experience using this device to assist TRI in Chinese patients. The aim of this study was to investigate the efficacy and safety of the Guidezilla guide extension catheter in complex coronary interventions. Thirty-two patients’ clinical characteristics, angiographic details, and in-hospital outcome retrospectively collected between June 2015 and August 2017. Patients were 59.44 ± 10.48 years of age and 26 (81%) were men. The most frequent target vessels were the RCA (34%) and LAD (31%), patients had complex type C (53%) or B (47%) lesions, severely tortuous (41%) and angulated (22%).With the use of Guidezilla, technique success was 100%, and procedural success was 94%. The mean diameter of the deployed stents was 2.97 ± 0.37 mm, and the length was 27.19 ± 8.14 mm. The estimated mean distance of Guidezilla intubation into the target vessel was 7.66 ± 2.29 cm.The Guidezilla catheter extension safely facilitated successful completion of TRI in complex coronary artery lesions. This device can help interventionalists successfully perform difficult procedures. However, in many patients, the size of the radial artery limits the guide catheter (GC) to a size no larger than 7F. Also procedures involving complex coronary artery anatomies, extreme vessel tortuosity, calcification, angulation, and chronic total occlusions (CTO) are often time consuming and challenging7. TRI procedures can fail because of arterial spasms, failure to puncture the access site, failure to cannulate the lesion vessels, and lack of adequate guide support. Most of these obstacles can be dealt with by certain tips and tricks. One solution is use of a guide catheter extension system (GCES).Transradial intervention (TRI) is often chosen for percutaneous coronary interventional (PCI) procedures because of fewer complications, earlier patient mobilization, and improved clinical outcomes compared with the transfemoral approach11. The GuideLiner catheter is a rapid GCES with a long flexible tubular end that can be deeply advanced into lesions, providing support without the need to disconnect it from the mother guide14. The Guidezilla GCES is a unique, rapid exchange mother-and-child catheter. For difficult or complex procedures such as anchor balloons, deep seating, buddy wire technique, super-stiff guide wires, or GC change to a more supportive configuration17, the Guidezilla is simpler, quicker, more effective especially for transradial PCI, where the GC lacks support. Guidezilla, has a 25 cm catheter with a polymer proximal collar, and a 1.45 mm inner-diameter that has more room to deliver intervention device, and the 1.68 mm outer diameter reduces GC interference, which is smaller than the GuideLiner , Heartrail II catheter , GuideLiner , and Guidezilla . The Proxis device and the Heartrial II catheter are 120 cm catheters that are introduced into the mother guide and require removing the Y-connectorThus, the purpose of this study was to describe our preliminary clinical experience with Guidezilla for back-up support and balloon and stent delivery in the treatment of complex coronary lesions via the transradial approach report at a single center in China.Thirty-two consecutive patients with coronary artery disease (CAD) and TRI procedures utilize Guidezilla at between June 2015 and August 2017. All had undergone angiography and all had failed conventional techniques. The study was approved by the ethics committee of West China Hospital and complied with ethical principles of the Declaration of Helsinki. All patients gave written informed consent before enrollment.19, lesion complexity, access site, procedure success and complications, and in-hospital outcome were recorded. Data collected and reviewed by two cardiologists experienced in analysis of quantitative coronary arteriography. Indications for use of the Guidezilla GCES included: (1) anomalous or angulated take-off of native coronary arteries, (2) proximal tortuous vessels, (3) extreme calcification or long lesions, (4) for back-up support of delivery of balloons, stents, rotational atherectomy or aspiration devices, (5) or failure with other techniques. Success was defined as stent placement in the target lesion with residual stenosis of less than 20% and TIMI 3 flow. Procedural success was defined as technique success without major Guidezilla-related complications. Deep intubation was defined as depth more than 2 cm.Patient demographics, target vessel, ACC/AHA lesion typeTransradial PCI techniques with Guidezilla were performed by experienced interventionalists following standard clinical protocols with right radial artery access and a 6F GC and radial sheath . Dual antiplatelet drugs were administered orally before performing PCI. Intra-arterial nitroglycerin (200 µg) and unfractionated heparin (70–100U/kg) were administered during the PCI procedure after achieving arterial access. The choice of other drugs, intervention approach, equipment, and technique was also at the operator’s discretion. Selective coronary artery angiography (CAG) was performed using diagnostic 5F multifunctional catheters . The 6F radial sheath was removed immediately after the PCI procedure, and a radial compression bandage was used to prevent bleeding of the access puncture site. The bandage was removed after 6 h, provided no bleeding occurred.We used the 6F version Guidezilla GCES that has two radiopaque marker bands to increase visibility and facilitate accurate placement and positioning in the aorto-ostium of the coronary arteries. The radiopaque safety tip is soft and flexible, which reduces the risk of vessel damage and complications. A hydrophilic surface coating provides a smooth finish that reduces friction. The procedures began by positioning the GC and advancing the guide wire (GW) across the target lesion. The Guidezilla was then advanced over the GW through the hemostatic valve of the Y-connector to intubate the target lesion. When the Guidezilla was in position, balloons, and stents were delivered over the same initial GW. This technique permitted deep intubation with back-up support and great coaxial alignment. In patients where a kissing balloon was needed, a wire exchange was performed followed by balloon dilation of the side branch through the stent struts. Before final inflation of the kissing balloon could be performed, the Guidezilla had to be removed.This was not a comparative study. Continuous variables were expressed as means and standard deviation (SD) and categorical variables were expressed as number and percentage (%). Data analysis was performed with SPSS software version 19.0 . All authors take responsibility for all aspects of the reliability, interpretation, and freedom from bias of the data.A total of 32 consecutive procedures were performed using Guidezilla. Baseline clinical characteristics of the patients are presented in Table Guidezilla GCES only through TRI access was used in 30 of the 32 procedures (94%). Both through the TRI and femoral access was used in 2 procedures (6%), because the 2 cases with chronic total occlusion (CTO), which need both transradial and transfemoral approaches to achieve contralateral injection or retrograde manipulation.The target vessel was the RCA 34%) and LAD (31%). Patients had complex type C (53%) or B (47%) lesions, severely tortuous (41%) and angulated 22%). Details of the procedures are shown in Tables 2%. Detai4% and LA21. Using a Guidezilla GCES within a 6F GC, we performed interventions easily without the possibility of losing access to the coronary arteries while changing out the GC. TRI with complex coronary anatomy is often challenging and time consuming. Thus, proper PCI strategy with proper coronary intervention devices is crucial to ensure the success of the procedure. The PCI procedural success rate with the use of GCES ranges from 93% to 98%23. Farooq et al. demonstrated that GCES may allow deeper intubation of the GC, referred to as “rail-roading”14. Takahashi et al. noted that use of GCES provides substantial improvement in back-up support for complex coronary interventions24. The GuideLiner GCES has been used for selective contrast injection, providing better visualization of target lesions with smaller amounts of contrast, which is described in detail in the Twente GuideLiner registry22. Currently, four GCES devices are commercially available, the Proxis, Heartrail II, GuideLiner, and Guidezilla. The Guidezilla became available in China only recently. In our series, the main indications for the Guidezilla GCES were: (1) anomalous or angulated take-off of native coronaries; (2) proximal tortuous vessels; (3) extreme calcification or long lesions; (4) as back-up support for delivery of balloons, stents, and other equipment such as rotational atherectomy or aspiration devices; or (5) failure using other techniques. In our example case, we could not initially to deliver any equipment, and the stent could not pass through the RCA stenosis because of tortuosity, calcification, and angulation. A 6F Guidezilla was successfully introduced into the RCA, and a 2.5 mm anchor balloon was introduced into the distal LCX without difficulty using the mother-and-child maneuver with the Guidezilla catheter to achieve a successful result. We recommend limiting the extension of the Guidezilla catheter to <15 cm beyond the tip of the GC, in order to avoid complication, operator should pay attention not to extend the whole segment in the target vessel. Guidezilla catheter segment length is 25 mm, the manufacturer’s instructions suggested extension of the catheter out of the guide catheter less than 15 cm.Otherwise, it is possible that the mother catheter and child catheter lose the coaxiality and impede withdrawal of the device. In present study, the longest intubation depth of Guidezilla into the target vessel was 12 cm as further distal advancement of the Guidezilla device could cause the entire guide segment to track outside of the guide catheter and impede withdrawal of the device, and it is important to maintain coaxial alignment. For patients with renal insufficiency and the expectation of selective angiography , a Guidezilla GCES may be considered as a first choice. The patient described in the present study had a baseline creatinine of 204 µmol/L with compromised renal function. PCI was completed using less than 100cc of contrast, which minimizing contrast load and decreased the possibility of contrast-associated nephropathy. The patient was discharged 3 days later and remained asymptomatic at 1-year follow up. This is in line with a report by Tunuguntla et al.25 on the use of a GuideLiner catheter to minimize contrast during PCI in a patient with chronic kidney disease (CKD).Reports of complications associated with the Guidezilla GCES are limited. We experienced coronary stent stripping in two procedures (6%) and proximal dissection of the RCA in one (3%). Stent stripping from its delivery balloon occurred on the introduction into the proximal Guidezilla catheter edge. The same event has been reported by Waggoner et al.21, who described the proximal junction transition as the site of stent stripping in their case. The stainless steel collar of the Guidezilla is not as flexible as the polymer collar of the GuideLiner, so passing through the acute angle of the aortic arch caused the stent to encounter the proximal edge of the stainless steel collar during transition to the GCES. This appears to work against introducing stents into the device when it is within an acute angulation of a vessel. In our experience the solution was to remove the Guidezilla before pulling back an unimplanted stent. Farooq et al.14, reported that there was a small risk of damage to large or bulky stents as they enter the collar. They advised using low-profile stents with the GCES, avoiding ones than 4 mm in diameter.To the best of our knowledge, this is the first report of the successful use of the Guidezilla GCES for highly complex procedures in a series of 32 patients in China. The results show that the Guidezilla was a useful and safe adjunct tool during challenging TRI procedures. Previous reports described similar techniques in smaller patient series31. In difficult lesions, compared with other techniques, such as anchoring balloons, deep seating, buddy wires, super-stiffer wires, or GC change to a more supportive configuration17, the Guidezilla is simple, quick, and effective. It is especially helpful in transradial PCI where GC lack passive support, or in complex procedures.One of our patients experienced coronary dissection because of high pressure balloon dilation, which was not related to the Guidezilla use. Similar complications reported during GCES procedures include stent deformation or dislodgement on withdrawal, coronary artery ischemia or dissection, pressure damping, and balloon kinkingOur data was retrospective and obtained at a study single center, and the study sample was small, and accordingly native bias might have affected the accuracy and efficacy of our statistical analysis. However, this trial implemented rigorous inclusion criteria to reduce the risk of confounding bias. So, larger studies will be needed to further investigate our findings, meanwhile, we are expanding the sample size and performing a follow-up of these patients. Design modification of future GCES devices, especially the steel collar, may minimize the risk of stent stripping that we observed. Prospective randomized trials of the efficacy and safety of GCES techniques are warranted.The Guidezilla GCES safely facilitated successful completion of TRI in complex coronary artery lesions. Guidezilla use was associated with a highly success rate with no major complications. We recommend this device to assist in difficult lesions, particular in TRI procedures. It was also suitable for a patient with renal insufficiency. We believe this technique is a first-line choice of radial interventionalists treating patients with complex coronary lesions or CKD, reducing contrast use and total fluoroscopy time.


We investigate the application of high resolution in vivo and ex vivo MRI, in combination with tensor-based morphometry (TBM), to uncover morphological differences in the rTg4510 mouse model of tauopathy. The rTg4510 mouse also offers a novel paradigm by which the overexpression of mutant tau can be regulated by the administration of doxycycline, providing us with a platform on which to investigate more subtle alterations in morphology with morphometry. Both in vivo and ex vivo MRI allowed the detection of widespread bilateral patterns of atrophy in the rTg4510 mouse brain relative to wild-type controls. Regions of volume loss aligned with neuronal loss and pathological tau accumulation demonstrated by immunohistochemistry. When we sought to investigate more subtle structural alterations in the rTg4510 mice relative to a subset of doxycycline-treated rTg4510 mice, ex vivo imaging enabled the detection of more regions of morphological brain changes. The disadvantages of ex vivo MRI may however mitigate this increase in sensitivity: we observed a 10% global shrinkage in brain volume of the post-mortem tissues due to formalin fixation, which was most notable in the cerebellum and olfactory bulbs. However, many central brain regions were not adversely affected by the fixation protocol, perhaps due to our “in-skull” preparation. The disparity between our TBM findings from in vivo and ex vivo MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of in vivo MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes, ex vivo offers enhanced sensitivity to discrete morphological changes.With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between  Since Nature published the initial sequence of the  is a powerful, non-invasive imaging technology which is increasingly employed for phenotyping transgenic mice; this is largely due to advances in MRI hardware and computer power, which facilitate the application of sophisticated image processing techniques  controls . Mice were maintained at ~37°C using heated water tubing and a warm air blower with a feedback system (SA Instruments).All imaging was performed using a 9.4T VNMRS horizontal bore scanner (Agilent Inc.). The key differences between the A 120 mm diameter imaging gradient set  was used. A 72 mm birdcage radiofrequency (RF) coil was employed for RF transmission and a quadrature mouse brain surface coil  was used for signal detection. Tuning and matching of the coil was performed manually.eff) = 43 ms, ETL = 4; NSA = 1. Total imaging time was ~1 h and 30 min.A T2-weighted, three dimensional (3D) fast spin echo (FSE) sequence was implemented for structural imaging with the following parameters: Field-of-view (FOV) = 19.2 × 16.8 × 12.0 mm; resolution = 150 × 150 × 150 μm; repetition time (TR) = 2,500 ms, effective echo time  and heparin; second with 50 mL of Formalin and 8 mM Magnevist, at a flow rate of 3 mL per minute. Following perfusion, the animal was decapitated, defleshed, and the lower jaw removed. All brains were stored in-skull at 4°C and soaked in Formalin doped with 8 mM Magnevist® for 9 weeks prior to ex vivo scanning  was used. A 35 mm birdcage RF coil was employed for RF transmission and signal detection. Tuning and matching of the coil was performed manually.ex vivo images of multiple brains simultaneously. A 3D gradient echo (GE) sequence was implemented for structural imaging with the following parameters: FOV = 32 × 25 × 25 mm; resolution = 40 × 40 × 40 μm; TR = 17 ms; TE = 4.54 ms; flip angle = 51°; NSA = 6. Total imaging time was 11 h 36 min  was calculated from the resulting brain mask for each individual image. For l et al. . A multiin vivo and ex vivo data, so as to minimize this step as a source of variation between the methods: we did not expect the physical variation between groups to differ between in vivo and ex vivo. We performed mass-univariate statistics (two-tailed t-tests) at each voxel, fitting a General Linear model to reveal the most significant voxels contributing to global differences. The resulting statistical parametric maps were corrected for multiple tests using the False Discovery Rate .We transformed the deformation fields from this registration by taking the log of the determinant of the Jacobian matrix calculated at each voxel in the final average image space, to give that voxel's relative expansion or contraction from the final average image to each original image. These values were smoothed with a 0.2 mm FWHM Gaussian kernel to account for registration error and to render the values closer to a normal distribution. This was chosen to enhance physical differences between groups at approximately the same scale .where n = 3) using the following formulae:SNR and CNR were calculated from WT mice  required in a future ex vivo or in vivo study to show meaningful differences between the WT and untreated rTg4510 groups, with specified statistical power. We chose a conventional significance level of α = 0.05, a false negative rate β = 0.2, and initially assumed the WT group provided a reasonable estimation of local structural variability within the rTg4510 mouse population. To detect a 25% local volume difference between WT and untreated rTg4510 groups measured in Jdet values, at each voxel, the required number of animals in each arm of the study is  = 0.975; likewise, Z1−β = 0.84 for 1−β = 0.8. WTstdev is the standard deviation of the WT Jdet values, from GWR, at a particular voxel. These vary across the brain depending upon local WT variability. Narm is rounded up to the nearest integer.where Jdet values is known post-hoc, the effect sizes (Cohen's d), both in vivo and ex vivo, may be visualized and compared at each voxel. This helps to quantify which regions are most different, between groups, regardless of statistical significance:As the actual difference between mean UT and WT d using a pooled standard deviation, replacing WTstdev with σpooled:We calculated Figure 5 shows equivalent slices from the in vivo and ex vivo group-wise average images, overlaid with the d and Narm required at each voxel to detect a 25% variation in Jdet from the WT mean, giving a realistic lower bound for future studies of the rTg4510 mouse.Brain samples were processed using a Tissue TEK® VIP processor . After processing, sections were embedded in paraffin wax to allow coronal brain sections to be cut. Serial sections (6 μm) were taken using HM 200 and HM 355  rotary microtomes.2O2 (0.3%); 30 min in normal goat serum ; 60 min in primary antibody; 30 min in biotinylated goat anti-mouse IgG ; 30 min avidin-biotin complex solution ; 5 min in 3,3′-diaminobenzidine . Apart from the last two steps, PBS with 0.05% Tween-20 (PBS-T) was used for diluting reagents and washes between steps. Sections were then counterstained with haematoxylin before dehydration and cover-slipping.Immunohistochemistry (IHC) was performed using a primary antibody for tau phosphorylated at serine 409  and the neuronal marker NeuN . Following de-paraffinisation and rehydration of the tissue sections, antigen retrieval was performed using the Lab Vision PT module system (Thermo Scientific), where sections were heated to 100°C for 20 min in citrate buffer . Slides were transferred to a Lab Vision Autostainer (Thermo Scientific) where the following incubations were performed: 10 min in Hpost-hoc Tukey multiple comparison was performed to identify significant differences between the groups.To quantify the density of PG-5 and NeuN positive neurons, stained sections were digitized using the Scanscope AT slide scanner (Aperio) at 20 × magnification. Imagescope software  was used to view the digitized tissue sections and delineate the boundaries of the cortex. PG-5 positive cells were manually counted within the delineated region and NeuN positive cells were quantified using a nuclear detection algorithm ; both were expressed as a percentage of the total area. These analyses were performed in a blinded fashion. A one-way ANOVA with in vivo and ex vivo imaging protocols , which maximized the utility of the MRI scanner by imaging overnight.In order to explore image quality, we investigated quantitative differences in SNR and CNR measurements from WT animals Table . The SNRls Table . This wain vivo images compared to the ex vivo images in 7 of the 9 regions investigated: the caudate putamen (55%), corpus callosum (271%), cortex (42%), hippocampus (79%), olfactory bulb (36%), midbrain (61%), and thalamus (59%). Meanwhile, the SNR ex vivo was significantly greater in the cerebellum (50%). Conversely, we observed a three-fold increase in CNR between gray matter (cortex) and white matter  structures in the ex vivo images compared to in vivo (p ≤ 0.01).We observed an increase in SNR of the in vivo and ex vivo imaging protocols (detailed in Table 3in vivo vs. 40 μm3ex vivo) of the in vivo acquisition will have been key contributors to the increased SNR in vivo. Theoretically, if all other imaging parameters were the same, this increase in voxel size in vivo would result in an increase in SNR by a factor of ~ 53 when compared to ex vivo  for the in vivo and ex vivo mouse brain specimens using a previously published multi-atlas segmentation protocol   and the doxycycline-treated rTg4510 mice (p ≤ 0.01)  although this observation was most marked in vivo. The Narm was also elevated in the entorhinal cortex of the in vivo data (Narm >15), suggesting that a greater sample size is required to recover changes within this structure; this is likely both due to reduced WT ventricle volumes and increased WT variance around these structures. Despite these observations, we were able to recover structural changes occurring in both of these regions in vivo with a reduced sample size (10 rTg4510 mice and 8 WT controls), suggesting the volume changes were greater than 25% of the WT volume.The n = 8), untreated rTg4510 (n = 10) and treated rTg4510 (n = 7) mice following ex vivo imaging.In order to corroborate the MRI findings with alterations occurring at the cellular level, quantitative immunohistochemistry was performed on each of the individual WT (2) compared to WT mice  (p ≤ 0.05)  compared to the untreated rTg4510 mice (p ≤ 0.01)  Figure . These r) Figure . Followi) Figure . No sign2)  compared to untreated rTg4510 mice (p ≤ 0.001)  Figure .in vivo and ex vivo MRI are fully understood in order to maximize sensitivity to morphological differences. A number of publications have previously addressed the trade-offs associated with imaging in vivo and ex vivo mouse brains .Another important consideration when imaging in vivo and ex vivo imaging protocols will all have contributed to the differences in SNR and CNR, making it difficult to untangle and isolate an overriding factor that is influencing these values. An alternative approach for this study would have been to implement identical imaging protocols, thus eliminating the effects of hardware, sample preparation and sequence optimization on these quantitative measurements of image quality. However, given the trade-offs associated with both approaches, we believed this study was better executed by applying protocols which had been individually optimized to meet the unique demands of in vivo and ex vivo scanning.It is important to note that the differences in the ex vivo MRI . This variability is dependent upon the ability of the registration algorithm to successfully align equivalent voxels, which itself depends upon constraint parameters  as well as on the inherent image contrast of the brain structures. Low contrast regions may register poorly: structures with relatively homogeneous intensities have less information to inform registration. Here, misalignments may arise, resulting in greater local WTstdev, and hence a greater local effect size (or Narm) requirement in order to achieve the desired power. This appears to be the case in the midbrain and striatum of the in vivo group, where there is lower structural contrast than ex vivo, and consequently, greater Narm. Additionally, the variability in the cortex may be due to misregistrations with external material on the surface of the skull; a greater problem at lower resolutions, where the separation of this material from the brain is less distinct.The ability of TBM to detect a local volumetric expansion or contraction is dependent upon the standard deviation of Post-hoc tests can inform future studies. As the WTstdev and WTmean vary between brain regions, the power of each test varies and different sample size estimates are prescribed, throughout the brain. Notably, around the ventricles, where structural variability between animals was higher, sample size estimates were elevated. In most brain regions, especially ex vivo, small group sizes appear sufficient to differentiate groups. This is also dependent upon the effect size chosen . Smaller changes would require greater Narm in each group. To obtain a useful sample size for a future study focussing on a specific brain region , it would be advisable to use that region to set the N per study arm. The group sizes in this study were sufficient to reveal significant group differences throughout most of the brain.in vivo and ex vivo MRI in conjunction with TBM for detecting regions of morphometric change in the rTg4510 mouse model. Our findings support the utility of in vivo MRI for assessment of morphological changes in transgenic mice, where atrophy was detected in equivocal regions to ex vivo imaging. In addition, the in vivo data does not suffer from dehydration or distortion artifacts, which may confound ex vivo studies. Our TBV findings suggest that tissue shrinkage is similar in rTg4510 mice and WT controls, with relative preservation of key central brain structures such as the cortex and hippocampus. The TBM results also indicated that ex vivo MRI may offer increased sensitivity to subtle morphological changes with the same sample size, such as the response to a therapeutic intervention.In this work, we explored the compromises and trade-offs between We hope that this work will help support and inform research groups working in the field of preclinical MRI, and shape their decision about the best way to image their transgenic mice.ex vivo tissues: HH and OI. Performed the histology: TM, ZA, AF, and MH. Analyzed the MRI data: NP and DM. Contributed image processing analysis tools: MC, MM, and SO. Provided the transgenic mice and contributed toward our understanding of the MRI changes: RJ, MO, and EC. Wrote, edited and critically evaluated the manuscript: HH, NP, IH, JW, EF, and ML.Conceived and designed the experiments: HH, NP, DM, IH, JW, NC, JO, RJ, MO, EC, SO, and ML. Performed the MRI experiments: HH, OI, IH, NC, JO, and JW. Perfuse-fixed and prepared the RJ, TM, ZA, MH, AF, MO, and EC are employees of Eli Lilly and Company. The work was carried out as part of a basic research collaboration with Eli Lilly and Company, who helped fund the imaging costs. Lilly also provided the rTg4510 mice used in this study, helped with study design and carried out histopathology in the manuscript. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear Editor,KRT6A, KRT6B, KRT6C, KRT16 or KRT17 .Pachyonychia congenita (PC) is an ultra‐rare hereditary skin disorder primarily characterized by severe, painful and highly debilitating plantar keratoderma, variable hypertrophic nail dystrophy, epidermal cysts, leukokeratosis and other features.www.pachyonychia.org) since 2004. As of April 2017, we have identified 113 distinct pathogenic KRT6A, KRT6B, KRT6C, KRT16 or KRT17 mutations in 774 individuals from 419 unrelated families who are registered in the International Pachyonychia Congenita Research Registry (http://www.pachyonychia.org/pc-data/). With the analysis of a large number of PC patients, the older classification of PC‐1 and PC‐2 subtypes has been shown to be misleading.Our laboratory has run an international molecular genetic diagnostic service for PC in association with the patient advocacy organization Pachyonychia Congenita Project  was reported in The Journal of Dermatology as the causative mutation in a patient with late‐onset PC.KRT6B is a common single nucleotide polymorphism (SNP), present in the dbSNP database under the accession number . According to the ExAC database , in a sample of 60 508 individuals subjected to exome sequencing, 2960 were heterozygous and 57 were homozygous for the minor allele of the SNP rs61746355, p.Gly499Ser. This equates to approximately 5% of the population being either heterozygous or homozygous for the p.Gly499Ser variant in K6b. This high‐frequency SNP is inconsistent with the rarity of PC. Although Guo and colleagues did not observe this SNP in 100 control individuals, who are presumed to be of Chinese ancestry,Recently, a novel GJB6, and especially FZD6, important candidate genes to analyze in this family.We would recommend that the authors fully sequence all exons and splice sites of the five keratin genes associated with PC and cross‐reference any detected variations against ExAC or other online SNP databases to identify the actual causative mutation. In addition, given that the phenotype is somewhat unusual and few mutations have been reported in association with delayed‐onset PC previously, it may also be prudent to consider other genes involved with phenotypes that resemble PC. Based on the large number of PC patients in the International PC Research Registry, it is highly unusual for a patient to present only with nail changes, making None declared.


The aim of this study was to evaluate intraocular pressure (IOP) and retinal nerve fiber layer (RNFL) changes in patients with carotid artery stenosis (CAS) after carotid artery stenting.This study was conducted as a cross-sectional, non-randomised clinical case series. Fifteen male patients (mean age: 63.6±9.1) with CAS and more than 70% carotid artery narrowing were included. All of the patients were followed in the department of neurology and were operated in the interventional radiology division. Eighteen healthy male subjects (mean age: 63.7±5.3) were included in the control group. All of the healthy subjects had a detailed ophthalmological examination and subjects with any chronic eye disease were excluded from the study. All of the participants had a detailed ophthalmological examination including tonometry using Goldmann applanation tonometry and RNFL analysis using optical coherence tomography (RTVue-100 5.1).There were no ocular ischemic symptoms in any of the participants. The mean IOP value was 15.1±2.1 mmHg in the control group and 16.6±2.4 mmHg before stent implantation, 16.4±2.2 mmHg at 1 week after implantation, 16.6±2.5 mmHg at 1 month after implantation, and 16.7±2.9 mmHg at 3 months after implantation in the CAS group. Mean RNFL thickness was 105±6 µm in the control group; in the CAS group, mean RNFL thickness values were 98±27 µm before stent implantation and 103±11 µm, 101±10 µm, and 101±11 µm at 1 week, 1 month, and 3 months after stenting. There were no significant differences between the CAS group and control group regarding IOP and RNFL thickness values (p>0.05). IOP and RNFL thickness also did not show any statistically significant changes from preoperative measurements in 3 months postoperative follow-up in the CAS group (p>0.05).IOP and RNFL thickness remained unchanged after carotid stent implantation in carotid artery stenosis patients with no signs of ocular ischemic syndrome. At the same time, ophthalmologic findings can sometimes lead us to suspect CAS and facilitate the early diagnosis of stenosis before the patient develops symptoms like stroke.3 Patients who develop ocular ischemia may exhibit an increase in intraocular pressure (IOP) due to neovascularization; however, aqueous humor production decreases in some patients due to ciliary body ischemia, resulting in no IOP increase.4 Based on these data, in this study we aimed to compare changes in IOP and retinal nerve fiber layer (RNFL) thickness in patients who underwent CS.Carotid artery stenosis (CAS) is an important obstructive artery disease that can cause cranial ischemic infarction and stroke, and is the leading cause of ischemic stroke.The study included 15 male patients  who were examined in the neurology department and diagnosed with CAS based on a finding of >70% narrowing of the carotid artery on color Doppler ultrasound (CDUS) and who underwent CS in the interventional radiology unit. Eighteen male participants  were included as the control group. The study was conducted in accordance with the principles of the Declaration of Helsinki, informed consent forms were obtained from all participants, and approval was granted by the Ethics Committee for local clinical trials (protocol number: 09.2015.090 70737436-050.06.04).The CS patients were asked specifically about hypertension, diabetes, and their alcohol and smoking history. Patients were ophthalmologically evaluated preoperatively and at postoperative 1 week, 1 month, and 3 months. All participants underwent a detailed eye examination. Best visual acuity was assessed using the Snellen chart. Snellen visual acuity values were converted to LogMAR values for statistical comparison. The anterior segment was assessed by slit-lamp examination. For IOP measurement, a mixture of 0.5% proparacaine and fluorescein was instilled into the eye and IOP was measured by Goldmann applanation tonometry. The average of three measurements was recorded. Optic nerve head (ONH) imaging was performed on all participants with the RTVue RT-100 spectral domain optical coherence tomography  device in the ONH and 3D modes for glaucoma screening. The ONH program and three-dimensional disc program of the RT-100 were used for RNFL analysis. The ONH scanning protocol consisted of 12 radial images with a length of 3.7 mm, each making 455 scans transecting the center of the optic disc, and 13 concentric rings, each making between 425-965 scans and with diameters ranging from 1.3 to 4.9 mm. An RNFL thickness map was created from the RNFL thicknesses measured from the area within a 3.45 mm diameter of the disc center. The average and superior and inferior hemisphere RNFL thicknesses of the patients were evaluated .The central corneal thickness (CCT) and axial lengths (AL) of all patients were measured by the same ophthalmologist using Haag-Streit International/LS 900 Lenstar. The lenses were evaluated for cataract after pupil dilation with tropicamide and phenylephrine eye drops. A detailed fundus examination including the entire retinal periphery was then conducted using a Volk SuperField NC lens. The eyes were evaluated for the presence of venous stasis retinopathy, iris neovascularization, glaucoma, optic nerve injury, vascular embolism, occlusion, and ocular ischemic syndrome (OIS).Patients with visual acuity less than 6/10, spheric refraction exceeding -4 or +3 diopters (D), cylindrical refraction ≥±3 D, uveitis, glaucoma and retinal disease, optic disc damage, corneal and vitreal opacities, pupillary anomalies, history of ocular surgery other than phacoemulsification, cataract with NC<4, C<5, p<3 according to the LOCS II classification, systemic disease that may affect the measurements, or current drug treatment were not included in the study.Before the procedure, patients were given detailed information about the treatment process and possible complications, and written consent forms were obtained. Patients whose procedures were planned were started on double antiaggregant therapy  3 days before the procedure. Patients who did not receive double antiaggregant therapy in advance and those undergoing emergency intervention were taken into surgery after being administered a loading dose of 450 mg clopidogrel. Hemogram, creatinine, and coagulation tests were performed as part of routine preparation. For these preoperative preparations, the patients were hospitalized the day before the procedure and monitored.All procedures were conducted in an angiography unit equipped with a Siemens Artis Zee Bi-plain Angiography device, and all patients were monitored during CS. Electrocardiogram, oxygen saturation, and non-invasive arterial blood pressure were monitored during the procedure. In all patients, the right femoral artery was preferred as the entry site, and local anesthesia was applied to the area. At the beginning of the procedure, all patients were administered 5000 U of heparin intravenously.After entering the femoral artery using the Seldinger technique, in 13 patients a 7F vascular sheath was inserted into the femoral artery and a 7F guiding catheter was advanced and positioned in the main carotid artery to be treated, while in 2 patients a 6F long vascular sheath was positioned directly in the main carotid artery. The guiding catheter and vascular sheath system was washed with pressurized isotonic serum throughout the procedure. Firstly, imaging of the neck and intracranial segments and intracranial branches of the carotid artery was performed to evaluate the hemodynamic changes that should occur in the intracranial vascular tree before and after the procedure and the possible presence of intracranial stenoses. Carotid angiography was then performed by administering contrast material via the catheter or vascular sheath placed in the main carotid artery to be stented, and a road map was obtained. Prior to the CS procedure, the guide wire of the protection filter was passed through the targeted stenosis and the filter was opened in a straight segment. Protection filters were routinely used in all patients; the Boston Scientific Filter Wire EZ Embolic Protection System was used in 13 patients and the Spider FX™ Embolic Protection Device was used in 2 patients. The monorail stent system was expanded above the guide wire carrying the filter, at the level of the lesion so as to encompass the area of stenosis determined using the road map. The Cristallo Ideale™ Carotid Stent System Self-Expanding stent was used in 11 patients and the Protege® RX Carotid Stent System Self-Expanding Nitinol stent was used in 4 patients. The stenosis was positioned high in 4 patients, so predilatation was performed with a 3x20 mm balloon prior to stenting in order to allow the stent to safely pass through at the level of the lesion. Postdilatation was performed on all patients after expanding the stent to allow it to reach its optimal span. Postdilatation was performed using a 6x20 mm balloon in 6 patients and a 5x20 mm balloon in 9 patients. After the procedure was completed, contrast material was administered to reevaluate the neck and intracranial arteries.In the postoperative period, double antiaggregant therapy  was administered to the patients for 3 months, to be followed by lifelong 100 mg acetylsalicylic acid prophylaxis.SPSS  for Windows version 21.0 was used in statistical analysis of the study data. Mean ± standard deviation and percentage values were used for the descriptive statistics. Conformity of the data to normal distribution was assessed with the Kolmogorov-Smirnov test. Parametric tests were used to analyze numerical data with regular distribution, while nonparametric tests were used to analyze numerical data with irregular distribution.Student’s t-test and the Mann-Whitney U test were used for intergroup comparisons and the paired intragroup comparisons of means. The chi-square test was used in the analysis of proportional data. Correlation analyses were done with the Pearson test. The statistical significance level was accepted as p<0.05 in analyses in which there were no variables from similar categories. When variables from the similar category were analyzed together, the significance level was decided according to the Bonferroni correction based on p<0.05.There were no significant differences between patients diagnosed with CAS and the control group in terms of mean age, spherical equivalents, visual acuity, CCT, or AL. A comparison of the patient and control groups’ general findings is provided in None of the patients had ocular pain, retinal hemorrhage, or glaucoma. No complications were observed in any of the patients in follow-up examinations after stenting.No statistically significant differences were observed when the preoperative, postoperative 1 week, postoperative 1 month, and postoperative 3 month IOP values of patients in the study group were compared with the control group (p<0.05) .There were also no statistically significant differences when the preoperative (n=15), postoperative 1 week (n=14), postoperative 1 month (n=8), and postoperative 3 month (n=10) IOPs of the patients were compared (p=0.963) .No statistically significant differences were observed when the preoperative, postoperative 1 week, postoperative 1 month, and postoperative 3 month RNFL values of patients diagnosed with CAS were compared with the control group (p<0.05) .As the ophthalmic artery is a branch of the ICA, ocular involvement can occur in any case of ICA stenosis. Ocular involvement can range from transient unilateral acute blindness caused by emboli that break off from the atherosclerotic plaque in the stenosis, to chronic OIS due to persistent hypoperfusion or complete blindness due to occlusion of the central retinal artery or ophthalmic artery. OIS is characterized by ocular pain, decreased vision, patchy hemorrhages in the retina, and enlargement in the veins. Due to ocular hypoperfusion, any stenosis of the ICA can lead to ischemic retinopathy, neovascular glaucoma, ischemic optic neuropathy, retinal artery occlusions, cataract, and ocular hypotony. OIS and other findings also serve as indicators of cerebral ischemic disorders.4 Rubeosis iridis is sometimes the only symptom associated with carotid stenosis.5 OIS is more common in carotid stenosis patients with weak collateral connections. The decrease in retrobulbar blood flow in patients with OIS can be demonstrated by CDUS. Retrograde flow, which is a predictor of high-grade carotid stenosis, can be seen in some patients. This retrograde flow leads to further exacerbation of ocular ischemia by further reducing retrobulbar blood flow due to the vascular steal phenomenon.8 Decreased vision and pain due to increased IOP may occur in ocular ischemia. In some cases, these symptoms may be the first clinical signs of CAS.Microaneurysms, narrowing of the retinal arterioles, and venous dilation are observed on fundus examination due to decreased flow in the ophthalmic artery. When the ocular perfusion pressure lowers and approaches intraocular pressure, ischemia develops in both the posterior and anterior segments of the eye. Venous-stasis retinopathy limited to the posterior progresses to an OIS that also includes the anterior if the stenosis continues. Microproliferations that develop in the retinal vasculature and the iris form fibroadhesions. As a result, the anterior iridocorneal angle is occluded and intraocular pressure increases. If neovascularization is not treated, it can progress to neovascular glaucoma. After treating the carotid stenosis, these patients show improvements in their visual symptoms. In some patients, aqueous humor production decreases due to ciliary body ischemia, and there may be no increase in IOP.3 evaluated 145 patients exhibiting these symptoms for carotid stenosis and found that amaurosis fugax had a 30% predictive value of clinical suspicion of carotid stenosis. Hollenhorst plaques were detected in 22 eyes, but only 4 of these patients had more than 60% stenosis in the carotid artery. In the same study, the authors reported that the presence of Hollenhorst plaques was found to be positively correlated with CAS at a rate of 18.2%, that the predictive values of other ocular symptoms such as ischemic optic neuropathy, retinal artery and vein occlusion, and optic atrophy were weak, and that stenosis was observed in one out of 5 patients who underwent CDUS after venous stasis retinopathy was detected, and its predictive value was 20%. Ultimately, they stated that Hollenhorst plaques and venous stasis retinopathy were of moderate value in the prediction of CAS.3 None of the patients in our study exhibited rubeosis iridis, neovascular glaucoma, or retinal artery or vein occlusion.Hemispheric neurological symptoms, amaurosis fugax, and Hollenhorst plaques detected in ophthalmologic examination are findings that require imaging in the diagnosis of CAS. Retinal artery occlusion and ischemic optic neuropathy may also be related to carotid stenosis, as mentioned above. However, the predictive value of ocular findings in diagnosing stenosis is a subject of debate. Over 3 years, McCullough et al.11 We also evaluated patients’ pre- and posttreatment IOP values in regards to possible CAS-related changes in ocular blood flow and the risk of glaucomatous optic neuropathy due to circulatory impairment, and observed no significant difference between the patient and control groups. In addition, no significant differences emerged when the pretreatment and posttreatment 1-week, 1-month, and 3-month IOP values of patients with CAS were compared with one another. This can be explained by the lack of patients with OIS in our patient group and the absence of ciliary body ischemia caused by stenosis, in which case there is no reduction in aqueous humor production.12Studies show that the balance between ocular blood flow and IOP is important for ONH circulation. It has been demonstrated that as IOP increases, there is a decrease in the end diastolic flow rate and an increase in the resistance index of the arteries that supply the ocular structures, and end diastolic flow rate has been shown to negatively correlate with glaucoma progression.13 compared the RNFL values of 25 patients diagnosed with CAS and 25 age-matched healthy control subjects and found no significant differences. In contrast, Pavan14 reported RNFL thinning in 8 CAS patients with over 70% stenosis. No difference was observed between our control group and patient group in terms of RNFL; however, there was also no change in the IOP and RNFL values of the patient group after stenting.Sayin et al.Ocular symptoms may be the first sign of serious carotid atherosclerotic disease. In this case, ophthalmologic examination is important for the prognosis of these patients. Patients at high risk for ischemic stroke can be referred for early intervention. In case of any retinal findings of OIS on ophthalmologic examination or a history of temporary monocular vision loss, the patient can be referred to the neurology clinic upon suspicion of CAS, thereby preventing ischemic neurological damage.In our study, there were no changes in baseline RNFL thickness and IOP values after stenting in patients with CAS who did not develop OIS. This finding must be supported by future studies including larger patient groups.


Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients. The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients.CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables. The predictive power of each parameter was explored using CV events as the main outcome.p < 001).During a median follow up of 65 months (ICR: 36–100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%). A total of 35 CV deaths occurred during that period. Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events. Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19–1.46, In COPD patients attending pulmonary clinics, CAC was the best independent non-invasive predictor of CV events. This tool may help evaluate the risk for a CV event in patients with COPD. Larger studies should reproduce and validate these findings. COPD patients are at high risk of major cardiovascular (CV) events. Several non-invasive CV risk markers have been proposed to predict these events in the general population but never been compared in COPD patients.Coronary Artery Calcium (CAC) is the best non-invasive CV risk marker that predicts major CV events in this population of COPD patients.The incorporation of this tool into daily practice of practitioners caring for patients with COPD could help detect high risk patients for future major CV events.Chronic Obstructive Pulmonary Disease (COPD) and cardiovascular disease (CV) are two of the leading causes of death in the world . SeveralAlthough the recent update of the COPD GOLD guidelines recommend an evaluation for the presence of associated comorbidities , they doIn order to help clinicians caring for COPD patients better detect risk of future CV events, we decided to evaluate the ability of different non-invasive tools in predicting cardiovascular events in a population of real-life patients with COPD attending pulmonary clinics.1)/Forced Vital Capacity (FVC) ratio of less than 0.7. All post bronchodilation measurements were performed 15 min after the inhalation of 400 μg of albuterol. To be enrolled, COPD patients had to be clinically stable and without exacerbations for 8 weeks prior to entry, and receiving optimal therapy according to international guidelines [Participants were former and current smokers of at least 10 pack-years with previous spirometric diagnosis of COPD and regularly seen in our pulmonary clinic. All patients signed the consent form previously approved by the Human Review Board . Subjects were consecutively enrolled from January 2006 to March 2016. COPD was confirmed by history and a post-bronchodilator Forced Expiratory Volume in the first second  charts , 18. In Morning fasting blood and spot-urine samples were collected simultaneously while at rest and before any other test. The microalbuminuria (MAB) or urinary albumin excretion was determined as the urine albumin (milligrams) to creatinine (grams) ratio in the morning urine. Urine albumin concentration was determined by a standard turbidometric method (coefficient of variation 5.5%). Serum and urine creatinine concentrations were analyzed using the Jaffe reaction and quantified by a photometric method. Fasting serum levels of glucose, high sensitivity CRP, glycated haemoglobin (HbA1c) and cholesterol were also determined.All individuals were enrolled in a lung cancer screening program  and undeEAT volume was assessed by two independent observers  unaware of the clinical information, using a commercially available software tool  based on attenuation-dependent segmentation methods. Concordance coefficient between observers was 0.95; (95% CI: 0.93–0.96). Observers manually traced the pericardium at its superior extent , at mid-ventricular level, and at the end of the pericardial sac, which defined the inferior extent of the pericardial volume. The software automatically interpolated between the user-defined traces. Automatically traced contours were manually adjusted to the pericardium if needed. Epicardial adipose tissue volume was defined as any fat tissue located within the pericardial sac. A predefined threshold of −195 to −45 HU was used to identify voxels corresponding to fat .Each of the four main coronary arteries was identified . Calcification in each artery was categorized as absent, mild, moderate, or severe and scored by the radiologist as 0, 1, 2, or 3, respectively. Calcification was classified as mild when less than one-third of the length of the entire artery showed calcification, moderate when one-third to two-thirds of the artery showed calcification, and severe when more than two-thirds of the artery showed calcification. With four arteries thus scored, each subject received a coronary arterial calcium (CAC) score ranging from 0 to 12 .Major CV events  or deaths were registered reviewing each patient chart or contacting their family members.Data was summarized as relative frequencies for categorical variables, mean (SD) for normally distributed variables and median (25th–75th percentile) for non-normal data. To explore the association between Framingham score and CV event we used Spearman’s correlation coefficient.p < 0.05). Because most of the factors found to be independently associated with CV events in the univariable analysis are included also in the Framingham score, we only compared this score and CRP levels with CAC in the multivariable analysis.To determine which factors best predicted the risk of developing a CV event, a Cox analysis was used. We first performed a univariable analysis with CAC, age, hypertension, total cholesterol, LDL-cholesterol, Framingham score, and SCORE charts and then a multivariable analysis including those that were statistically significant in the univariate analysis , and during this period 44 CV events were recorded: 12 (27.3%) acute myocardial infarction (AMI), 10 (22.7%) ischemic heart disease/angina events, 12 (27.3%) peripheral artery disease events requiring surgery and 10 (22.7%) strokes. In addition 35 deaths occurred during this period, 6 (17.5%) due to cardiac causes, 16 (46%) due to respiratory causes, 4 (11%) due to lung cancer, 5 (14.5%) due to other cancers, and 4 (11%) from other causes.1 in L  or % predicted  between those with and without a CV event respectively.No differences were found in FEVr = 0.19) although statistically significant (p = 0.001).Table Table The present study of patients with COPD attending our clinic shows that amongst the clinical, radiological and laboratory tools available to clinicians, the CAC score is the most powerful tool to evaluate the risk of suffering a major CV event in this high risk population.It has been shown that additive models of individuals CV risk factors do not explain their interaction and synergy between variables and outcomes. Therefore, in the last decades, the concept of global risk assessment has been developed. One of the first tools to evaluate this global risk assessment was the one proposed by the Framingham study through its index . AlthougCalcification of the coronary is an active process and can be seen in each of the stages of the development of an atherosclerotic plaque. The presence of calcium in the coronary artery is pathognomonic of coronary atherosclerosis, confirmed by histopathology and intravascular ultrasound studies –27. Ther1 was associated with higher levels of serum CRP, and a higher frequency of metabolic syndrome and coronary artery calcification on chest CT. However, in our study, the association between CRP level and CV events lost significance when compared with other noninvasive CV risk factors like CAC.The present study showed that elevated levels of CRP were associated with major CV events in the univariable analysis. Previously, Park et al.  studied Interestingly, Romundstad et al. , exploriTwo unexpected findings from the present work were that SCORE and EAT were not associated with the development of CV event. As far as we can tell, this is the first time that these two well established noninvasive CV markers are specifically explored in a COPD population. They have been shown to predict CV outcomes in the general population but maybe for these specific markers we need a larger population and a longer follow up time if they are to be useful in patients with COPD.The main strength of the present study is that it explored clinical, analytical and radiological non-invasive CV risk markers in a population of COPD patients prospectively followed for a long period of time. It also explored, for the first time, the potential utility of commonly used CV risk assessment tools like the Framingham index and the SCORE charts in this high risk population. The present study also had several limitations. Firstly, it was conducted in Caucasian patients with COPD followed in a tertiary center University Hospital and therefore the findings may not be applicable to the general population of patients with COPD. Secondly, a limited proportion of women were included in this study  precluding the extrapolation of these findings to women with COPD. Thirdly, most patients included in the study had mild to moderate COPD, however, there is sufficient evidence showing that patients with mild to moderate COPD are the ones with higher risk of CV diseases , 42.Our findings also convey a practical message. The use of CT scans of the thorax is increasing and this information may actually extends the use of such a tool, to help identify those subject within the COPD population were preventive measures such as smoking cessation, exercise promotion, detection and control of diabetes and dyslipidemia may help avoid subsequent CV events.In this cohort of patients with COPD from a pulmonary clinic of a tertiary University Hospital, CAC was the best predictor of CV events independently of other CV risk factors. If larger studies in different settings validate these findings, the incorporation of this tool to the practice of practitioners caring for patients with COPD could help detect high risk patients for future CV events.