Excessive weight gain and elevated blood pressure are significant risk factors for adverse pregnancy outcomes such as gestational diabetes, premature birth, and preeclampsia. More effective strategies to facilitate adherence to gestational weight gain goals and monitor blood pressure may have a positive health benefit for pregnant women and their babies. The impact of utilizing a remote patient monitoring system to monitor blood pressure and weight gain as a component of prenatal care has not been previously assessed.The objective of this study is to determine the feasibility of monitoring patients remotely in prenatal care using a mobile phone app and connected digital devices.In this prospective observational study, 8 women with low risk pregnancy in the first trimester were recruited at an urban academic medical center. Participants received a mobile phone app with a connected digital weight scale and blood pressure cuff for at-home data collection for the duration of pregnancy. At-home data was assessed for abnormal values of blood pressure or weight to generate clinical alerts to the patient and provider. As measures of the feasibility of the system, participants were studied for engagement with the app, accuracy of remote data, efficacy of alert system, and patient satisfaction.Patient engagement with the mobile app averaged 5.5 times per week over the 6-month study period. Weight data collection and blood pressure data collection averaged 1.5 times and 1.1 times per week, respectively. At-home measurements of weight and blood pressure were highly accurate compared to in-office measurements. Automatic clinical alerts identified two episodes of abnormal weight gain with no false triggers. Patients demonstrated high satisfaction with the system.In this pilot study, we demonstrated that a system using a mobile phone app coupled to remote monitoring devices is feasible for prenatal care. Excessive weight gain and elevated blood pressure are significant risk factors for adverse pregnancy outcomes such as gestational diabetes, premature birth, and preeclampsia -4. The ifeasibility of using digital health tools to manage prenatal care. Feasibility was determined by studying the following specific outcomes: (1) patient engagement with the app and the remote monitoring tools, (2) accuracy of the remotely collected data, (3) efficacy of the alert systems, and (4) patient satisfaction.The purpose of this study is to determine the This prospective observational study was conducted between July 2014 and January 2015 in the Department of Obstetrics & Gynecology at the George Washington University Hospital, an urban academic medical center that delivers approximately 2900 babies per year. Pregnant women between the ages of 18 to 40 years old presenting for routine prenatal care in the first trimester were asked to participate in the study over the course of a recruitment period of one month. Inclusion criteria included self-reported regular usage of an iPhone and low-risk pregnancy status per established guidelines [There was no cost to the patients or provider for participation. Once consented, participants were given access to the Babyscripts  mobile prenatal care platform consisting of a mobile phone app and connected devices. Patients received training on how to use the app and the devices as part of the enrollment process. All patients signed an end-user licensing agreement to use the app, permitting Babyscripts to access non-identifiable data collected by the app. Institutional review board (IRB) approval was granted prior to commencing the study (IRB# 051422).The Babyscripts platform was designed through a collaboration between the George Washington University Medical Faculty Associates and 1Eq Inc., the manufacturer of Babyscripts. The platform consists of a mobile phone app connected to a wireless weight scale and sphygmomanometer. The Babyscripts app contains evidence-based educational information related to prenatal care delivered at gestational age-specific times during pregnancy in the form of a to-do list . This inIn addition to the Babyscripts app, participants received connected devices including a weight scale  and a sphygmomanometer . As part of participation, patients collected weight and blood pressure data on a weekly basis.Data points generated by the use of connected devices automatically populated the Babyscripts app for review by the patient as well as the provider. Patients were provided automated feedback about their individual weight and blood pressure goals. Abnormal values activated alerts to the patient and physician to communicate more urgently. For example, elevated blood pressure or abnormal weight gain or weight loss generated an automated alert to the clinician. The alert system consisted of an email to the office’s triage nurse as well as an email and an in-app notification to the patient. If the alert was not addressed in 15 minutes, an automated phone call was placed to the triage nurse to alert the provider of the abnormality. The alert remained active until it was acknowledged by the provider.Engagement with app and remote monitoring devices was measured by recording the number of times that a patient interacted with the app or recorded an at-home weight or blood pressure reading.To measure the accuracy of remote monitoring, remote measurements were compared to in-office measurements. For in-office data, 2 trained abstractors reviewed the electronic medical record and then compared the data for discrepancies. Abstractors were not blinded to the study purpose. Standardized data collection sheets were used for data collection and all patient data was stored in a server compliant with the Health Insurance Portability and Accountability Act of 1996 (HIPAA).To measure the efficacy of the alert system, each patient’s home measurements were reviewed and abnormal values were cross-checked with the report of clinical alerts. If there were any discrepancies, a more detailed review was performed.Patient satisfaction was measured using a 12-question survey that was completed by participants after 20 weeks of platform usage. Questions were based on established satisfaction surveys that measure patient-centered outcomes . Survey P values and confidence intervals were calculated.Statistical analysis was used to compare trends in the patient data collected remotely versus collected in-office. All statistical analyses were performed in the R programming environment  . StandarFor this feasibility study, 8 patients were recruited and consented to participate at 8 to 10 weeks gestation, and were followed through delivery. Most patients were primiparous, married, with private insurance, and no major pregnancy risk factors. The age range of the participants was from 25 to 33 years with body mass indexes (BMIs) of 17.3 to 33.8 . One patP<.001) and mean number of blood pressure measurements  exceeded the number of data points collected in the office (10).Patient interaction with the mobile app averaged 5.5 times per week over the 6-month study period. Weight data collection averaged 1.5 times per week and blood pressure data collection averaged 1.1 times per week. One patient (#323) stopped collecting data after 29 weeks gestational age due to residence change. Remote patient monitoring increased the total number of data points collected throughout pregnancy compared to routine office measurements during prenatal care visits . The meaP>.05 for all patients)  of in-office systolic blood pressure values compared to home measurement. Diastolic measurements tracked very closely with systolic measurements.Weight measurements acquired by remote digital devices did not differ from in-office measurements (atients) . The difAfter reviewing data sets of all clinical variables and all organized alerts, no incidences of inappropriate alerts or unaddressed alerts were discovered. There was a total of 2 alerts fired during the study, both related to inappropriate weight gain (patient 313 and 323). Patient 313 did not gain weight over a 4-week interval, which generated an automatic clinical alert. As a result of this alert, the patient’s obstetrician was notified and subsequently scheduled a more urgent office visit and closer monitoring . For patThe patient satisfaction survey assessed themes of patient-provider relationship, engagement, patient education, and patient satisfaction and had a completion rate of 75% (6/8) . We atteAll 6 participants who completed the survey felt comfortable with the concept and technical aspects of remote monitoring, were able to easily access provider resources through Babyscripts, and had an easy time remembering to use Babyscripts. Most  of the participants felt that the app assisted with healthy pregnancy-related behaviors, were satisfied with prenatal care, felt more connected with their provider, and felt more knowledgeable about their pregnancy.The main finding of this study was that the use of a novel pregnancy platform, which incorporates remote monitoring and a clinical alert system, is feasible as evidenced by high patient-app engagement, accurate at-home measurements of weight and blood pressure, efficacy of the alert system, and high patient satisfaction scores.Interaction with the app met expectations and collection goals. The app was designed to provide regular educational information regarding pregnancy and prenatal care. Patient interaction with the mobile app averaged 5.5 times per week over the 6-month study period demonstrating that patients are visiting the app almost daily. The app was also designed to prompt patients to record weight and blood pressure at least weekly. Given these collection goals, the average interaction per week was chosen as a metric for engagement. Weight data collection averaged 1.5 times per week and blood pressure data collection averaged 1.1 times per week, which is a significant increase from the current standard of only recording blood pressure and weight during office visits. Based on discussions with experts, we concluded that more frequent readings were unlikely to add additional clinical information.Accuracy of remote measurements are essential to make appropriate clinical management decisions. Remotely collected data tracked closely with in-office data demonstrating the accuracy of the remote devices. Blood pressure values measured in the office were mildly (<10%) elevated compared to the remote measurements, which has been previously described in the literature comparing at home blood pressure measurements to office measurements .In addition, this platform demonstrated that automated alerts may be an effective way to notify the patient and provider regarding abnormal change in weight or blood pressure. The goal of the alert system is to facilitate earlier identification of pregnancy complications and optimize timely intervention. The described monitoring system has the ability to collect data more frequently than office visits alone, allowing for the potential to develop predictive models to screen normal pregnancies and identify pregnancy risk earlier.The major limitations to this study include the small sample size and the threat of selection bias due to a convenience sample. It is possible that our results will not be reproduced in a different population or larger population. There are a number of possible biases within the participant population that limit our ability to demonstrate feasibility. The limitations based on the breadth of the study population include a mostly married cohort with private insurance, and 75% (6/8) patients were experiencing their first pregnancy. The fact that this was their first pregnancy makes it difficult for them to compare mobile prenatal care with other models of prenatal care. None of the women had significant past medical history nor used tobacco. Despite the attempt to choose a healthy cohort of women, 25% (2/8) of the women did experience a complication of pregnancy, specifically growth delay in one fetus and preeclampsia in another. While the sample size was small, it was ethnically diverse including 3 Caucasian women, 3 African-American women, 2 Hispanic women, and 1 Asian-American woman. Future studies will include examining the efficacy within specific ethnic and racial populations.Second, researchers were not blinded to the purpose of the study, introducing the possibility of bias when assessing our primary outcomes. Finally, the lack of a comparison group limits the ability to draw conclusions about improved outcomes compared to usual prenatal care. However, this is a pilot study to determine the feasibility of a novel system, with plans for more rigorous studies in the future addressing these and other limitations.In the future, prenatal care is likely to incorporate more personalized care that integrates mobile technology, individualized risk stratification, and remote monitoring. As such, this study is the first to demonstrate the feasibility of using a digital health platform to remotely collect data in near real-time and to stratify for high-risk outcomes using an effective alert system. Future studies will compare prenatal care assisted by mobile health technology compared to routine care evaluating comparative-effectiveness and patient-centered outcomes.


Worldwide, at least 200 million people are affected by peripheral vascular diseases (PVDs), including peripheral arterial disease (PAD), chronic venous insufficiency (CVI) and deep vein thrombosis (DVT). The high prevalence and serious consequences of PVDs have led to the development of several diagnostic tools and clinical guidelines to assist timely diagnosis and patient management. Given the increasing number of diagnostic methods available, a comprehensive review of available technologies is timely in order to understand their limitations and direct future development effort.This paper reviews the available diagnostic methods for PAD, CVI, and DVT with a focus on non-invasive modalities. Each method is critically evaluated in terms of sensitivity, specificity, accuracy, ease of use, procedure time duration, and training requirements where applicable.This review emphasizes the limitations of existing methods, highlighting a latent need for the development of new non-invasive, efficient diagnostic methods. Some newly emerging technologies are identified, in particular wearable sensors, which demonstrate considerable potential to address the need for simple, cost-effective, accurate and timely diagnosis of PVDs.The online version of this article (10.1186/s12938-018-0494-4) contains supplementary material, which is available to authorized users. Peripheral vascular disease (PVD) is a major cause of morbidity and mortality globally, with significant financial burdens on critical healthcare resources –10. VascPeripheral arterial disease (PAD) occurs with narrowing or blockage of the arteries with the formation of fatty deposits/plaque also known as atheroma. The body segment supplied by the impaired artery is then deprived of oxygen-rich blood and nutrients , often rChronic venous insufficiency (CVI), also known as post thrombotic syndrome, occurs with unrestrained ambulatory venous hypertension associated with venous wall and value incompetence , 19. NorDeep vein thrombosis occurs with the formation of a blood clot in the deep venous system, most commonly in the lower limbs  . While sEarly diagnosis and management of PVD is crucial to address the high rates of mortality and morbidity, however around 50% of people are asymptomatic and therefore do not necessary seek medical assistance, or are not screened by clinicians in the absence of diagnosed disease. Establishing effective and efficient clinical non-invasive diagnostic tools to determine vascular competence is essential particularly for asymptomatic PVD patients who have the same risk of morbidity and mortality as those with more obvious symptoms , 28, 29.This paper provides a comprehensive review of the available non-invasive methods for the assessment of peripheral hemodynamic function in the lower extremities and recommendations for an ideal non-invasive diagnostic tool to confirm/exclude the presence of PVDs. Three primary validated non-invasive technologies  are discussed in detail. Subsequently, emerging diagnostic techniques are presented. The limitations and strengths of each method are identified, followed with recommendations for an ideal non-invasive method to diagnose PVDs.Plethysmography measures blood volume changes in the lower extremities. The principle of plethysmography for limb volume measurement was first introduced by Francis Glissonioin in 1677 using water displacement , 31. LatStrain gauge plethysmography (SGP) was first introduced in 1953 and later improved in the 1990s , 40–42. Strain gauge plethysmography’s reliability has been questioned because of the lack of validation studies . ReferenParameters indicative of DVT detection (venous emptying and venous outflow rate), muscle pump function (venous refilling volume), and the presence/absence of venous reflux  were tested for disease sensitivity . CombinePhoto plethysmography (PPG), first introduced in the 1930′s to assess the vascular system, uses an infrared light source and a light receptor to estimate the variation of blood volume . There aA study of 63 healthy subjects and 44 PAD patients compared PPG derived pulse wave analysis techniques extracted timing, amplitude and shape characteristics for both toes and for right-to-left toe differences and compared these to diagnosis using the Ankle Brachial Index Table . SensitiPPG has also been used to evaluate venous reflux, with a reported sensitivity of 100% and specificity of 60%, in a relatively small study of 10 healthy subjects and 10 subjects with deep venous reflux diagnosed using duplex ultrasonography . The venExaminations of the clinical utility of PPG in the diagnosis of deep vein thrombosis (DVT) have reported sensitivity between 83 and 100% and specificity between 35 and 89% Table  48–51].–51.48–51Thomas et al. used a different criterion for assessing the performance of LRR versus venography in a group of 131 legs with clinically suspected DVT, classifying a DVT by a flat or a virtually flat LRR trace . Using tIn 1939, Nyboer introduced the concept of impedance plethysmography (IPG), and in the 1970′s several IPG devices became commercially available particularly for the diagnosis of PVDs , 58. IPGIn a study of 33 legs with arteriography confirmed arterial obstruction greater than 50% diameter, compared to 28 healthy control legs, IPG waveform analysis  provided a sensitivity and specificity greater than 90% . ThreshoAnderson evaluated IPG for detecting CVI in 44 subjects compared to Doppler ultrasound . Venous Impedance plethysmography to detect the presence of DVT evaluates the patient in supine position with the leg elevated above the level of the heart Fig. . A thighAir plethysmography (APG) was first introduced by Christopoulos et al. in 1987 for evaluation of venous function in the lower extremities , 75. An In a study of 186 extremities, APG derived VFI demonstrated sensitivity of 80% and specificity of ~ 94% for detecting venous reflux when compared to venography and duplex scanning results . The invAir plethysmography can also be used to detect the presence of venous occlusion. Venous obstruction affects the relationship between venous volume and pressure , 77. HarSeveral plethysmography methods have been developed since 1677 for the assessment of peripheral vascular function noninvasively. Table Vascular ultrasonography is a non-invasive diagnostic method utilizing a handheld transducer to direct an inaudible sound wave with a frequency of 1–30 MHz into the vessel of interest to assess vascular competency . ComputeB-mode (brightness mode) ultrasonography or grey-scale imaging generates a two dimensional real-time picture to visualize the structure of blood vessels and provides information about diameter change in large veins , 82, 83.Dauzat et al. evaluated the clinical value of B-mode for DVT detection in a group of 145 patients and reported a sensitivity of 94% and a specificity of 100% compared to venography . O’LearyContinuous wave (CW) Doppler ultrasound is routinely used for clinical screening. Venous flow is heard as a low-pitched blowing sound and a normal venous blood flow should be in phase with respiration , 80. If Pulsed wave Doppler mode can be used for categorizing peripheral arterial stenosis . AlthougDuplex ultrasound combines the use of B-mode imaging, PW, CW Doppler modes when evaluation of the anatomy and hemodynamic function of the vascular system is needed . Duplex Duplex ultrasound is arguably the most important and widely used non-invasive tool for the investigation of chronic venous diseases . It can At the beginning of the 21st century, the use of duplex ultrasound was extended to detect venous obstruction and its extent . ContinuColour duplex imaging can also be used to evaluate the direction and velocity of blood flow and thus detect the location of arterial occlusion/stenosis and venous reflux , 98, 99.Vascular ultrasonography is one of the most commonly used non-invasive methods employed by vascular laboratories to define anatomy, hemodynamic and lesion morphology. Ultrasound examination is considered to be the gold standard and a very powerful tool in establishing diagnosis and aiding therapeutic management of chronic venous insufficiency and peripheral arterial disease, revealing sites of reflux and/or obstruction in the venous system, arterial occlusions and stenosis . HoweverIn the 1950′s, Winsor first described the Ankle Brachial Index (ABI), a simple non-invasive method for assessing arterial perfusion . It remaA single ABI measurement may not be sufficient for diagnosis even in symptomatic cases . In suchSegmental blood pressure measurement, unlike ABI measures, can be used to localize the site of stenosis or occlusion in PAD , 121. FoA reference arm blood pressure measure is also taken and normally is at least 30 mmHg lower than thigh pressure , 122. InLimitations of this method include inappropriate cuff sizing resulting in false blood pressure readings . An averToe blood pressure measurements to evaluate peripheral arterial disease was introduced in 1965 , 126 andA study of 174 subjects with diabetes and 53 non-diabetic subject found that diabetic patients with an ABI < 1.3 had ABI–TBI differences within the normal ranges for healthy controls, whereas those with an ABI ≥ 1.3 had abnormal ABI–TBI differences . The autA review of 22 studies  found TBThe measurement of toe blood pressure is technically more complicated than measuring ankle blood pressure . The addAlthough the ABI is relatively cheap, requiring minimal and inexpensive equipment, and is widely clinically applied, it has a low sensitivity when used in patients with diabetes or the elderly with calcified arteries, where the ABI values are inflated mimicking false negative normal values . This isPulse wave velocity is defined as the velocity at which the arterial pulse wave, generated by heart contraction, propagates through the arteries . The apparteries , 158. Paarteries . Howeverarteries .Although the use of PWV as a diagnostic measure is quite old, its use for the diagnosis of PAD is relatively new. In two studies with sample sizes of 105 and 440 healthy subjects and 35 and 38 subjects with PAD, PWV was reduced in the presence of PAD when measured between the heart-feet  and femoThe application of PWV as a measure of arterial stiffness has been motivated by the development of new devices to assist measurement. In a recent review PulsePen , Complior , SphygmoCor , photoplethysmography, ultrasound and magnetic resonance imaging (MRI) have been identified for non-invasive PWV measurement . A numbeVascular optical tomographic imaging (VOTI) is a new non-invasive imaging system, which can be used to directly measure distal perfusion in the foot by extracting information about haemoglobin concentration . AlthougThe system uses the transmitted lights to construct a cross-section image of haemoglobin concentration at the mid metatarsal region. Lower light intensities are indicative of higher haemoglobin concentration, which is itself representative of better perfusion .The VOTI system was originally introduced in 2007 and in 2015 the system was used to assess PAD in the lower extremities of a group of 40 subjects . SubjectA peak haemoglobin concentration threshold of 6.1% during 60 mmHg venous occlusion resulted in sensitivity of 85%, specificity of 73% and accuracy of 80% in detecting PAD . The reqRecently, the use of polymer-based sensors has shown potential for diagnosis of PVDs. Such sensors basically consist of two main components, a highly elastic polymer carrier (e.g. rubber) and an integrated conductive element (e.g. carbon). Typically, deformation of the sensor generates proportional changes in the impedance of the sensor.In 2014, Breen et al. embedded commercially available Conductive Rubber Cord Stretch Sensors , also known as Electro Resistive Bands (ERB), in a piece of stretchable fabric  in terms of sensitivity, specificity and accuracy is associated with this paper as Additional file Considering the prevalence and the adverse impacts of PVDs, it is no surprise that diagnostic methods have been developed since the 1670s. The timeline in Fig. Plethysmographic methods have the best utility to detect both arterial and venous disease including occlusions, chronic venous insufficiency and deep vein thrombosis. However, plethysmography devices are cumbersome and require a highly trained practitioner limiting their use. Plethysmography assessment also takes a considerable amount of time to complete, and typically lacks the potential to localize the site of stenosis/occlusion.Doppler methods can provide information about the location of vascular dysfunction. Duplex ultrasound is the gold standard method for PVD diagnosis and is the most sensitive non-invasive method that currently exists. However, similar to plethysmographic techniques, expensive equipment and highly trained practitioners are required. Also, Doppler vascular assessment is even more time consuming than plethysmography. As such plethysmography and Doppler methods have limited use for PVD screening or everyday use in the clinic.In contrast, ABI is relatively simple, fast and cheap and is recommended as an initial diagnostic tool in primary care, however it has poor sensitivity in patients with calcified arteries. Similar to plethysmography, ABI lacks localization capability. Other versions of brachial methods, such as the segmental blood pressure measurement, can assist pathology localization and toe brachial methods can counter medial artery calcification, increasing specificity for people with PAD and diabetes. However, segmental pressure measurement is not reliable and the Toe Brachial Index requires more time than an ABI, and specific environmental conditions.Many noninvasive methods have been developed to aid the diagnosis of PVDs. However, given the rising number of patients with PVD and the shortcomings of current methods, there is still a need for new non-invasive diagnostic tools. The continuous effort for proposing noninvasive techniques for diagnosis of PVDs over more than 300 years further highlights the need for developing new diagnostic techniques. While Duplex ultrasound and plethysmography can be excellent means of PVD diagnosis, training requirements limit their more widespread use. Any potential alternative should be intuitive and simple to use, minimizing these training requirements. The high cost of Doppler ultrasound and plethysmography devices is another hurdle against their availability. While asymptomatic patients are also at high risk of morbidity/mortality, the time and cost of such diagnostic methods typically limits their use for symptomatic patients.Ideally, a new solution will provide an early diagnosis of all three common types of PVD accurately, easily, cheaply, quickly and without extensive training. Advances in wearable technology and polymer-based sensors are probably the most likely candidates to address the clinician requirements for an ideal system. They may also provide continuous monitoring during functional activity and exercise, a capability that is notably missing in existing devices but which may add to diagnostic capability. No such wearable or polymer-based device is yet validated for diagnosis of any PVDs. However, the polymer-based technology is developing, with the prospect of providing early diagnosis due to their low-cost, minimum training requirement and the ability to provide relatively immediate information about both peripheral arterial and venous functionality.Additional file 1: Table S1. Summary of the performance of the discussed noninvasive methods used for PVD diagnosis.


The Care-Related Quality of Life survey for Chronic Heart Failure (CaReQoL CHF) is a newly developed patient-reported outcome measure (PROM) that measures care-related quality of life in patients diagnosed with chronic heart failure. This study describes the psychometric properties of the questionnaire and its relationship with disease severity and global rating of quality of care.Insurance companies selected patients with a recorded diagnosis of chronic heart failure and for whom the hospital submitted a billing statement in the last year. Exploratory factor analysis, Cronbach’s alpha and item-rest correlation were used to construct the CaReQoL CHF. Construct validity was assessed by examining the mean values of the CaReQoL CHF scales for the categories of the widely-used New York Heart Association (NYHA) functional classification and by correlating the global rating of quality of care with the CaReQoL CHF scales.One thousand eighteen patients with chronic heart failure filled out the CaReQoL CHF (RR: 35.7%). The CaReQoL CHF consists of 20 items and three scales: social and emotional problems, physical limitations, and being in safe hands. The mean scores of the three scales differed significantly for the NYHA categories, particularly for the social-emotional problems and physical limitation scales. The ‘being in safe hands’ scale showed a moderate positive correlation with the global rating of quality of care.The CaReQoL CHF is a concise and valid PROM that matches patients’ priorities in healthcare. It adds a new element to existing quality of life questionnaires for patients with chronic heart failure, that is ‘being in safe hands’ scale. This scale is relevant for patients because they experience anxiety and tension about their condition. Future research should determine whether the CaReQoL CHF can help healthcare providers in daily practice to focus treatment on outcomes of care that are relevant to individual patients. Healthcare providers have to take patients’ preferences and needs into account . AccordiAn advantage of using PROMs in clinical practice is that the outcomes can help healthcare providers monitor individual patients in between consultations and evaluate and manage their treatment , 4. In aIn people with a chronic illness, measurements of physical, mental and/or social functioning and/or  quality of life are often used to monitor outcomes of care , 8. WideOne such group with chronic disease is people with chronic heart failure. Patients with chronic heart failure suffer from shortness of breath, fatigue and swelling in the ankles and legs . In the Kelkar et al.  identifiIn the present paper we report on the development of a new PROM for chronic heart failure, which was deemed necessary as Dutch patients reported a key priority that was not captured in existing PROMs. This key priority was whether patients felt they were “safe”, that is, properly monitored such that they felt comfortable and confident to proceed with daily activities.Psychometric properties: what are the psychometric properties of the CaReQoL CHF in terms of dimensional structure and Cronbach’s alpha?Validity: how are the reported outcomes measured by the CaReQoL CHF related to disease severity and global rating of quality of care?Based on focus groups with heart failure patients and inspired by the MLHQ and the KCCQ, we developed the Care-Related Quality of Life survey for Chronic Heart Failure (CaReQoL CHF). In the present paper, we examine the psychometric properties and construct validity of the CaReQoL CHF. Our research questions were:In the literature review, we found that the following themes were common in existing disease-specific PROMs for chronic heart failure: physical limitations, participation in society, and feelings of anxiety or tension –26. We aWe selected 31 hospitals with a large number of declarations for heart failure. In each of these hospitals, insurance companies randomly selected roughly 100 patients with a recorded diagnosis of chronic heart failure and for whom the hospital submitted a billing statement in the last year . We selected patients from several hospitals via insurance companies because we wanted to get more insight in possible differences between hospitals and, more pragmatically, insurance companies were willing to help us get access to patients. Patients were able to choose whether they wanted to fill in the questionnaire online or on paper (mixed-mode). In week 1 patients were sent an invitation to fill in the online version of the CaReQoL CHF. In week 2 patients were sent a thank you/reminder note. In the event of non-response, patients were sent a paper version of the CaReQoL CHF in week 5 and a final reminder in week 7. No ethical approval and consent for publication for the study was necessary, as research by a non-encroaching survey such as used in this study is not subject to the Dutch Medical Research Involving Human Subjects Act (WMO).In the present paper, the reliability and validity of the CaRe-QoL CHF will be addressed. Furthermore, the dimensional structure was assessed with exploratory factor analysis (promax rotation), including Bartlett’s test of sphericity and Kaiser-Meyer-Olkin as a measure of sampling adequacy. We used listwise deletion for the factor analysis, meaning that only respondents with no missing values were taken in account. This avoids imputation of missing items. As a rule of thumb, items with a factor loading higher than .6 were included in the CaReQoL CHF. Cronbach’s alpha and item-rest correlation gave insights into the test reliability of the scales and redundant items . The selp < .001), indicating that the variables correlated highly enough for factor analysis. The Kaiser-Meyer-Olkin value was high, with a score of .93, indicating factor analysis should yield distinct and reliable factors. Following factor analysis  and reliability analysis, 20 items were retained in the final version of the CaReQoL CHF. The results of the factor- and reliability analyses for those items are presented in Table The CaReQoL CHF was filled out by 1018 respondents (RR: 35.7%). Table Factor analyses resulted in three scales: (1) social and emotional problems, (2) physical limitations and 3) being in safe hands. One item about having contact with friends and family was retained despite the slightly lower factor loading (.59), because patients talked about the subject a lot in the focus group discussions. Table  being inp-values <.05). Social and emotional problems were positively related to physical limitations (r = .63) and negatively related to ‘being in safe hands’ (r = −.24). Physical limitations were negatively associated with being in safe hands (r = −.08).Correlation between the scales ranged from −.08 to .63 (p < .05) for every scale of the CaReQoL CHF between the four NYHA categories . This means that the more social and emotional problems and physical limitations a patient experiences, the lower their global rating of quality of care. Being in safe hands was positively associated with global rating of care . Therefore, the more they felt they were in safe hands, the higher the global rating of quality of care.The scales social and emotional problems and physical limitations showed a small negative association with global rating of quality of care  can be alleviated by knowing that healthcare providers are watching over them. This is also found in a meta-analysis  and a stWe regarded ‘being in safe hands’ as an outcome of care. However, it could also be argued that it is a process aspect of care because it comprises aspects of care delivery and care coordination . In addiA limitation of this study was that the (self-reported) NYHA classification was used for criterion validation, although we concede of course that there are no real gold standards in the validation of outcome measurements , 41. FurThis study is to be considered a starting point in the development of the CaReQoL CHF. It would be valuable to perform confirmatory factor analysis and to assess the convergent validity of the CaReQoL CHF by comparing scores with those on questionnaires such as the MLHQ and KCCQ. Future research may also employ longitudinal measurement with the CaReQoL CHF to assess the responsiveness of the CaReQoL CHF. Responsiveness addresses the ability of a PROM to detect change over time in the construct measured . The preWe developed a new instrument for measuring care-related outcomes in patients suffering from chronic heart failure, the CaReQoL CHF. It is a concise and valid PROM that matches patients’ priorities in healthcare. The instrument requires further validation, but possesses at least one promising feature that may be relevant for chronic heart failure patients in general, which is that it covers the theme ‘feeling in safe hands’. This theme was identified as being very important by the patients, but lacking in existing PROMs. In addition, the instrument is rather short compared to other existing instruments which is generally considered desirable. Future research should further establish the validity and reliability of the instrument by comparing scores with those on other questionnaires and possibly confirmatory factor analysis.


Patients were stratified into four groups using sex-specific median values of LVMI and rapid eGFR decline. The composite outcome was progression to maintenance dialysis or death. 32 patients had the composite outcome during a median follow-up of 2.7 years. In multivariate Cox analysis, compared with patients with non-rapid eGFR decline and lower LVMI, those with non-rapid eGFR decline and higher LVMI , rapid eGFR decline and lower LVMI , and rapid eGFR decline and higher LVMI  had an increased risk of progression to adverse outcomes. LVMI and eGFR decline synergistically effect the prognostic implications in CKD G3 and G4 patients.The effect of left ventricular mass index (LVMI) and estimated glomerular filtration rate (eGFR) decline rate on outcome prediction in patients with chronic kidney disease (CKD) remains unclear. We included 306 CKD G3 and G4 patients with LVMI assessed through echocardiography. Rapid decline in renal function was defined as the eGFR slope <−3 mL/min/1.73 m Chronic kidney disease (CKD) is an emerging major public health issue worldwide. Some patients with CKD experience a progressive loss of kidney function and progression to end-stage renal disease. Furthermore, many patients with CKD may not survive to reach the maintenance dialysis stage13567CKD considerably increases the risk of CVD. Given that CKD and CVD share many of the same risk factors, abnormal cardiac structure and function is one of principal predictors of adverse clinical outcomes1011Therefore, the present study investigates whether the combination of the LVMI and eGFR decline rate is associated with the composite outcome of disease progression to maintenance dialysis or death in CKD G3 and G4 patients.2 and female: 118.9 g/m2), 306 patients with CKD G3 and G4 were stratified into four groups. On the basis of the decline rate in renal function  and sex-specific median value of the LVMI . The median eGFR slope value was −0.9  mL/min/1.73 m2/year. Patients with rapid eGFR decline and a higher LVMI were more likely to have lower baseline eGFR and lower serum albumin levels, as well as higher systolic blood pressure, uric acid levels, and proteinuria prevalence, and a higher number of serum creatinine measurements compared with those with non-rapid eGFR decline and a lower LVMI.Of the 306 patients, 217 (70.9%) were men, and 174 (56.9%) had diabetes. The mean age was 67.1 ± 11.6 years and the mean baseline eGFR was 33.4 ± 10.8 mL/min/1.73 mIn total, 18 patients died  and 14 progressed to maintenance dialysis during a median follow-up of 32.0  months. 2 = 35.87 to 61.78, p-value < 0.001). Furthermore, the addition of the LVMI to the model containing adjusted model and the eGFR decline rate resulted in further significant improvement in the prediction of the composite outcome .We analyzed the effect of adding the LVMI on the prediction of the composite outcome . The adjWe also identified the risk factors for the each two outcomes. High LVMI, fast decline in eGFR, and low baseline eGFR were associated with commencing dialysis . High LVThis study investigated the effect of the interaction between the LVMI and renal function decline rate on the adverse outcomes in patients with CKD G3–4 over an observation period of 2.7 years. Our results showed the synergistic effect of the LVMI and eGFR decline rate on the prediction of an unfavorable composite outcome, including maintenance dialysis or death in patients with CKD G3 and G4.CKD and CVD share certain risk factors, such as hypertension, vascular stiffness, and endothelial dysfunction10et al.The well-known risk factors, such as the baseline eGFR, proteinuria, and arterial hypertension, contribute to the development of unfavorable outcomes in CKD. However, the mechanisms involved in CKD progression are complicated, and these traditional elements cannot explain the entire risk of CKD progression. Paoletti 2/year, respectively. The observation period is not long enough to have renal progression to maintenance dialysis in these patients. Besides, the relatively small number of events  might be one of the reasons of incomplete analysis. Because the study included only patients with G3 to G4 CKD, our results might not be generalizable to all CKD populations. Future work that includes more patients with different stages of CKD is necessary for more clearly elucidating the relationship between the LVMI and renal function decline rate. Additionally, cardiac magnetic resonance imaging (CMRI) is the gold standard tool for assessing LV dimensions as well as the degree of cardiac fibrosis in CKD patientsBased on the competing risk between maintenance dialysis and death in CKD patients, we performed competing risk analysis and the adjusted HR of death in those with rapid eGFR decline and higher LVMI compared to those with non-rapid eGFR decline and lower LVMI was 11.027 , G4 (eGFR = 15–29 mL/min/1.73 m2), and G5 (eGFR <15 mL/min/1.73 m2) based on the participants’ baseline eGFR. However, we excluded 5 patients who refused to undergo echocardiography, 8 patients with poor quality of echocardiographic image visualization, and 51 patients with less than three available serum creatinine measurements during follow-up. We also excluded 9 patients who died and 30 who required dialysis therapy within 3 months after study enrollment to avoid incomplete observation of decline in renal function. Moreover, 109 patients with CKD G5 were excluded because of complex factors influencing outcomes and dialysis commencement decisions20This was a retrospective and observational study at a regional hospital in Taiwan. 518 dialysis independent patients with CKD G3 to G5 were enrolled from the outpatient department of internal medicine during January 2007–May 2010. Kidney function was quantified as the eGFR calculated by the equation of the 4-variable Modification of Diet in Renal Disease (MDRD) Study3 − LVIDd3] − 13.6. LVMI was calculated as LV mass divided by body surface area.To assess cardiac structure and function, echocardiographic examination was performed using VIVID 7  by two experienced cardiologists blinded to the clinical data of the study patients. Two-dimensional and two-dimensionally guided M-mode images were recorded from the standardized views according to the American Society of Echocardiography recommendationsvs. never), examination findings , renal function status (baseline eGFR and proteinuria), and medications . Demographic characteristics and medical history were obtained through the baseline medical chart records and by reviewing physicians’ charts and interviews with the study patients. BMI was defined as body weight (in kilograms) divided by the squared height (in meters). Blood pressure was measured using a manual sphygmomanometer at the baseline visit with participants in the sitting position after 5 minutes of rest. Overnight fasting blood samples were measured for laboratory data. The compensated Jaffé method was used for measurement of serum creatinine. Proteinuria was detected by dipsticks . Proteinuria of ≥1+ was defined as a positive result. Urine and blood samples were measured within one month of study enrollment.We collected baseline variables of the study patients at the baseline visit, including demographic characteristics (age and sex), comorbidities, such as diabetes, hypertension, coronary artery disease, cerebrovascular disease, smoking habit  for the triglycerides level, intact parathyroid hormone level, and number of serum creatinine measurements. The study participants were stratified into four groups according to the decline rate of kidney function (non-rapid or rapid eGFR decline) and sex-specific median value of the LVMI. Multiple comparisons among the study groups were performed using one-way analysis of variance followed by a post hoc test adjusted with a Bonferroni correction. The survival curve for the composite outcome was illustrated using the Kaplan–Meier method and the four groups were compared using the log-rank test. Time to the composite outcome and covariates were analyzed using a Cox proportional hazards model. Covariates were selected into multivariate Cox models if their p-value was <0.05 in univariate analysis. A p-value of <0.05 was considered statistically significant. Statistical analyses were conducted using SPSS 22.0.0.0  and SAS 9.2  for Windows.Data presented as percentages for categorical variables were analyzed using the How to cite this article: Huang, J.-C. et al. Prognostic Significance of Left Ventricular Mass Index and Renal Function Decline Rate in Chronic Kidney Disease G3 and G4. Sci. Rep.7, 42578; doi: 10.1038/srep42578 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


It has been suggested that an inadequate blood supply caused by uterine fibroids may lead to decreasing fertility. Therefore, a quantitative evaluation of blood flow in the uterus might be a good tool for infertility treatments. For the first step, the ability to perform arterial spin labeling (ASL)-MRI in pelvic organs was examined by measuring blood flow in the uterine muscle layer.Three normal volunteer women, seven patients with one uterine fibroid and four patients treated with GnRH analogue for uterine fibroids, were enrolled in this study. Perfusion of normal uterine myometrium was examined using non-enhanced ASL-MRI. The region of interest was set in the uterine muscle layer, with a point in the iliopsoas or gluteus muscle. The ASL perfusion index was calculated as . The ASL perfusion indexes in the secretory phase of all 3 volunteers were significantly lower than the indexes in the proliferative phases (P < 0.05). In patients with fibroids, all three types of fibroids  were included. In seven patients harboring a single uterine fibroid, the ASL perfusion indexes of myometrium on the fibroid-positive side increased 4.9 fold compared with that of the fibroid-negative side. With GnRH analogue treatment, ASL perfusion in myometrium decreased to 39% on average (P < 0.05).We utilized the ASL-MRI technique to evaluate perfusion of uterine myometrium. For clinical use, an inadequate blood supply caused by uterine fibroids is known to lead to decreasing fertility. The ASL-MRI technique might be useful to evaluate blood supply as a quantitative measurement of fertility in patients with uterine fibroids. In the uterus, adequate blood flow is important to maintain fertility, while vascular abnormalities are associated with clinical symptoms such as abnormal bleeding, implantation failure and gestation discontinuation  techniques have been examined to assess tissue perfusion without contrast media. ASL is a Magnetic Resonance (MR) perfusion method using magnetic-labeled arterial blood water as an endogenous tracer. ASL is thought to be especially useful for evaluating cerebral blood flow .From August 2012 to September 2013, non-enhanced MR perfusion studies using ASL were performed on volunteers and patients with fibroids as part of the routine pre-operative MRI examination at Yaesu Clinic. This study was approved by the institutional reviewed board, and informed consent was obtained from the patients for the examinations.2, imaging/tagging slice thickness 10/200 mm. Imaging time for each inversion time was 90 s. The slice which exhibited the maximum area of uterine fibroid was used.Uterus perfusion measurements were acquired in an axial slice on a 3 T Philips Achieva  with 32ch Cardiac Torso coil using a FAIR single shot Turbo spin-echo acquisition scheme. Briefly, labeling pulse was positioned to cover bilateral common iliac arteries. From 1 to 3 s after labeling, signal intensities were measured at uterus. Detail Parameters were as followed; repetition time/echo time 3600/5.9 ms, echo train length 21, matrix 128 × 96, FOV 230 × 230 mmIn a pilot study, we examined various scan timings of the ASL signal after labeling. As shown in Fig. 2 diameter circle. We set 4–5 points of the ROI in the uterine muscle layer, a point in the iliopsoas/gluteus muscle, which was shown in the same image, and a point in the air as background. The perfusion index was calculated as . To compare data of different time points, data were corrected by adjusting background ASL value. We examined various subjects as described below.A visual evaluation of the colored perfusion map calculated on the MR scanner using software provided by the MR vendor and a region of interest (ROI) analysis were performed by two experienced radiologists. The ROI consisted of a 5 mmTo examine the effect of hormonal status, the ASL perfusion indexes of uterine muscle were obtained in proliferative and secretory phase, respectively, from three healthy volunteers who had regular menstrual cycles and normal uterus and ovaries . The uterine cavity was divided into five equal parts in the image, and five points of ROI were set at muscle layer just outside of the junctional zone. ROIs were set at the same locations in both proliferative and secretory phases.To examine the effect of uterine fibroids, we evaluated seven patients who each possessed one fibroid. In this examination, all subjects were examined during the proliferative phase. We set 2 ROIs at muscle layer, just outside of the junctional zone, on the fibroid-positive side and -negative side, respectively. We then determined the average ASL perfusion index on each side, and compared the averages for the fibroid-positive and -negative side.Four patients with uterine fibroids treated with GnRHa were enrolled in this study (one patient with a single fibroid and three patients with multiple fibroids). In this examination, the subjects underwent their first MRI during the proliferative phase, and ROIs were set at myometrium, just outside of the junctional zone. After two or three rounds of GnRHa, the patients underwent a second MRI. ROIs were set at the same locations in myometrium before and after GnRHa treatment, and ASL perfusion indexes were compared.Statistical analysis was performed by using JMP Pro 11 software . ASL perfusion indexes are shown as the mean + S.E.M relative to an adjusted value of 1.0 for the mean value of the other one. The data were analyzed by the student’s t test for paired comparison. A P value of less than 0.05 was considered significant.The ASL perfusion indexes of myometrium in normal uterus were measured in the proliferative and secretory phases. Signal intensities during the secretory phase were evaluated as a relative ratio to that of the proliferative phase. As shown in Fig. Figure Table The effect of GnRHa on ASL perfusion in myometrium was evaluated. ASL data obtained from 4 ROIs were averaged. The fibroid size and ASL perfusion index of all patients decreased after GnRHa treatment Table . The perThere is no correlative relationship between the decreasing ratio of fibroid size and change in ASL index before and after GnRHa.In the present study, we utilized the ASL-MRI technique to evaluate perfusion of myometrium, and showed the ability to perform the technique by the findings that (1) normal myometrium perfusion during the secretory phase was significantly lower than that of the proliferative phase, (2) perfusion of myometrium on the fibroid-positive side was significantly higher than that of the fibroid-negative side and (3) with GnRHa treatment, ASL perfusion in myometrium decreased to 39% on average.The two most common methods for measuring perfusion with MRI are based on dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) (Wolf and Detre Secondly, we used the ASL-MRI technique to demonstrate the influence of fibroids in myometrium perfusion. Doppler ultrasound examination revealed that in women with fibroids, blood flow in the uterine artery was higher than in women without fibroids (Sladkevicius et al. In recent studies, fibroids have been shown to exhibit high levels of pro-angiogenic factors, which cause an increase in angiogenesis and vascular density in the normal myometrium surrounding fibroids (Tal and Segars Finally, we confirmed that the ASL-MRI technique could detect the decrease of myometrial blood supply with GnRHa treatment. The use of GnRHa prior to fibroid surgery reduces fibroid volume, and also improves pre-operative anemia, and intra-operative blood loss (Lethaby et al. In the present study, we could not compare ASL signal data with perfusion data obtained by using contrast agents, due to the clinical limitations in which contrast agents were not used for patients with fibroids in our clinic. In the brain MRI, it appears that blood flow can be estimated correctly in the grey matter of the brain by using ASL techniques (Wintermark et al. We evaluated myometrium perfusion using ASL-MRI. This technique has successfully been performed in the uterus to assess tissue perfusion without contrast media. Future uses of this technique may include fibroid analysis in the investigation into infertility and assessment of malignant tumors.


Restless legs syndrome (RLS) is a frequent sensorimotor disorder characterized by an urge to move the legs, with symptoms appearing during the night and disturbing nocturnal sleep. There is a growing body of evidence that RLS correlates with an increased risk of cardiovascular diseases and hypertension. The aim of this study was to test the hypothesis that patients with RLS have higher blood pressure (BP) during the night than people without RLS.We have analyzed polysomnographic (PSG) recordings of 30 patients with RLS and 27 subjects without the sleep disorder. During PSG, beat-to-beat BP measurement was performed.p < 0.05; 123.5 vs. 116.1 mmHg, p < 0.05). There was no noticeable dip in the values of nocturnal systolic pressure of patients with RLS.Patients with RLS have higher nocturnal and sleep-time systolic blood pressure compared to controls (124.4 vs. 116.5 mmHg, Our results support the hypothesis that RLS and hypertension are linked. Thus, we believe patients with RLS require close observation with regard to cardiovascular risk factors. Restless legs syndrome (RLS) is a sensorimotor disorder with a prevalence in the general population of 5–8.8 %  and is cAs described in an extensive review by Ferini-Strambi et al. , mountinAttempts to explain the relationship between RLS and BP on the basis of the microarchitecture of sleep have focused on the role of periodic limb movements in sleep (PLMS). PLMS are stereotypical, involuntary movements of the lower limbs during sleep, lasting from 0.5 to 10 s, in series with intervals of 5 to 90 s between single movements . An incrA possible role of RLS as a risk factor for hypertension or cardiovascular morbidity was analyzed in large epidemiologic projects. The impact of PLMS on blood pressure was assessed in single night polysomnographic studies. RLS and PLMS are frequently considered as a clinical continuum although they are not synonymous. Therefore, publications focusing on the influence of RLS on nocturnal blood pressure are missing. Based on these data, the aim of this study was to test the hypothesis that nocturnal blood pressure is higher in patients with RLS than in subjects without sleep disorders.We performed a retrospective analysis of polysomnographic (PSG) recordings and clinical data of 30 consecutive patients with RLS, diagnosed at the Vitalmed Sleep Clinic in Helsinki, Finland. All patients were diagnosed according to the International Restless Leg Syndrome Study Group (IRLSSG) diagnostic criteria . The diaTwenty-seven subjects with no clinical sleep disorder were included as the control group. These subjects were consecutive patients that underwent a somnological diagnostic battery due to subjective complaints of daytime fatigue or sleepiness, and the results of the diagnostic procedures  revealed that no control subjects had any significant sleep disorder. The subjects underwent a PSG recording and were included only if they were not prescribed any drugs potentially influencing sleep architecture. The clinical data of the patients were taken from their medical files.The examined and control groups were selected to detect a 10 % difference in values of blood pressure with power test 0.75 ).Patients underwent a single PSG study. All recordings were performed with the SOMNOscreen plus PSG system . Sleep recordings included four EEG leads, two bilateral electro-oculogram leads (EOG), bilateral chin electromyographic leads (EMG), two surface EMG leads placed on the left and right anterior tibialis muscles (recording periodic limb movements (PLMs) in sleep and wake). Respiration was recorded with a nasal cannula, thoracic and abdominal strains, and finger oxymetry. Electrocardiograms were recorded with a single precardial lead. The PSG included beat-to-beat blood pressure measurement determined via measurement of pulse transit time (PTT) . The meaThe PSG recordings were scored according to the American Academy of Sleep Medicine guidelines . The folFor the assessment of the cardiovascular system, the following values were calculated: mean systolic and diastolic blood pressure , and heart rate (HR) during the “day” , during the night (defined as the time between “lights-off” and “lights-on” moments), and during wake and sleep periods.Values of nocturnal and diurnal blood pressure were compared between patients with RLS and controls. Values of daytime and sleep BP were compared for each group to check whether a nocturnal dipping of BP appears. Patients with RLS were further divided into 2 subgroups: subjects with a significant (>15) PLMSI and subjects without significant PLMSI The cut-off value of PLMSI >15 was chosen accordingly to available literature . Values The study was approved by the Independent Bioethical Committee for Scientific Research at the Medical University of Gdansk.Participants included 30 RLS patients and 27 controls. Their demographic and clinical data are presented in Table Patients with RLS had shorter total sleep time, lower sleep efficiency, longer sleep latency, longer time of wake after sleep onset, and a higher index of periodic limb movements (PLMS-I). Nineteen patients with RLS (63.3 %) had PLMSI higher than 15. The exact data on sleep parameters are presented in Table Mean values of blood pressure measured during daytime and wake did not differ between the groups. There was a statistically significant difference in mean values of systolic blood pressure measured during nighttime and during sleep Table .Table 3MIn the control group, values of systolic BP during the night and sleep were significantly lower than the values of systolic BP during the day. However, no such difference was observed in the RLS group, nor was it observed for the values of diastolic BP in either group Table .Table 4Dr = 0.24; p = 0.07) and nocturnal diastolic BP  in the examined population  and without increased PLMSI .Logistic regression models were built to clarify the relation between sleep parameters and systolic BP during night and sleep. The only significant factor influencing the values of systolic blood pressure in night and in sleep was PLMSI  between values of daytime (evening) and nighttime values of systolic blood pressure.We have compared very similar groups of subjects, differing clinically in terms of the presence of RLS. Prevalence of symptoms of metabolic syndrome and cardiovascular morbidity was not significantly higher among patients with RLS, which remains in concordance with results of epidemiologic studies , 19, 20.Our findings are in concordance with the results of studies showing a higher prevalence of cardiovascular risk factors, like hypertension or hypercholesterolemia in patients with RLS. Such a conclusion was drawn from both large population-based studies , 19–24 aThe patients with RLS in our study had significantly higher values of nocturnal systolic blood pressure compared to the controls. A number of published articles have described the connection between RLS and/or PLMS, and increases in both heart rate and blood pressure. For example, Manconi et al. found a significant increase in heart rate following PLMS . PennestThe higher values of nocturnal systolic BP found in patients with RLS may be related to their disturbed sleep architecture. Indeed, patients with RLS had longer sleep latency and longer time of wake after sleep onset (WASO) what may result in higher values of BP in night. It must be noted then that systolic BP measured separately for the period of sleep was also higher in the group of patients with RLS.Surprisingly, significant differences between the groups were found only for values of systolic blood pressure. Values of diastolic blood pressure were higher in the RLS group but that difference did not reach statistical significance. Data published so far showed that RLS and/or PLMS influence both systolic and diastolic BP, nevertheless some exceptions. Siddiqui et al. found that PLMS without arousal did not lead to a significant increase of diastolic BP . Oh et aWe also noted that unlike the control group, in which systolic blood pressure dipped at night, there was no significant change from diurnal to nocturnal systolic blood pressure in the group of patients with RLS. Notably, recently published data showed that RLS is an independent determinant for a non-dipping blood pressure pattern . FurtherAnother issue requiring further studies is the time course of changes of BP during the nights in patients with RLS. In our study, we have focused on overall nocturnal blood pressure while it would be of interest to observe whether values of BP differ between parts of nights dominated by slow-wave sleep and REM sleep. Such an analysis should become a part of upcoming projects.The main limitation of our study, besides the relatively small group size, was that the patients were not drug-naïve in terms of antihypertensive drugs. Nevertheless, it was determined that the drug regimen was stable in the patients. The relatively low BP in both groups suggests that hypertension was well controlled in the patients, and the lack of difference in the daytime BP between the groups  allows us to draw conclusions from the comparison of nocturnal blood pressure.Participants of our study underwent only a single night in a sleep laboratory, and some changes in their sleep architecture could result from the first night effect. We wanted our results to be comparable with results from other groups, and published papers focusing on relation between RLS, PLMS, and BP were based upon single night observations –15, 31.Another factor that could have influenced our results was presence of respiratory effort related arousals (RERAs). Patients with sleep-related breathing disorders were excluded from the study, and therefore, RERAs were not included in the analysis. It was believed that in groups selected in this way, respiratory events would not have much impact on values of blood pressure. Nevertheless, in must be remembered that RERAs, when present, have a significant impact on functions of cardiovascular system , 33. TheOur study showed that patients with RLS are at a higher risk of developing increased blood pressure during the night. This result does not establish a causal relation between RLS and hypertension, but some practical conclusions may be drawn from this study. First, blood pressure in patients with RLS should be monitored with 24-h ambulatory blood pressure monitoring (ABPM), as they may have normal values of blood pressure during the day but increased blood pressure at night. Second, a higher evening dose of the patient’s preferred antihypertensive drug should be considered in patients with RLS and hypertension, in an effort to prevent the increased nocturnal blood pressure. Future studies should concentrate on (1) clarifying the direction of the relationship between RLS and hypertension, (2) clarifying the relationship between RLS and metabolic disorders such as hypercholesterolemia, and (3) assessing the influence of RLS therapy on the dysregulated blood pressure.


Robot-assisted laparoscopic radical prostatectomy and robot-assisted radical cystectomy have gradually become the preferred choices for urologists as they allow surgeons to perform complex procedures more precisely and effectively. The pneumoperitoneum, which is normally applied in these surgeries to provide visual clarity and space to perform the procedure, may cause hemodynamic disturbance, potentially myocardial injury. Thus surgeons have recently considered opting for the low-pressure pneumoperitoneum to lower this negative impact.Herein we describe a protocol for a clinical trial to compare the impact of prolonged low-pressure and standard-pressure pneumoperitoneum on myocardial injury after robot-assisted surgery.This study is designed to be a bicenter clinical trial. In total 280 patients scheduled to undergo robot-assisted laparoscopic radical prostatectomy or robot-assisted radical cystectomy will be enrolled and randomized into two groups, with standard- (12–16 mmHg) and low-pressure (7–10 mmHg) pneumoperitoneum, respectively. Troponin T will be measured as the primary endpoint to assess the extent of myocardial injury. Nt-proBNP and hemodynamic indexes will also be recorded for further analysis.The significance of this study is emphasized by the fact that there are few studies that have focused on the impact of prolonged pneumoperitoneum on myocardial injury, which is relevant to postoperative mortality. We hope that the conclusions drawn from this study could provide reference and basis to the future of the pneumoperitoneum in clinical practice.https://www.clinicaltrials.gov with the Identifier NCT02600481 on November 5, 2015Registered at The online version of this article (doi:10.1186/s13063-016-1609-5) contains supplementary material, which is available to authorized users. Robot-assisted surgery allows doctors to perform complex procedures with more precision, flexibility and control. As two major applications, robot-assisted laparoscopic radical prostatectomy (RALRP) and robot-assisted radical cystectomy (RARC) were firstly reported in 2000 –3 and 202, and an intra-abdominal pressure (IAP) of 12 to 16 mmHg is considered to be appropriate. SPP usually changes the IAP and systemic hemodynamics [2 pneumoperitoneum is performed, the absorption of CO2 may lead to arrhythmias, mild acidemia and even severe acidemia; mean blood pressure, heart rate and pulmonary vascular resistance can also be increased [Standard-pressure pneumoperitoneum (SPP) is usually achieved by insufflating the abdominal cavity with COdynamics  causing dynamics . Cardiacdynamics , renal [dynamics  and testncreased . RALRP ancreased . The prencreased , 20. All2 as compared to LPP in laparoscopic cholecystectomy [To lower the impact of pneumoperitoneum on myocardial physiological status while providing appropriate space for operation, low-pressure pneumoperitoneum (LPP) at a range of 7–10 mmHg is considered optimum by surgeons. Numerous clinical trials have been done to compare LPP with SPP in laparoscopic cholecystectomy, the duration of which is often under 2 h . A high stectomy . Cardiacstectomy . Prolongstectomy . In addistectomy . A randostectomy , 26. Huastectomy . Prolongstectomy . An elevstectomy . The N-tstectomy . It has stectomy .The present study was designed to compare the effects of prolonged LPP and SPP on myocardial injury after a relatively long period of surgery. The TnT level is chosen as a primary endpoint for the evaluation of myocardial injury as it has been shown to be a sensitive predictor of cardiac injury. Our working hypothesis is that LPP can result in improved myocardial outcome after robot-assisted urological surgery.This study is a prospective, bicenter, single-blinded, randomized controlled clinical trial to investigate the different effects of prolonged LPP and SPP on myocardial injury after RALRP and RARC Fig. .Fig. 1StPatients who are scheduled to undergo long-duration RALRP or RARC in the Huadong Hospital Affiliated to Fudan University and the Ruijin Hospital Shanghai Jiao Tong University School of Medicine, in line with the inclusion criteria, will be recruited. From the previous data and estimation, the annual number of patients meeting the criteria is over 170.Scheduled to undergo RALRP or RARC, with an estimated duration of over 3 hAmerican Society of Anesthesiologists’ (ASA) classification of I or IIAge is between 18 and 80 yearsPreoperative troponin T level is normalInclusion criteria:Patients with preoperative cardiopulmonary dysfunction who cannot undergo prolonged surgeries in the Trendelenburg position and/or those with severe pulmonary dysfunction with a New York Heart Association (NYHA) classification of III–IVBody Mass Index >30 and weight <18 kgAny intraoperative situation as follows: (1) any cause to cancel the operation or change robot-assisted urological surgery to open surgery, (2) intraoperative cardiovascular accidentsExclusion criteria:This clinical trial will be conducted in the Huadong Hospital Affiliated to Fudan University and the Ruijin Hospital Shanghai Jiao Tong University School of Medicine, which are tertiary referral centers in Shanghai, China.2 pneumoperitoneum will be administrated using automatic insufflators .This study will consist of two arms, the low-pressure pneumoperitoneum group (LP) and the standard-pressure pneumoperitoneum group (SP). The estimated number of patients hospitalized for prolonged robot-assisted urological surgery is 140 in each group. The IAP for the LP group will be held at 7–10 mmHg, while it will be held at 12–16 mmHg for the SP group, both insufflated at low speed (2 L/min), during the robot-assisted urological surgery. The COThis will be from 1 January 2016 to 31 December 2017.2/ETCO2) and invasive measurements of blood pressure will be exerted on all the subjects involved. All subjects will be premedicated with midazolam 2–4 mg administered intravenously after peripheral intravenous (IV) access has been established, following which a central venous catheter will cannulate the right jugular vein. General anesthetic induction will be performed with lidocaine (1 mg/kg), sufentanil (0.3 μg/kg), propofol ) and rocuronium (0.6 mg/kg) administered intravenously in sequence. Endotracheal intubation will be performed after muscle relaxation is adequate (TOF is 0). Two to three percent (1.0–1.5 MAC) sevoflurane in a 50:50 (v/v) oxygen-air mixture (1 L/min) and remifentanil (0.1–0.3 μg/kg/min) will be used for anesthetic maintenance until the end of surgery. To achieve adequate analgesia, sufentanil (0.15 μg/kg) will be administered additionally at the time of incision and suture, respectively. To maintain appropriate neuromuscular block, cisatracurium is continuously infused at a rate of 1–2 μg/kg/min until 20 min before surgery completion. Depth of anesthesia is monitored with Narcotrend  and the ideal value is 37–64.Clinical monitoring throughout the surgery, including electrocardiography, arterial oxygen saturation/end-tidal carbon dioxide  and Ringer’s solution are continuously infused at a ratio of 1:3 to replace fluid losses . When it is imperative, blood products are transfused to maintain physiological balance.2 level within 35–55 mmHg, the tidal volume or the respiratory rate will be adjusted appropriately.The patients will be mechanically ventilated using volume-controlled ventilation mode and a protective lung ventilation strategy. To maintain an ETCOPatients will be extubated in the Postanesthesia Care Unit (PACU). This action allows the depth of anesthesia to be maintained at a constant level until the last measurement is completed. A patient-controlled intravenous analgesia (PCIA) pump with a concentration of 1.5 mg/mL flurbiprofen axetil injection will be used for all patients postoperatively.During the surgery, a Trendelenburg position of 30° will be applied to all the subjects involved. The position will be adjusted by using the in-built Compass app for the iPhone 6S , stroke volume (SV), stroke volume variation (SVV) and cardiac output will be measured using the FloTrac system .The troponin T level is set as the primary endpoint for this trial to evaluate myocardial injury, and this will be measured for each patient who will undergo prolonged robot-assisted urologic surgery at the following four time points: Ta (2 to 3 h after surgery), Tb (6 h after surgery), Tc (12 h after surgery) and Td (24 h after surgery) using the fifth-generation high-sensitivity TnT assay.2 pneumoperitoneum is established), T3 (5 min after positioning in the Trendelenburg position), T4 (45 min after Trendelenburg positioning) and T5 . Respiratory parameters  and tidal volume (Vtide)) will be recorded at all five time points mentioned above.Nt-proBNP levels will be measured and recorded at the same time points as for TnT, by the Cobas e 411 analyzer . Hemodynamic indexes, including heart rate, MAP, CVP, stroke volume (SV), stroke volume variation (SVV) and cardiac output will be measured at the five time points: T1 (5 min after induction), T2 (5 min after COBased on the summary statistics for the troponin T (TnT) values , 32, we Patients will be recruited in two hospitals: Huadong Hospital Affiliated to Fudan University and Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patients who meet the eligibility criteria will be randomly assigned to the two treatment groups: SP or LP. The randomization plans will be implemented using statistical software R, and will be stored in an online database. After a clinical evaluation, the surgeon will register the patient using a unique ID assigned to the patient and used to select a random assignment from the database. The physicians will be aware of the group to which the patients are allocated while the patients will not.The data will be collected according to the primary and secondary endpoints at the time points, and using the methods, described above. All the data will be deposited safely in the in-built server in Huadong Hospital with full confidentiality. Participants in this study will be referred to by a code which differs from their true name. Procedures for data management will be approved by the trial manager and other clinicians before the first participant is enrolled.t test or a Fisher’s exact test will be performed as appropriate. The homogeneity of the data collected from the two hospitals will be assessed using the Mantel-Haenszel test. The impact will further be investigated by varying the TnT cutoff, and by examining the effects of CAD and its interaction effect with the main treatment (SP/LP); some other covariates will be justified using a logistic regression model. The distributions of the TnT levels measured at different times will be estimated and the distributional differences will be evaluated between the patients treated with LP and SP, respectively. In addition, the association between the TnT levels measured at T0, T1, T2, T3 and T4 (the peak TnT levels measured at 24 h after surgery) will be assessed. Receiving Operating Characteristic (ROC) curves will be used to assess the value of using the high-sensitivity TnT assays for early detection of elevated TnT levels among patients treated with LP and SP, respectively. The impact of LPP and SPP on pulmonary mechanics and oxidative stress at difference time points will be evaluated using regression analysis, with the effects of CAD and other covariates justified. A statistical analysis plan will be drafted and approved before unlocking the dataset.The impact of prolonged LPP and SPP on myocardial injury after robot-assisted urological surgery will be evaluated by comparing the changes in the patients with TnT levels of 0.01 or lower. A 2 pneumoperitoneum are complicated, may consist of an intra-abdominal mechanical compressive effect, neurohumoral responses and changes induced by the systemic absorption of CO2 [Prolonged robot-assisted urological surgery in the Trendelenburg position may include several risk factors that can affect cardiopulmonary physiological status. Our study is designed to investigate the effects of different IAPs on myocardial injury. Physiological changes caused by COn of CO2 . AlthougTo our knowledge, the adverse effects caused by utilizing pneumoperitoneum include mechanical compression effects: systemic vascular resistance (SVR), mean arterial pressure (MAP), cerebral blood flow (CBF) and intracranial pressure (ICP) will be increased , 36. On 2 absorption. Hypercapnia may cause a decrease in myocardial contractility. Vasopressin, renin, aldosterone and catecholamine levels also increase sharply after CO2 pneumoperitoneum is established [Additionally, significant hypercapnia and acidosis may occur due to COablished , with thThe Trendelenburg position required by the prolonged robot-assisted urological surgery may cause increased venous return and decreased lung compliance, thus affecting cardiopulmonary function , 28, 29.Other rare complications of pneumoperitoneum include pneumothorax, inadvertent gas embolism, vascular injury and inadvertent extraperitoneal insufflation.2 and airway pressure are commonly assessed to assure adequacy of ventilation and blood gas analysis will be conducted when necessary. Other rare complications will be appropriately treated as soon as they are detected.As described above, the pneumoperitoneal physiology in the Trendelenburg position is intricate. We aim to protect the patients from injury by careful preoperative examination, so that undiagnosed conditions can be identified and pretreated. Standard intraoperative monitoring will be used for all patients, and invasive hemodynamic monitoring (Vigileo with the FloTrac system) will be used to monitor the cardiovascular response to pneumoperitoneum and position changes. ETCOData attrition of the clinical trial would affect the validity of our results markedly. In this study, approaches will be adopted to minimize any impact this may bring. The designed follow-up period of this study is only 24 h post surgery, so it is unlikely that the patients who meet the inclusion criteria would drop out, which is confirmed by the ongoing preliminary trial. Besides, we have the capability for a rapid response to any perioperative emergency events. If attrition does occur, we will carefully discuss the reasons and estimate the impact on the trial. If it is not a source of bias we will employ the complete-case method, where the missing data will be excluded from the analysis. As we have a population large enough to complete the trial in the designated period, this is believed to be the simplest and most efficient method for our study.The main limitation of this trial is the inevitable bias in age and sex distribution of the enrolled patients. Although the age range in the inclusion criteria is set at 18–80 years, most patients requiring urological surgery, especially resection, are middle-aged and elderly men. Thus the conclusion drawn by this study might be not applicable to female patients and cases in different age groups.As the trial designed in this study is bicenter, the bias caused by the differences in execution between centers and patient preference of hospital selection might be a challenge. Both the hospitals participating in this trial are tertiary referral centers in Shanghai, but located over 20 km apart and there is an existing long-term collaboration between the two hospitals, which is the basis of this study. From the past years’ patient baseline data, there is no significant competitive recruitment or imbalance between the two hospitals. Thus it could be supposed that the potential bias of those enrolled would not markedly affect the outcome of this study. However, to eliminate any bias caused by variability in anesthesiologists’ abilities, regular meetings and training for clinicians participating in this clinical trial will be ongoing and continued into the future.Inclusion of eligible candidates in the study has not yet started; enrollment is expected to start in January 2016.


Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury.We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions.AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations , ≥3 other nephrotoxic drugs , infection , and cystic fibrosis . Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%.After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation.The online version of this article (doi:10.1007/s00228-017-2204-8) contains supplementary material, which is available to authorized users. ISHLT.org). Many of these lung transplantation patients develop acute kidney injury (AKI) [Each year, approximately 4000 lung transplantations are performed worldwide (ry (AKI) –3. Prevery (AKI) . AKI in ry (AKI) . One sucry (AKI) –11.Tacrolimus nephrotoxicity in the early phase after transplantation is associated with several pharmacokinetic factors, which influence tacrolimus blood concentrations profoundly. For instance, the bioavailability of tacrolimus is highly variable due to gut dysmotility, changes in metabolism, and altered clearance due to liver injury . FurtherWe hypothesized that tacrolimus nephrotoxicity might have a crucial role in the development of AKI after lung transplantation. Therefore, the purpose of this retrospective study was to investigate the development and recovery of kidney injury after lung transplantation and relate AKI to whole-blood tacrolimus trough concentrations.All lung transplantation patients hospitalized at the University Medical Center Utrecht (UMCU) from July 2001 to February 2011 were retrospectively studied. Tacrolimus whole-blood trough concentrations were analyzed during the first year post transplantation. The immunosuppressive regimen consisted further of basiliximab, corticosteroids, and mycophenolate mofetil. Cofactors influencing tacrolimus blood concentrations and renal function were recorded as well. AKI was defined by the “Kidney Disease: Improving Global Outcomes” (KDIGO) Clinical Practice Guideline criteria and CKD by the “CKD Epidemiology Collaboration equation” (CKD-EPI). Both were solely based on measurement of creatinine. For more detailed information on the variables, covariates, and the used statistical analyses, see the supplemental text “χ2 88.09, 2 df, p < 0.001). Table A total of 186 patients were included. Twenty-nine patients died in the first year, 11 of whom within 14 days. Patients died of bleeding (9), heart failure (1), primary graft failure (1), acute rejection (1), infection (5), hemorrhagic cerebrovascular accident (3), chronic respiratory failure (4), carcinoma (1), or an unknown cause (4). Two peaks in the age distribution were observed . The most serious AKI (“AKI stage 3”) was especially frequent within the first 2 weeks after transplantation and occurred most often on days 6 and 7  . Within the first 14 days after transplantation, 85 patients (46%) developed AKI  Fig. S. Forty-tAs can be seen in Fig. Patients often received at least one drug that could increase tacrolimus concentrations  and 36% on day 5 (63 out of 173) and within 2 weeks 97%) , “infection” , “CF”  and " ≥3 nephrotoxic drugs other than tacrolimus"  were all significantly associated with AKI in GEE analyses when day 2 to day 6 were concerned (Table p < 0.001). Significant differences in cumulative incidence of the combined outcome “death and severe CKD” were also observed between the three categories of patients (p = 0.002). The cumulative incidence of death significantly differed between groups 1 and 2 on the one hand and group 3 on the other (p < 0.001). The cumulative incidence of the combined outcome death and severe CKD also differed between groups 1 and 2 on the one hand and group 3 on the other (p = 0.001). The mortality rate and severe CKD incidence rate did not differ significantly between CF and non-CF patients .AKI was recovered in 19% of patients (16 out of 85) at 1 month Fig. S. At 1 yeWe draw three main conclusions from the data with respect to AKI after lung transplantation: (1) it frequently occurs in the first 14 days, (2) it shows low recovery rates and often evolves to severe chronic kidney disease, and (3) it is related to increased whole-blood tacrolimus trough concentrations.We found high incidence rates of AKI similar to other studies on renal function in lung-transplanted patients treated with tacrolimus , 17. TheApart from the high incidence rates of AKI, we observed a low rate of convalescence from AKI. Such low improvement rates of AKI have been reported previously. Wehbe et al. reported that recovery to the pretransplant renal function occurred in 34% of lung transplant patients with AKI . This isA high whole-blood tacrolimus trough level was a risk factor for the development of AKI. Tacrolimus was above the therapeutic range in more than half of the patients in the first 6 days, which emphasizes the challenges of tacrolimus dosing in the early phase after transplantation. In particular, patients with SIRS or septic shock (the majority of patients) may have organ failure, which changes the pharmacokinetics. This, in turn, may lead to these supra-therapeutic whole-blood tacrolimus levels. Also, after recovery from clinical instability, tacrolimus dosage remains challenging. After 6 months, almost one out of ten patients still exhibited supra-therapeutic whole-blood tacrolimus trough levels.Interestingly, the median whole-blood tacrolimus trough concentrations were not that far above the therapeutic range in the first week after transplantation. This may indicate that the whole-blood tacrolimus trough concentrations were not the only contributing factor to tacrolimus toxicity. We hypothesize that the unbound tacrolimus plasma concentrations are potentially more responsible for the nephrotoxicity than the whole-blood tacrolimus concentrations. Only the unbound plasma concentration of a drug is biologically active and potentially toxic. Tacrolimus is highly bound to erythrocytes, albumin, α1-acid glycoprotein (AGP), and high-density lipoprotein (HDL) in stable clinical conditions, though the capacity of tacrolimus to bind may widely fluctuate in times of systemic inflammation and shock . ErythroThere are some limitations to this study due to the retrospective design. Several explanatory variables influencing the pharmacokinetics of tacrolimus could not be investigated because of the number of missing values. For instance, the effect of variations in variables like acidosis, changes in fluid balance, gut motility, or variations in concentrations and activity of CYP 3A4/5 and P-glycoprotein could not be examined. They all may have an effect on whole-blood tacrolimus concentrations and should be considered as residual confounders.The whole-blood tacrolimus trough concentrations were measured at approximately 12 h after administration. Tacrolimus elimination half-life time and time to trough level may substantially variate in solid organ recipients . TherefoCystic fibrosis patients showed unexpectedly higher whole-blood tacrolimus concentrations. Cystic fibrosis patients generally have a decreased bioavailability and higher phase II metabolism resulting in a lower area under the concentration-time curve , 32. WheDifferent definitions of renal function complicate the comparison of the results with other studies , 33, 34.Investigations like ultrasound, biopsy, and urine analyses are not performed at a regular basis in clinically unstable lung transplant patients. Therefore, other causes of kidney injury are not excluded in this cohort and may have had an effect on kidney function. All AKI was attributed to tacrolimus, and this might lead to an overestimation of the nephrotoxicity caused by tacrolimus. Important alternatives are the predisposing factors for AKI, which are shown in Table AKI is common after lung transplantation and is associated with both morbidity and mortality. We related supra-therapeutic whole-blood tacrolimus concentrations, next to three or more other nephrotoxic drugs, CF, and infection to AKI in the first week after transplantation. There was a high occurrence of hemodynamic instability perioperatively. Whereas hemodynamic instability is a known cause of AKI, recovery to pretransplant renal function is expected. We observed an ongoing deterioration of renal function even when patients were considered stable. We related supra-therapeutic whole-blood tacrolimus concentrations early after transplantation to the emergence of AKI. This study underlines the significance of unraveling tacrolimus pharmacokinetics early after transplantation in order to decrease AKI in this vulnerable group of patients.All authors made substantial intellectual contributions to conception and design , acquisition of data and data analysis , and writing or interpretation of the data . All authors contributed to drafting the article or revising it critically for important intellectual content and gave final approval of the version to be published and approved of the order in which their names will be listed in the manuscript. M.A.S. and C.C.H. had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.ESM 1(DOCX 267 kb)


Vascular dysfunction is highly prevalent if not ubiquitous in patients with hypertension. We compared two different measures of vascular function obtained from digital volume waveforms with measures of ventricular-vascular load derived from 24-hour blood pressure (BP) recordings in patients with hypertension.Digital pulsatile volume waveforms were captured via plethysmography  and used to derive augmentation index (a measure of ventricular-vascular coupling) and the pulse wave amplitude-reactive hyperemia index (a measure of microvascular reactivity). Ambulatory arterial stiffness index (AASI) and the BP variability ratio (BPVR) were derived from 24-hour ambulatory BP recordings.There was a positive association between PAT-AIx and AASI . There was also a positive association between PAT-AIx and BPVR . PAT-AIx was not associated with PWA-RHI . PWA-RHI was not associated with AASI or BPVR (P > 0.05).PAT-AIx is associated with ambulatory measures of vascular function and may offer clinical insight into vascular burden and cardiovascular disease risk in patients with hypertension independent of information obtained from PWA-RHI. The digital volume waveform provides clinically useful information on peripheral vascular function and cardiovascular disease (CVD) risk. Peripheral arterial tone (PAT) makes use of pneumatic finger cuffs to assess volume change of the whole of the digit enclosed within the device , non-invasively generating a pulse volume waveform. Change in the amplitude of this volume waveform following a regional ischemic stimulus  is a measure of resistance vessel reactivity that is associated with peripheral and coronary vascular function and is also a predictor of CV risk and future CV events -3.A second measure easily obtained from the digital volume waveform using PAT is the augmentation index (AIx). As a measure of systemic vascular function and vascular-ventricular coupling, the AIx is a useful therapeutic target and secondary endpoint associated with numerous cardiovascular morbidities and mortality -6. AlthoThe ambulatory arterial stiffness index (AASI) is an integrated measure of systemic vascular function derived from 24-hour blood pressure recordings. This measure has been proposed to reflect dynamic arterial stiffening, left ventricular function/cardiac contractility, vascular resistance, wave reflection and overall vascular-ventricular coupling -13. AlthTwenty four individuals with a history of hypertension (defined as SBP > 140 mmHg or DBP > 90 mmHg or being on an antihypertensive medication) recruited from the Tufts Medical Center preventive cardiology clinic, participated in this study. Exclusion criteria included ongoing myocardial ischemia, moderate to severe heart failure , severe valvular disease, peripheral arterial disease , LDL-cholesterol > 100 mg/dL, unstable cardiac symptoms, renal insufficiency (serum creatinine > 2 mg/dL), active liver disease, chronic obstructive pulmonary disease, bronchial asthma, uncontrolled hypertension defined as baseline BP > 190/100 mmHg, Raynaud’s disease and/or finger deformities. This study was approved by the Institutional Review Board at Tufts Medical Center. Written informed consent was obtained from all the study participants prior to obtaining vascular measures.The presence or absence of the following cardiovascular risk factors was assessed in each subject: gender, hyperlipidemia , coronary artery disease , family history of CAD (having first or second degree relatives with CAD), and smoking status (having smoked at least five times per day within the last month).2 – P1/P1 * 100).Beat-by-beat pulse wave amplitude was captured in all patients using finger arterial tonometry  as previously described in detail . With paThe pulse wave amplitude-reactive hyperemia index (PWA-RHI) was calculated as the ratio of the average PWA over a 1-minute epoch starting after 5-minute of ischemia induced by brachial cuff inflation to a supra-systolic BP, divided by the average PWA of a 3.5 minutes baseline epoch. The PWA obtained from the finger of the non-occluded arm was also measured continuously and served as a control signal. Final values were normalized to the contra-lateral hand to account for any drift in the magnitude of the signal due to systemic factors. This was done automatically using customized computer software.Ambulatory BP was monitored in 24 patients with a commercially available device  once every 20-minute during the day (between 6 am and 10 pm) and once every 60-minute during the night (between 10 pm and 6 am). Ambulatory arterial stiffness index (AASI) was computed as the slope of the regression line (not forced through the origin) of systolic versus diastolic BP , 25. AASNormality of distribution was assessed using Kolmogorov-Smirnof and Shapiro-Wilk tests. Group comparisons were made using analysis of variance with Tukey post hoc testing where appropriate. Chi-square tests were used to compare categorical variables. If significant group differences in potential confounders existed, analysis of covariance was used to statistically remove the influence of these parameters of outcome variables of interest. Pearson’s correlation coefficients were used to assess relationships between variables of interest. All data are reported as means ± SEM. A priori significance was set at P < 0.05.Patient descriptive characteristics are presented in As seen in PAT-AIx was associated with AASI in patients with hypertension. PAT-AIx was also associated with BPVR and was higher in those patients devoid of nocturnal reduction in BP (i.e. non-dippers) versus those with nocturnal reduction in BP (i.e. dippers). PWA-RHI was not associated with AASI, BPVR and did not differ between dippers and nondippers. Thus PAT-AIx may offer clinical insight into vascular burden and cardiovascular disease risk in patients with hypertension independent of information obtained from PWA-RHI.The seminal work of Takazawa and colleagues previously used photoplethysmography (PTG) to capture the digital volume waveform , 29. PTGThe ambulatory arterial stiffness index (AASI) is an integrated measure of systemic vascular function derived from 24-hour blood pressure recordings that is associated with target organ damage -18 and iWith sleep, there is a well-noted reduction in blood pressure. Numerous studies note that non-dipping status  is associated increased arterial stiffness , 36, tarPWA-RHI has gained acceptance as a non-invasive measure of microvascular endothelial function. PWA-RHI is associated with conduit and coronary endothelial function , 42, car